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WO2025215360A1 - Procédé - Google Patents

Procédé

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Publication number
WO2025215360A1
WO2025215360A1 PCT/GB2025/050755 GB2025050755W WO2025215360A1 WO 2025215360 A1 WO2025215360 A1 WO 2025215360A1 GB 2025050755 W GB2025050755 W GB 2025050755W WO 2025215360 A1 WO2025215360 A1 WO 2025215360A1
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WIPO (PCT)
Prior art keywords
car
cells
patient
seq
cell
Prior art date
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Pending
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PCT/GB2025/050755
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English (en)
Inventor
Wolfram Brugger
Yiyun Zhang
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Autolus Ltd
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Autolus Ltd
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Priority claimed from GBGB2408341.2A external-priority patent/GB202408341D0/en
Application filed by Autolus Ltd filed Critical Autolus Ltd
Publication of WO2025215360A1 publication Critical patent/WO2025215360A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/11—T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/30—Cellular immunotherapy characterised by the recombinant expression of specific molecules in the cells of the immune system
    • A61K40/31—Chimeric antigen receptors [CAR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A61K40/4202—Receptors, cell surface antigens or cell surface determinants
    • A61K40/421—Immunoglobulin superfamily
    • A61K40/4211—CD19 or B4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6867—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from a cell of a blood cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the cancer treated
    • A61K2239/48—Blood cells, e.g. leukemia or lymphoma
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • the present invention relates to methods for selecting a bridging therapy for a patient having a B-cell malignancy who is about to receive treatment with CAR-T cells.
  • CAR T cell chimeric antigen receptor T cell
  • Tisagenlecleucel (Tisa-cel, Kymriah®) was the first CD 19 CAR T therapy to be approved for use in children and young adults with relapsed/refractory (r/r) ALL by the U.S. Food and Drug Administration (FDA) in 2017, with approvals in adult r/r diffuse large B-cell lymphoma (DLBCL) and in adult r/r follicular lymphoma (FL) later on.
  • Axicabtagene ciloleucel (axi-cel; Yescarta®) was approved for adult patients with r/r DLBCL, adult patients with r/r large B-cell lymphoma (LBCL), and adult r/r follicular lymphoma (FL).
  • Lisocabtagene maraleucel (liso-cel; Breyanzi®) was approved for adult patients with r/r DLBCL and r/r LBCL after one prior therapy.
  • Brexucabtagene autoleucel (brexu-cel, Tecartus®) were approved for use in r/r MCL in and r/r B-ALL.
  • Bridging therapy serves two purposes: to control disease while waiting for CAR T cell infusion and to reduce the risk of CAR T cell-associated toxicities by debulking the disease.
  • Bridging therapy may be indicated in patients during the period between T cell apheresis and initiation of lymphodepleting chemotherapy because of the proliferative nature of relapsed and refractory B-cell malignancies. However, this is not necessarily the case for isolated extramedullary leukaemias when local control may be sufficient. There is no consensus on the optimal bridging therapy regimen, and no randomized data comparing regimens exists.
  • B-ALL B-cell acute lymphoblastic leukaemia
  • bridging was diverse, including combinations of rituximab, gemcitabine, etoposide, steroids, cisplatin, cytarabine, ibrutinib, and lenalidomide.
  • the median time to manufacture in this trial was 23 (range not available) days. Though the exact numbers were not included, it was reported that the majority of the 50 patients who enrolled in the study but discontinued participation before receiving CAR T did so due to progressive disease or death.
  • a subgroup analysis of seven patients from the JULIET trial who were excluded from the original efficacy data who had a complete response to bridging therapy and subsequently received CAR T infusion has also been published (Bishop et al., 2019, Blood Adv 3:2230-6).
  • bridging therapy ranged from 2 days to 129 days, and a variety of regimens were used. Of these patients, five remained progression-free for more than 12 months, and this group of patients was found to have low rates of cytokine release syndrome (CRS) and neurotoxicity.
  • CRS cytokine release syndrome
  • the TRANSCEND (NCT02631044) study evaluated the use of liso-cel in patients with DLBCL and bridging therapy was allowed. Of the 344 patients enrolled, 159 (59%) received bridging therapy which included combinations of rituximab, gemcitabine, oxaliplatin, steroids, bendamustine, lenalidomide, brentuximab vedotin, and ibrutinib.
  • the ZUMA-2 trial (NCT02601313) evaluating brexu-cel in MCL included 74 patients of which 25 (35%) received bridging therapy. Bridging for these patients included steroids, ibrutinib, acalabrutinib, or a combination. Of the 25 patients who received bridging, 17 had imaging assessments before and after, and the majority of those patients were found to have an increase in tumour burden. Three patients died of progressive disease before receiving CAR T treatment. The median time to manufacture was reported as 16 (11-28) days (Wang et al . , 2020, N Engl J Med 382: 1331 -42) .
  • bridging therapy was used in 158 (53%) of patients and consistent of combinations of steroids, chemotherapy, radiation, or targeted therapies such as lenalidomide or ibrutinib.
  • a multivariate analysis from this study demonstrated worse overall survival at 12 months in patients who received bridging therapy (56% vs. 81% in patients who did not receive bridging therapy, p ⁇ 0.001).
  • Another single-institution retrospective study evaluated 64 patients with non-Hodgkin lymphoma, 49 of whom received commercial CAR T (Dwivedy Nasta, 2019, Blood 134(Suppl l):4108). Thirty-four (69%) of these 49 patients received bridging therapy to reduce tumour burden or palliate symptoms. Bridging therapies included combination chemoimmunotherapy, radiation alone, systemic therapy with radiation therapy, targeted treatments, or combination treatment. Of the patients who received chemoimmunotherapy, three of 12 had progressive disease at the time of CAR T infusion and of five patients who received radiation alone, one had progressive disease at the time of CAR T infusion.
  • bridging therapy is associated with higher rates of toxicity and poorer overall survival. This is likely reflective of the fact that bridging therapy is often used in patients with more aggressive disease, a higher burden of disease at baseline, or disease that is refractory to chemotherapy.
  • the present inventors have designed a bridging therapy protocol using an anti-CD22 antibody-drug conjugate which worked well in patients with B cell malignancies. Surprisingly, this bridging therapy was extremely effective in patients with high disease burden.
  • the present invention provides a method for selecting a bridging therapy for a patient having a B-cell malignancy who is about to receive treatment with CAR-T cells, which comprises the following steps:
  • the patient may undergo leukapheresis to prepare the population of CAR T cells specific for a B-cell malignancy.
  • the patient may have previously received chemotherapy but the BM blast percentage is still > 5%.
  • the BM blast percentage at screening may be more than or equal to 20%.
  • the BM blast percentage at screening may be more than or equal to 50%.
  • the BM blast percentage at screening may be more than or equal to 75%.
  • the anti-CD22 antibody-drug conjugate may be administered at least 1 week before the administration of the lymphodepleting therapy.
  • the patient may receive a lymphodepleting pre-conditioning treatment before CD 19 CAR- T cell infusion.
  • the population of CAR T cells specific for a B-cell malignancy may be autologous.
  • the anti-CD22 antibody-drug conjugate may be administered after leukapheresis.
  • the anti-CD22 antibody-drug conjugate may be selected from Inotuzumab ozogamicin (Besponsa), inotuzumab, and epratuzumab.
  • the anti-CD22 antibody-drug conjugate may be Inotuzumab ozogamicin.
  • the B-cell malignancy may be selected from the group consisting of acute lymphoblastic leukemia (ALL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Burkitt lymphoma, lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia or WM), cutaneous B-cell lymphoma (CBCL), diffuse large B-cell lymphoma (DLBCL), and anaplastic large cell lymphoma (ALCL).
  • ALL acute lymphoblastic leukemia
  • FL follicular lymphoma
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • MCL mantle cell lymphoma
  • MZL marginal zone lymphoma
  • Burkitt lymphoma lymphoplasmacytic lymphoma
  • the CAR T cells may be specific to CD 19 or CD20.
  • the CAR-T cells may be specific to CD 19.
  • the anti-CD19 CAR may comprise: a) a heavy chain variable region (VH) having complementarity determining regions (CDRs) with the following sequences:
  • CDR3 - SLLYGDYLDY (SEQ ID No. 3); and b) a light chain variable region (VL) having CDRs with the following sequences: CDR1 - SASSSVSYMH (SEQ ID No. 4);
  • the present invention provides a method for improving the outcome of treatment with CAR-T cells for a patient having a B-cell malignancy, wherein the patient presents > 5% blasts in the BM at screening, which method comprises the step of administering an anti-CD22 antibody-drug conjugate to the patient after leukapheresis but prior to pre-conditioning the patient for CAR-T cell treatment.
  • the patient may present > 20% blasts in the BM at screening.
  • the patient may present > 50% blasts in the BM at screening.
  • the patient may present > 75% blasts in the BM at screening.
  • the present invention provides a method for treating a B-cell malignancy in a subject which comprises the step of using anti-CD22 antibody-drug conjugate as bridging therapy prior to treatment with anti-CD19 CAR-T cells, wherein the CAR comprises: a) a heavy chain variable region (VH) having complementarity determining regions (CDRs) with the following sequences:
  • VH heavy chain variable region
  • CDRs complementarity determining regions
  • CDR3 - SLLYGDYLDY (SEQ ID No. 3); and b) a light chain variable region (VL) having CDRs with the following sequences: CDR1 - SASSSVSYMH (SEQ ID No. 4);
  • the method for treating a B-cell malignancy may comprise the following steps: i) administering the anti-CD22 antibody-drug conjugate to the patient after leukapheresis; ii) pre-conditioning the patient; and iii) administering anti CD- 19 CAR-T cells to the patient.
  • the method for treating a B-cell malignancy may comprise the following steps: i) leukapheresis of the patient to obtain a T cell composition for preparation of the anti-CD19 CAR-T cells; ii) administering the anti-CD22 antibody-drug conjugate to the patient; iii) pre-conditioning the patient; and iv) administering the anti CD-19 CAR-T cells to the patient.
  • FIG. 1 CD19 CATCAR (AUTO1).
  • This CAR is a type I transmembrane protein.
  • the scFv (anti-CD19 CAT19) at the aminoterminus is linked to a CD8 stalk and transmembrane domain which is linked to an endodomain comprised of a fusion between 4-1BB and CD3( ⁇ .
  • FIG. 1 Proliferation of T Cells Transduced with CD19 (CAT) CAR and CD19 (FMC63) CAR.
  • CAR chimeric antigen receptor
  • CD19 cluster of differentiation 19
  • CPM counts per minute
  • NT Non-transduced
  • SEM standard error of the mean.
  • Data: mean SEM, n 4; * p ⁇ 0.05, ** p ⁇ 0.01, 2-tailed paired Student t-test
  • FIG. 4 Antigen-specific Killing of CD19-positive Tumour Cells by CD19 CAR T Cells.
  • CAR chimeric antigen receptor
  • CD19 cluster of differentiation 19
  • E effector cells
  • NT non-transduced
  • SEM standard error of the mean
  • SupTl Human T cell lymphoblastic lymphoma cell line
  • T target cells.
  • FIG. 6 Residual NALM-6 Tumour Cells in the Bone Marrow of Mice 2 Weeks Post CAR T Cell Infusion.
  • CAR chimeric antigen receptor
  • CD19 cluster of differentiation
  • NT non-transduced.
  • FIG. 7 Overview of the different stages of the clinical study.
  • CRS cytokine release syndrome
  • Cy cyclophosphamide
  • Flu fludarabine
  • ICANS immune effector cell associated neurotoxicity syndrome
  • Figure 8. Eligibility, Endpoints, and Disposition of the clinical study. Eighty-four percent of enrolled patients were infused with AUTO1.
  • R/R B-ALL Primary refractory; First relapse if first remission ⁇ 12 months; R/R disease after >2 lines of systemic therapy; R/R disease after allogeneic transplant; R/R Philadelphia chromosome-positive ALL if intolerant to/failed two lines of any TKI or one line of second-generation TKI, or if TKI therapy is contraindicated.
  • BM bone marrow
  • CR complete response
  • CRi complete response with incomplete recovery of counts
  • DoR duration of response
  • EFS event free survival
  • MRD minimal residual disease
  • OS overall survival.
  • Figure 10 Disease Response per IRRC Assessment. Seventy-six percent of infused patients achieved CR/CRi. Ninety-seven percent of responders with evaluable samples were MRD negative at 10-4 level by flow cytometry *One-sided p-value from the exact test on HO: ORR ⁇ 40% vs Hl : ORR >40%. CR, complete remission, CRi, CR with incomplete blood count recovery; IRRC, independent response review committee; MRD, minimal residual disease; ORR, overall remission rate.
  • Figure 11 Duration of Remission. Sixty-one percent of responders in ongoing remission without subsequent anti-cancer therapies. Thirteen percent of responders who proceeded to SCT while in remission were censored at the time of SCT. NE, not estimable.
  • FIG. 13 AUTO1 Expansion and Persistence.
  • CD 19 CAR-Positive T Cell Expansion and Persistence in the Peripheral Blood of Adult B ALL Patients Measured by qPCR. CAR-T cellular kinetics are consistent with the ALLCAR19 study (Roddie C et al., 2021. J Clin Oncol 39:3352-63).
  • AUC area under the curve; CV, coefficient of variation; Geo, geometric; PCR, polymerase chain reaction; SE, standard error.
  • Figure 14 Annotated amino acid sequence (SEQ ID NO: 10) of the CD19 CATCAR (AUTO 1).
  • R/R B-ALL primary refractory; first relapse if first remission ⁇ 12 months; R/R disease after >2 lines of systemic therapy; R/R disease after allogeneic transplant; R/R Philadelphia chromosome-positive ALL if intolerant to/failed two lines of any TKI or one line of second-generation TKI, or if TKI therapy is contraindicated.
  • ⁇ EFS the time from date of first infusion to the earliest of treatment failure, relapse, or death from any cause.
  • ALL acute lymphoblastic leukemia
  • B-ALL B- cell acute lymphoblastic leukemia
  • BM bone marrow
  • CAR-T chimeric antigen receptor T-cell
  • CR complete remission
  • CRi CR with incomplete hematologic recovery
  • DoR duration of remission
  • EFS event-free survival
  • EMD extramedullary disease
  • IRRC Independent Response Review Committee
  • MRD measurable residual disease
  • ORR overall remission rate
  • OS overall survival
  • R/R relapsed/refractory
  • TKI tyrosine kinase inhibitor
  • FIG. 18 Phase Ib/II study - All cohorts: Remission rate and MRD by status at lymphodepletion. *Morphologic disease defined as >5% BM blasts or presence of EMD regardless of BM blast status. ⁇ MRD status available for 64/73 patients, as assessed by NGS or flow cytometry. ⁇ MRD status available for 27/29 patients, as assessed by NGS or flow cytometry. BM, bone marrow; CR, complete remission; CRi, CR with incomplete hematologic recovery; EMD, extramedullary disease; MRD, measurable residual disease; NGS, next-generation sequencing.
  • the red dashed line denotes the Phase IIA null hypothesis (40%).
  • BM bone marrow
  • CR complete remission
  • CRi CR with incomplete hematologic recovery
  • EMD extramedullary disease
  • IRRC Independent Response Review Committee
  • ORR overall remission rate
  • SCT stem cell transplant.
  • FIG. 20 Phase Ib/II study - All cohorts: Event-free survival (EFS) in all treated patients. Censoring new non-protocol anti-cancer therapies including SCT with disease assessment by IRRC (data cut-off date: September 13, 2023). Median EFS: ITT population - 9.8 months (95% CI: 5.9, 12.9). CI, confidence interval; EFS, event-free survival; IRRC, Independent Response Review Committee; ITT, intent-to-treat; NE, not evaluable; SCT, stem cell transplant.
  • EFS Event-free survival
  • FIG. 23 Phase Ib/II study - All cohorts: Event-free survival (EFS) by leukemic burden prior to lymphodepletion. Censoring new non-protocol anti-cancer therapies including SCT with disease assessment by IRRC (data cut-off date: September 13, 2023). BM, bone marrow; CI, confidence interval; EFS, event-free survival; IRRC, Independent Response Review Committee; NE, not evaluable; SCT, stem cell transplant.
  • EFS Event-free survival
  • IRRC Independent Response Review Committee
  • NE not evaluable
  • SCT stem cell transplant.
  • Figure 25 Kaplan-Meier plot of EFS in patients who received bridging therapy with inotuzumab ozogamicin (INO) vs those who received bridging therapy without INO vs those who received no bridging therapy.
  • INO inotuzumab ozogamicin
  • Figure 26 Leukemic burden in patients receiving inotuzumab as bridging therapy.
  • BM bone marrow.
  • Figure 27 Median BM blast percentage at screening and lymphodepletion per type of BT.
  • Figure 28 Response outcomes by bridging therapy (BT) group.
  • a and B Kaplan-Meier analysis of outcomes by type of BT; A) event-free survival and B) overall survival.
  • BT bridging therapy
  • CI confidence interval
  • CR complete remission
  • CRi complete remission with incomplete haematological recovery
  • DoR duration of remission
  • INO inotuzumab ozogamicin
  • NE not estimable
  • ORR overall remission rate
  • FIG. 29 CAR T-cell persistence by bridging therapy (BT) group. *Time to loss of CAR T-cell persistence was defined as the days between the first AUTO1 infusion and the first time at which the AUTO1 transgene level, as measured by ddPCR in peripheral blood, dropped to zero from the last positive value.
  • BT bridging therapy
  • CAR chimeric antigen receptor
  • ddPCR droplet digital polymerase chain reaction
  • INO inotuzumab ozogamicin.
  • a classical chimeric antigen receptor is a chimeric type I trans-membrane protein which connects an extracellular antigen-binding domain to an intracellular signaling domain (endodomain).
  • the antigen-binding domain is typically a single-chain variable fragment (scFv) derived from a monoclonal antibody (mAb), but it can be based on other formats which comprise an antibody fragment or an antibody-like antigen-binding site.
  • a natural ligand of the target antigen a peptide with sufficient affinity for the target, a F(ab) fragment, a F(ab’)2 fragment, a F(ab’) fragment, a single domain antibody (sdAb), a domain antibody (dAb), a VHH antigen-binding domain or nanobody, an artificial single binder such as a DARPin (designed ankyrin repeat protein), an affibody, a fibronectin artificial antibody scaffold, an anticalin, an affilin, a VNAR, an iBody, an affimer, a fynomer, an abdurin/ nanoantibody, a centyrin, an alphabody, a nanofitin, or a single-chain derived from a T-cell receptor which is capable of binding the target antigen.
  • DARPin designed ankyrin repeat protein
  • a spacer is usually necessary to isolate the antigen-binding domain from the membrane and to allow it a suitable orientation.
  • a common spacer used is the Fc of IgGl. More compact spacers can suffice, e.g., the stalk from CD8a and even just the IgGl hinge alone, depending on the antigen.
  • a transmembrane domain anchors the protein in the cell membrane and connects the spacer to the endodomain.
  • an activating signal is transmitted to the T-cell on which the CAR is expressed thereby directing the specificity and cytotoxicity of the T cell towards cells expressing the target antigen.
  • CAR-encoding nucleic acids may be transferred to T cells using, for example, retroviral or lentiviral vectors to generate antigen-specific T cells for adoptive cell transfer.
  • the CAR binds the target-antigen, this results in the transmission of an activating signal to the T-cell it is expressed on.
  • the CAR directs the specificity and cytotoxicity of the T cell towards cells expressing the targeted antigen.
  • the antigen binding domain is the portion of CAR which recognizes antigen.
  • Numerous antigen-binding domains are known in the art, including those based on the antigen binding site of an antibody, antibody mimetics, and T-cell receptors.
  • the antigenbinding domain may comprise: a single-chain variable fragment (scFv) derived from a monoclonal antibody; a natural ligand of the target antigen; a peptide with sufficient affinity for the target; a single domain antibody; an artificial single binder such as a Darpin (designed ankyrin repeat protein); or a single-chain derived from a T-cell receptor.
  • the antigen-binding domain comprises: a single-chain variable fragment (scFv) derived from a monoclonal antibody ( Figure 2a).
  • a ‘target antigen’ is an entity which is specifically recognized and bound by the antigenbinding domains of a chimeric receptor provided herein.
  • the target antigen may be an antigen present on a malignant B cell, for example CD 19.
  • the human CD 19 antigen is a 95 kd transmembrane glycoprotein belonging to the immunoglobulin superfamily.
  • CD 19 is classified as a type I transmembrane protein, with a single transmembrane domain, a cytoplasmic C-terminus, and extracellular N-terminus.
  • CD 19 is expressed very early in B-cell differentiation and is only lost at terminal B-cell differentiation into plasma cells.
  • CD 19 is a biomarker for normal B cells as well as follicular dendritic cells.
  • CD 19 primarily acts as a B cell co-receptor in conjunction with CD21 and CD81. Upon activation, the cytoplasmic tail of CD 19 becomes phosphorylated, which leads to binding by Src-family kinases and recruitment of PI-3 kinase.
  • CD 19 is also expressed on all B-cells but not plasma cells. It is not expressed on other haematopoietic populations or non-haematopoietic cells and therefore targeting this antigen should not lead to toxicity to the bone marrow or non-haematopoietic organs. Loss of the normal B-cell compartment is considered an acceptable toxicity when treating lymphoid malignancies, because although effective CD 19 CAR T cell therapy will result in B cell aplasia, the consequent hypogammaglobulinaemia can be treated with pooled immunoglobulin.
  • the antigen-binding domain of a CAR which binds to CD 19 may be any domain which is capable of binding CD 19.
  • the antigen-binding domain may comprise a CD 19 antigen-binding domain as described in Table 2.
  • the gene encoding CD19 comprises ten exons: exons 1 to 4 encode the extracellular domain; exon 5 encodes the transmembrane domain; and exons 6 to 10 encode the cytoplasmic domain.
  • the antigen-binding domain of a CD 19 CAR herein may bind an epitope of CD 19 encoded by exon 1 of the CD 19 gene.
  • the antigen-binding domain of a CD 19 CAR herein may bind an epitope of CD 19 encoded by exon 2 of the CD 19 gene.
  • the antigen-binding domain of a CD 19 CAR herein may bind an epitope of CD 19 encoded by exon 3 of the CD 19 gene.
  • the antigen-binding domain of a CD 19 CAR herein may bind an epitope of CD 19 encoded by exon 4 of the CD 19 gene.
  • a CD19-binding domain exemplified herein comprises variable regions with complementarity determining regions (CDRs) from an antibody referred to as CAT 19, a) a heavy chain variable region (VH) having CAT 19 CDRs with the following sequences:
  • the CAT19 antibody is described in WO2016/139487.
  • Each CDR may, for example, have one, two or three amino acid mutations.
  • the CDRs may be in the format of a single-chain variable fragment (scFv), which is a fusion protein of the heavy variable region (VH) and light chain variable region (VL) of an antibody, connected with a short linker peptide of ten to about 25 amino acids.
  • the scFv may be in the orientation VH-VL, i.e., the VH is at the amino-terminus of the CAR molecule and the VL domain is linked to the spacer and, in turn the transmembrane domain and endodomain.
  • the CDRs may be grafted on to the framework of a human antibody or scFv.
  • the CAR may comprise a CD19-binding domain consisting or comprising one of the following sequences.
  • the CD 19 CAR may comprise the following VH sequence.
  • SEQ ID NO: 7 VH sequence from CAT 19 murine monoclonal antibody QVQLQQSGPELVKPGASVKISCKASGYAFSSSWMNWVKQRPGKGLEWIGRIYPG
  • the CD 19 CAR may comprise the following VL sequence.
  • the CD 19 CAR may comprise the following scFv sequence.
  • the CAR may consist of or comprise one of the following sequences.
  • the CAT19 CAR has a CD8a spacer and transmembrane domain, 4-1BB endodomain and TCR CD3z endodomain.
  • the CAR provided herein may comprise a variant of the polypeptide of SEQ ID NO: 1-10 having at least 80, 85, 90, 95, 98 or 99% sequence identity, provided that the variant sequence retain the capacity to bind CD 19 (when in conjunction with a complementary VL or VH domain, if appropriate).
  • the percentage identity between two polypeptide sequences may be readily determined by programs such as BLAST which is freely available at http://blast.ncbi.nlm.nih.gov.
  • the CD 19 CAR exemplified herein (/. ⁇ ., the CAT 19 CAR, SEQ ID NO: 10) has properties which result in lower toxicity and better efficacy in treated patients.
  • the CAT 19 CAR exemplified herein effects killing of target cells expressing CD 19 and proliferates in response to CD 19 expressing targets, but releases less Interferon-gamma.
  • a small animal model of an aggressive B-cell lymphoma showed equal efficacy and equal engraftment between the fmc63- and CAT19-based CAR-T cells, but surprisingly, less of the CAT19 CAR T-cells were exhausted than fmc63 CAR T-cells. See, Examples 2 and 3 of US Publication No.: 2018-0044417.
  • the CAT 19 CAR provided herein may cause 25, 50, 70 or 90% lower IFNy release in a comparative assay involving bringing CAR T cells into contact with target cells.
  • the CAT 19 CAR provided herein may result in a smaller proportion of CAR T cells becoming exhausted than equivalent fmc63 CAR T cells. T cell exhaustion may be assessed using methods known in the art, such as analysis of PD-1 expression.
  • the CAR may cause 20, 30, 40, 50, 60 of 70% fewer CAR T cells to express PD-1 that fmc63 CAR T cells in a comparative assay involving bringing CAR T cells into contact with target cells.
  • CD19 antigen-binding domain is based on the CD19 antigen-binding domain CD19ALAb (described in WO2016/102965) and comprises: a) a heavy chain variable region (VH) having CDRs with the following sequences:
  • Each CDR may, for example, have one, two or three amino acid mutations.
  • the CAR may comprise one of the following amino acid sequences.
  • SEQ ID NO: 19 Humanized CD19ALAb scFv sequence - Heavy 19, Kappa 7)
  • the scFv may be in a VH-VL orientation or a VL-VH orientation.
  • the CAR may comprise one of the following VH sequences:
  • the CAR may comprise one of the following VL sequences:
  • SEQ ID NO: 23 Humanized CD19ALAb VL sequence, Kappa 16
  • CD 19 antigen-binding domain is based on the CD 19 antigen-binding domain of monoclonal antibody fmc63 (FMC63) (described in Nicholson et al., 1997, Mol. Immunol., 34: 1157-65) and comprises: a) a heavy chain variable region (VH) having CDRs with the following sequences:
  • the CD 19 FMC63 CAR may comprise the following VH sequence.
  • the CD 19 CAR may comprise the following VL sequence.
  • the CD 19 FMC63 CAR may comprise the following scFv sequence.
  • the CAR may consist of or comprise the following sequence.
  • the CAR provided herein may comprise a variant of the sequence shown as any of SEQ ID NO: 25 to 33 having at least 80, 85, 90, 95, 98 or 99% sequence identity, provided that the variant sequence retain the capacity to bind CD 19 (when in conjunction with a complementary VL or VH domain, if appropriate).
  • the percentage identity between two polypeptide sequences may be readily determined by programs such as BLAST which is freely available at blast.ncbi.nlm.nih.gov.
  • the CARs of the cell may comprise a signal peptide so that when the CAR is expressed inside a cell, such as a T-cell, the nascent protein is directed to the endoplasmic reticulum and subsequently to the cell surface, where it is expressed.
  • the core of the signal peptide may contain a long stretch of hydrophobic amino acids that has a tendency to form a single alpha-helix.
  • the signal peptide may begin with a short positively charged stretch of amino acids, which helps to enforce proper topology of the polypeptide during translocation.
  • At the end of the signal peptide there is typically a stretch of amino acids that is recognized and cleaved by signal peptidase.
  • Signal peptidase may cleave either during or after completion of translocation to generate a free signal peptide and a mature protein.
  • the free signal peptides are then digested by specific proteases.
  • the signal peptide may be at the amino terminus of the molecule.
  • the signal peptide may comprise the amino acid sequence of any of SEQ ID NO: 34-39 or a variant thereof having 5, 4, 3, 2 or 1 amino acid mutations (insertions, substitutions or additions) provided that the signal peptide still functions to cause cell surface expression of the CAR.
  • the signal peptide of SEQ ID NO: 62 is compact and highly efficient. It is predicted to give about 95% cleavage after the terminal glycine, giving efficient removal by signal peptidase.
  • the signal peptide of SEQ ID NO: 35 follows.
  • the signal peptide of SEQ ID NO: 36 follows.
  • the signal peptide of SEQ ID NO: 37 follows.
  • the signal peptide of SEQ ID NO: 38 is derived from IgGl.
  • SEQ ID NO: 38 MSLPVTALLLPLALLLHAARP
  • the signal peptide of SEQ ID NO: 39 is derived from CD8.
  • the signal peptide for the first CAR may have a different sequence from the signal peptide of the second CAR.
  • CARs comprise a spacer to connect the antigen-binding domain with the transmembrane domain and spatially separate the antigen-binding domain from the endodomain.
  • a flexible spacer allows the antigen-binding domain to orient in different directions to facilitate binding.
  • the spacer may, for example, comprise an IgGl Fc region, an IgGl hinge or a CD8 stalk, or a combination thereof.
  • the spacer may alternatively comprise an alternative sequence which has similar length and/or domain spacing properties as an IgGl Fc region, an IgGl hinge or a CD8 stalk.
  • the first and second CARs may comprise different spacer molecules.
  • the spacer may, for example, comprise an IgGl Fc region, an IgGl hinge or a human CD8 stalk or the mouse CD8 stalk.
  • the spacer may alternatively comprise an alternative linker which has similar length and/or domain spacing properties as an IgGl Fc region, an IgGl hinge or a CD8 stalk.
  • a human IgGl spacer may be altered to remove Fc binding motifs.
  • the spacer for the CD 19 CAR may comprise a CD8 stalk spacer, or a spacer having a length equivalent to a CD8 stalk spacer.
  • the spacer for the CD 19 CAR may have at least 30 amino acids or at least 40 amino acids. It may have between 35-55 amino acids, for example between 40-50 amino acids. It may have about 46 amino acids. Examples of amino acid sequences for these spacers are given below:
  • SEQ ID NO: 40 (hinge-CH2CH3 of human IgGl)
  • SEQ ID NO: 41 human CD8 stalk
  • SEQ ID NO: 42 (human IgGl hinge):
  • SEQ ID NO: 43 (human IgGl hinge variation)
  • SEQ ID NO: 45 (IgGl Hinge - Fc modified to remove Fc receptor recognition motifs)
  • Modified residues are underlined; * denotes a deletion.
  • SEQ ID NO: 46 (CD2 ectodomain) KEITNALETWGALGQDINLDIPSFQMSDDIDDIKWEKTSDKKKIAQFRKEKETFKE KDTYKLFKNGTLKIKHLKTDDQDIYKVSIYDTKGKNVLEKIFDLKIQERVSKPKIS WTCINTTLTCEVMNGTDPELNLYQDGKHLKLSQRVITHKWTTSLSAKFKCTAGNK VSKESSVEPVSCPEKGLD
  • SEQ ID NO: 47 (CD34 ectodomain)
  • the transmembrane domain is the domain of the CAR that spans the membrane.
  • a transmembrane domain may be any protein structure which is thermodynamically stable in a membrane. This is typically an alpha helix comprising of several hydrophobic residues.
  • the transmembrane domain of any transmembrane protein can be used to supply the transmembrane portion provided herein.
  • the presence and span of a transmembrane domain of a protein can be determined by those skilled in the art using the TMHMM algorithm (http://www.cbs. dtu.dk/services/TMHMM-2.0/).
  • transmembrane domain of a protein is a relatively simple structure, z.e, a polypeptide predicted to form a hydrophobic alpha helix of sufficient length to span the membrane, an artificially designed transmembrane domain may also be used (US 7052906 Bl describes synthetic transmembrane components).
  • the transmembrane domain may be derived from CD28, which gives good receptor stability.
  • the CD28 transmembrane domain sequence is shown as SEQ ID NO: 48
  • the transmembrane domain may be derived from human Tyrp-1.
  • the tyrp-1 transmembrane domain sequence is shown as SEQ ID NO: 49.
  • the transmembrane domain may be derived from CD8 A.
  • the CD8 A transmembrane domain sequence is shown as SEQ ID NO: 50.
  • the endodomain is the signal-transmission portion of the CAR. After antigen recognition, receptors cluster, native CD45 and CD 148 are excluded from the synapse and a signal is transmitted to the cell.
  • the most commonly used endodomain component is that of CD3-zeta which contains three ITAMs. This transmits an activation signal to the T cell after antigen is bound.
  • CD3-zeta may not provide a fully competent activation signal and additional co-stimulatory signaling may be needed.
  • chimeric CD28 and 0X40 can be used with CD3-Zeta to transmit a proliferative / survival signal, or all three can be used together.
  • the cells provided herein comprise two CARs, each with an endodomain.
  • the endodomain of the first CAR and the endodomain of the second CAR may comprise: (i) an ITAM-containing endodomain, such as the endodomain from CD3 zeta; and/or (ii) a co-stimulatory domain, such as the endodomain from CD28; and/or (iii) a domain which transmits a survival signal, for example a TNF receptor family endodomain such as OX-40 or 4-1BB.
  • an ITAM-containing endodomain such as the endodomain from CD3 zeta
  • a co-stimulatory domain such as the endodomain from CD28
  • a domain which transmits a survival signal for example a TNF receptor family endodomain such as OX-40 or 4-1BB.
  • the endodomain of the CAR of the present disclosure may comprise combinations of one or more of the CD3-Zeta endodomain, the 4 IBB endodomain, the 0X40 endodomain or the CD28 endodomain.
  • the intracellular T-cell signalling domain (endodomain) of the CAR of the present disclosure may comprise the sequence shown as any of SEQ ID NO: 51-58 or a variant thereof having at least 80% sequence identity.
  • SEQ ID NO: 51 (CD3 zeta endodomain)
  • SEQ ID NO: 54 (CD28 endodomain)
  • Examples of combinations of such endodomains include 41BB-Zeta, OX40-Zeta, CD28- Zeta and CD28-OX40-Zeta.
  • SEQ ID NO: 56 (OX40-Zeta endodomain fusion)
  • a variant sequence may have at least 80%, 85%, 90%, 95%, 98% or 99% sequence identity to any of SEQ ID NO: 51-58 provided that the sequence provides an effective transmembrane domain/intracellular T cell signaling domain.
  • a nucleic acid provided herein encodes a CD 19 CAR of the disclosure.
  • the terms “polynucleotide”, “nucleotide”, and “nucleic acid” are intended to be synonymous with each other.
  • the nucleic acid may be, for example, an RNA, a DNA or a cDNA.
  • Nucleic acids may comprise DNA or RNA. They may be single-stranded or double-stranded. They may also be polynucleotides which include within them synthetic or modified nucleotides. A number of different types of modification to oligonucleotides are known in the art. These include methylphosphonate and phosphorothioate backbones, addition of acridine or polylysine chains at the 3' and/or 5' ends of the molecule. For the purposes of the use as described herein, it is to be understood that the polynucleotides may be modified by any method available in the art. Such modifications may be carried out in order to enhance the in vivo activity or life span of polynucleotides of interest.
  • codons “ccg” and “cca” both encode the amino acid proline, so using “ccg” may be exchanged for “cca” without affecting the amino acid in this position in the sequence of the translated protein.
  • RNA codons which may be used to encode each amino acid are summarised in Table 3.
  • Alternative codons may be used in one or more nucleic acids which encode co-stimulatory domains, such as the CD28 endodomain.
  • Alternative codons may be used in one or more domains which transmit survival signals, such as 0X40 and 4 IBB endodomains.
  • Alternative codons may be used in the portions of nucleic acid encoding a CD3zeta endodomain and/or the portions of nucleic acid encoding one or more costimulatory domain(s) and/or the portions of nucleic acid encoding one or more domain(s) which transmit survival signals.
  • the present disclosure also provides a vector, or kit of vectors which comprises one or more CAR-encoding nucleic acid.
  • a vector may be used to introduce the nucleic acid into a host cell so that it expresses the CAR.
  • the vector may, for example, be a plasmid or a viral vector, such as a retroviral vector or a lentiviral vector, or a transposon-based vector or synthetic mRNA.
  • the vector may be capable of transfecting or transducing a T cell.
  • a cell which comprises a CD 19 CAR of the present disclosure. It will be understood that this cell expresses the CAR, wherein the CAR binds CD 19, such that the cell recognises a target cell expressing CD 19.
  • CD 19 CAR engineered cells or engineered cells are also provided.
  • the cell may be any eukaryotic cell capable of expressing a CAR at the cell surface, such as an immunological cell.
  • the cell may be an immune effector cell such as a T cell or a natural killer (NK) cell.
  • an immune effector cell such as a T cell or a natural killer (NK) cell.
  • T cells or T lymphocytes are a type of lymphocyte that play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells (NK cells), by the presence of a T-cell receptor (TCR) on the cell surface.
  • TCR T-cell receptor
  • Helper T helper cells assist other white blood cells in immunologic processes, including maturation of B cells into plasma cells and memory B cells, and activation of cytotoxic T cells and macrophages.
  • TH cells express CD4 on their surface.
  • TH cells become activated when they are presented with peptide antigens by MHC class II molecules on the surface of antigen presenting cells (APCs).
  • APCs antigen presenting cells
  • TH1, TH2, TH3, TH17, Th9, or TFH which secrete different cytokines to facilitate different types of immune responses.
  • Cytotoxic T cells TC cells, or CTLs
  • CTLs destroy virally infected cells and tumor cells, and are also implicated in transplant rejection.
  • CTLs express the CD8 at their surface.
  • CD8+ cells recognize their targets by binding to antigen associated with MHC class I, which is present on the surface of all nucleated cells.
  • MHC class I MHC class I
  • adenosine and other molecules secreted by regulatory T cells the CD8+ cells can be inactivated to an anergic state, which prevent autoimmune diseases such as experimental autoimmune encephalomyelitis.
  • Memory T cells are a subset of antigen-specific T cells that persist long-term after an infection has resolved. They quickly expand to large numbers of effector T cells upon reexposure to their cognate antigen, thus providing the immune system with "memory" against past infections.
  • Memory T cells comprise three subtypes: central memory T cells (TCM cells) and two types of effector memory T cells (TEM cells and TEMRA cells). Memory cells may be either CD4+ or CD8+. Memory T cells typically express the cell surface protein CD45RO.
  • Treg cells Regulatory T cells
  • suppressor T cells are crucial for the maintenance of immunological tolerance. Their major role is to shut down T cell-mediated immunity toward the end of an immune reaction and to suppress auto-reactive T cells that escaped the process of negative selection in the thymus.
  • Treg cells Two major classes of CD4+ Treg cells have been described — naturally occurring Treg cells and adaptive Treg cells.
  • Naturally occurring Treg cells arise in the thymus and have been linked to interactions between developing T cells with both myeloid (CD1 lc+) and plasmacytoid (CD123+) dendritic cells that have been activated with TSLP.
  • Naturally occurring Treg cells can be distinguished from other T cells by the presence of an intracellular molecule called FoxP3. Mutations of the FOXP3 gene can prevent regulatory T cell development, causing the fatal autoimmune disease IPEX.
  • Adaptive Treg cells may originate during a normal immune response.
  • the T cell provided herein may be any of the T cell types mentioned above, in particular a CTL.
  • Natural killer (NK) cells are a type of cytolytic cell which forms part of the innate immune system. NK cells provide rapid responses to innate signals from virally infected cells in an MHC independent manner
  • NK cells (belonging to the group of innate lymphoid cells) are defined as large granular lymphocytes (LGL) and constitute the third kind of cells differentiated from the common lymphoid progenitor generating B and T lymphocytes. NK cells are known to differentiate and mature in the bone marrow, lymph node, spleen, tonsils and thymus where they then enter into the circulation.
  • LGL large granular lymphocytes
  • the CAR-expressing cells provided herein may be any of the cell types mentioned above.
  • CAR-expressing cells such as CAR-expressing T or NK cells may either be created ex vivo either from a patient’s own peripheral blood (1st party), or in the setting of a haematopoietic stem cell transplant from donor peripheral blood (2nd party), or peripheral blood from an unconnected donor (3rd party).
  • the present disclosure also provides a cell composition
  • a cell composition comprising CAR-expressing T cells and/or CAR-expressing NK cells, which cells express a CAR that binds CD 19, such that the cells can recognise a target cell expressing CD 19.
  • the cell composition may be made by transducing a blood-sample ex vivo with a nucleic acid according to the present disclosure.
  • T or NK cells provided herein may be derived from ex vivo differentiation of inducible progenitor cells or embryonic progenitor cells to T or NK cells.
  • an immortalized T-cell line which retains its lytic function and could act as a therapeutic may be used.
  • the CAR cells are generated by introducing DNA or RNA coding for the CARs by one of many means including, but not limited to, transduction with a viral vector, transfection with DNA or RNA. Cells may be activated and/or expanded prior to being transduced with CAR-encoding nucleic acid, for example by treatment with an anti-CD3 monoclonal antibody.
  • the T or NK cells provided herein may be made by: (i) isolation of a T or NK cellcontaining sample from a subject or other sources listed above, and (ii) transduction or transfection of the T or NK cells with a nucleic acid or a vector encoding the CD 19 CARs as described in the present disclosure.
  • the T or NK cells may then by purified, for example, selected on the basis of expression of the antigen-binding domain of the antigen-binding polypeptide.
  • the present invention also provides CD 19 CAR engineered cells, wherein the engineered cells are manufactured using a method with a manufacturing success rate of at least 80%.
  • the manufacturing success rate can be defined as the percentage of patient samples that give rise to a usable drug product at the end of the manufacturing process. It may also be referred to as the degree of manufacturability.
  • the manufacturing success rate is 80% or higher, 81% or higher, 82% or higher, 83% or higher, 84% or higher, 85% or higher, 90% or higher, 91% or higher, 92% or higher, 93% or higher, 94% or higher, 95% or higher, 96% or higher, 97% or higher, 98% or higher, 99% or higher, or 100%.
  • Patient samples may be leukapheresis products, which may be used fresh or may be frozen and thawed before use.
  • a high manufacturing success rate is particularly advantageous when treating relap sed/refractory conditions as described herein, since patients with these conditions are least likely to be able to survive treatment delays caused by manufacturing failures. It will also be clear to those of skill in the art that the degree of manufacturability can be discussed in terms of a manufacturing failure rate, which is preferably 20% or lower, 19% or lower, 18% or lower, 17% or lower, 16% or lower, 15% or lower, 14% or lower, 13% or lower, 12% or lower, 11% or lower, 10% or lower, 9% or lower, 8% or lower, 7% or lower, 6% or lower, 5% or lower, 4% or lower, 3% or lower, 2% or lower, 1% or lower, or 0%.
  • V2C/V2D Timely vein-to-certification/vein-to-delivery
  • V2C time from leukapheresis to quality release
  • V2D time from leukapheresis to delivery of product to the hospital
  • Removal of leukemic cells can be achieved by a number of methods known to the skilled person, such as T cell enrichment.
  • the present disclosure also relates to a pharmaceutical composition containing a plurality of CAR-expressing cells, such as T cells or NK cells provided herein.
  • Pharmaceutical compositions comprising the CD 19 CAR T-cell product described in Example 1 are provided.
  • the pharmaceutical composition may additionally comprise a pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutical composition may optionally comprise one or more further pharmaceutically active polypeptides and/or compounds.
  • Such a formulation may, for example, be in a form suitable for intravenous infusion.
  • the cell compositions of the present disclosure are capable of killing cancer cells recognizable by expression of CD 19, such as B-cell lymphoma cells.
  • CAR-expressing cells such as T cells, may either be created ex vivo either from a patient’s own peripheral blood (1st party), or in the setting of a haematopoietic stem cell transplant from donor peripheral blood (2nd party), or peripheral blood from an unconnected donor (3rd party).
  • CAR T- cells may be derived from ex-vivo differentiation of inducible progenitor cells or embryonic progenitor cells to T-cells.
  • CAR T-cells are generated by introducing DNA or RNA coding for the CAR by one of many means including transduction with a viral vector, transfection with DNA or RNA.
  • cancers which express CD 19 are B-cell lymphomas, including Hodgkin's lymphoma and non-Hodgkin’s lymphoma; and B-cell leukaemias.
  • the B-cell lymphoma may be Diffuse large B cell lymphoma (DLBCL), Follicular lymphoma, Marginal zone lymphoma (MZL) or Mucosa-Associated Lymphatic Tissue lymphoma (MALT), Small cell lymphocytic lymphoma (overlaps with Chronic lymphocytic leukemia), Mantle cell lymphoma (MCL), Burkitt lymphoma, Primary mediastinal (thymic) large B-cell lymphoma, Lymphoplasmacytic lymphoma (may manifest as Waldenstrom macroglobulinemia), Nodal marginal zone B cell lymphoma (NMZL), Splenic marginal zone lymphoma (SMZL), Intravascular large B-cell lymphoma, Primary effusion lymphoma, Lymphomatoid granulomatosis, T cell/histiocyte-rich large B-cell lymphoma or Primary central nervous system lymphoma.
  • DLBCL Diffuse large B cell lymph
  • the B-cell leukaemia may be acute lymphoblastic leukaemia, B-cell chronic lymphocytic leukaemia, B-cell prolymphocytic leukaemia, precursor B lymphoblastic leukaemia or hairy cell leukaemia.
  • the B-cell leukaemia may be acute lymphoblastic leukaemia (B-ALL or ALL).
  • the B-ALL may be adult ALL (aALL).
  • the patient may be 18 years of age or older.
  • Standard treatment for patients with aALL is typically divided into three different phases: induction, consolidation, and maintenance.
  • chemotherapeutic drugs such as vincristine, dexamethasone, prednisone, and an anthracy cline drug such as doxorubicin or daunorubicin.
  • Some induction regimens may also include cyclophosphamide, L-asparaginase (or pegaspargase), and/or high doses of methotrexate or cytarabine (ara-C).
  • TKI tyrosine kinase inhibitor
  • imatinib imatinib
  • TKI dasatinib
  • the next phase consolidation often consists of another fairly short course of chemotherapy, using many of the same drugs that were used for induction therapy in high doses.
  • TKI or second generation TKI is also continued for Ph+-ALL patients.
  • Response in patients often require consolidation an allogeneic haematopoietic stem cell transplant (HSCT).
  • HSCT haematopoietic stem cell transplant
  • the patient After consolidation, the patient is generally put on a maintenance chemotherapy program of methotrexate and 6-mercaptopurine (6-MP). In some cases, this may be combined with other drugs such as vincristine and prednisone.
  • 6-MP 6-mercaptopurine
  • a TKI or a second generation TKI is often included as well.
  • One or more of targeted immunotherapies for example inotuzumab ozogamicin, blinatumomab and/or approved CD 19 CAR-T therapies, and low dose radiation therapy may be also administered.
  • Treatment with the CD 19 CAR-expressing T cells provided herein is contemplated to help prevent the need of a subsequent allogeneic HSCT.
  • these CAR-T cells have been shown to not cause severe toxicities, such as severe CRS and ICANS, and to persist longer.
  • the methods provided herein slow or prevent progression of the cancer, diminish the extent of the cancer, result in remission (partial or total) of the cancer, and/or prolong survival of the patient without causing severe toxicities.
  • the present invention provides a method for selecting a bridging therapy for a patient having a B-cell malignancy who is about to receive treatment with CAR-T cells, which comprises the following steps:
  • the patient may be of Caucasian, Black, Latino or Hispanic, Asian or any other ethnicity.
  • the patient may be Latino or Hispanic.
  • the patient may be 18 years of age or older.
  • the patient may have a complex karyotype.
  • Complex karyotype refers to cytogenetic risks of hematologic malignancies associated with a poor prognosis that are well known in the art.
  • the patient may have received at least one prior line of therapy.
  • the patient may have received at least two prior lines of therapy.
  • the patient may have received at least three prior lines of therapy.
  • the patient may have received at least four prior lines of therapy.
  • the patient may have received at least five prior lines of therapy.
  • the patient may have received at least six prior lines of therapy.
  • the at least one prior line of therapy may have been inotuzumab ozogamicin and/or blinatumomab.
  • the patient may have received an allogeneic hematopoietic stem cell transplant (allo- HSCT or allo-SCT).
  • Allo- HSCT or allo-SCT allogeneic hematopoietic stem cell transplant
  • the patient may present extramedullary disease at screening.
  • the patient may undergo leukapheresis to prepare the population of CAR T cells specific for a B-cell malignancy.
  • the patient may have previously received chemotherapy but the BM blast percentage is still > 5%.
  • the BM blast percentage at screening may be more than or equal to 20%.
  • the BM blast percentage at screening may be more than or equal to 50%.
  • the BM blast percentage at screening may be more than or equal to 75%.
  • the patient having a B-cell malignancy who is about to receive treatment with CAR-T cells is understood to be a patient who has been leukapheresed and is waiting for the CAR- T cells to be produced and administered.
  • Bridging therapy refers to a therapeutic treatment or tool to stabilize or debulk disease between leukapheresis and CAR T cell administration.
  • the anti-CD22 antibody-drug conjugate may be administered at least 1 week before the administration of the lymphodepleting therapy.
  • the anti-CD22 antibody-drug conjugate may be administered at least 2 weeks before the administration of the lymphodepleting or pre-conditioning therapy.
  • the patient may receive a lymphodepleting pre-conditioning treatment before CD 19 CAR- T cell infusion.
  • the patient may be administered a preconditioning regimen comprising 120 mg/m 2 fludarabine (Flu) and 1000 mg/m 2 cyclophosphamide (Cy). This preconditioning regimen may be administered prior to CAR-T cell administration.
  • Fludarabine may be administered at 30 mg/m2 on Day -6, Day -5, Day -4, and Day -3 prior to being administered the first dose of CAR-T cells (i.e. Day 0). Fludarabine may be administered intravenously. Fludarabine may be administered over 30 min. Cyclophosphamide may be administered at 500 mg/m 2 on Day -6, and Day -5 prior to being administered the first dose of CAR-T cells (i.e. Day 0). Cyclophosphamide may be administered intravenously. Cyclophosphamide may be administered over 30 min.
  • the population of CAR T cells specific for a B-cell malignancy may be autologous.
  • the anti-CD22 antibody-drug conjugate may be administered after leukapheresis.
  • the anti-CD22 antibody-drug conjugate may be selected from Inotuzumab ozogamicin (Besponsa), inotuzumab, and epratuzumab.
  • the anti-CD22 antibody-drug conjugate may be Inotuzumab ozogamicin.
  • the B-cell malignancy may be selected from the group consisting of acute lymphoblastic leukemia (ALL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Burkitt lymphoma, lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia or WM), cutaneous B-cell lymphoma (CBCL), diffuse large B-cell lymphoma (DLBCL), and anaplastic large cell lymphoma (ALCL).
  • ALL acute lymphoblastic leukemia
  • FL follicular lymphoma
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • MCL mantle cell lymphoma
  • MZL marginal zone lymphoma
  • Burkitt lymphoma lymphoplasmacytic lymphoma
  • the CAR T cells may be specific to CD 19 or CD20.
  • the CAR-T cells may be specific to CD 19.
  • the anti-CD19 CAR may be a CAR as described in the context of chimeric antigen receptors (CARs) in previous sections, and its definitions and embodiments apply equally to this aspect of the invention.
  • CARs chimeric antigen receptors
  • the anti-CD19 CAR may comprise: a) a heavy chain variable region (VH) having complementarity determining regions (CDRs) with the following sequences:
  • CDR3 - SLLYGDYLDY (SEQ ID No. 3); and b) a light chain variable region (VL) having CDRs with the following sequences: CDR1 - SASSSVSYMH (SEQ ID No. 4);
  • the anti-CD19 CAR may comprise: a) a heavy chain variable region (VH) having CDRs with the following sequences: CDR1 - GVSLPDYG (SEQ ID NO: 25);
  • CDR3 - AKHYYYGGSYAMDY (SEQ ID NO: 27); and b) a light chain variable region (VL) having CDRs with the following sequences: CDR1 - QDISKY (SEQ ID NO: 28);
  • the present invention also provides a method for improving the outcome of treatment with CAR-T cells for a patient having a B-cell malignancy, wherein the patient presents > 5% blasts in the BM at screening, which method comprises the step of administering an anti- CD22 antibody-drug conjugate to the patient after leukapheresis but prior to preconditioning the patient for CAR-T cell treatment.
  • the patient may be of Caucasian, Black, Latino or Hispanic, Asian or any other ethnicity.
  • the patient may be Latino or Hispanic.
  • the patient may have a complex karyotype.
  • Complex karyotype refers to cytogenetic risks of hematologic malignancies associated with a poor prognosis that are well known in the art.
  • the patient may have received at least one prior line of therapy.
  • the patient may have received at least two prior lines of therapy.
  • the patient may have received at least three prior lines of therapy.
  • the patient may have received at least four prior lines of therapy.
  • the patient may have received at least five prior lines of therapy.
  • the patient may have received at least six prior lines of therapy.
  • the at least one prior line of therapy may have been inotuzumab ozogamicin and/or blinatumomab.
  • the patient may have received an allogeneic hematopoietic stem cell transplant (allo- HSCT or allo-SCT).
  • the patient may present extramedullary disease at screening.
  • the patient may present > 20% blasts in the BM at screening.
  • the patient may present > 50% blasts in the BM at screening.
  • the patient may present > 75% blasts in the BM at screening.
  • the anti-CD22 antibody-drug conjugate may be administered at least 1 week before the administration of the lymphodepleting therapy.
  • the anti-CD22 antibody-drug conjugate may be administered at least 2 weeks before the administration of the lymphodepleting or pre-conditioning therapy.
  • the patient may receive a lymphodepleting pre-conditioning treatment before CD 19 CAR- T cell infusion.
  • the patient may be administered a preconditioning regimen comprising 120 mg/m 2 fludarabine (Flu) and 1000 mg/m 2 cyclophosphamide (Cy). This preconditioning regimen may be administered prior to CAR-T cell administration.
  • Fludarabine may be administered at 30 mg/m2 on Day -6, Day -5, Day -4, and Day -3 prior to being administered the first dose of CAR-T cells (i.e. Day 0). Fludarabine may be administered intravenously. Fludarabine may be administered over 30 min.
  • Cyclophosphamide may be administered at 500 mg/m 2 on Day -6, and Day -5 prior to being administered the first dose of CAR-T cells (i.e. Day 0). Cyclophosphamide may be administered intravenously. Cyclophosphamide may be administered over 30 min.
  • the population of CAR T cells specific for a B-cell malignancy may be autologous.
  • the anti-CD22 antibody-drug conjugate may be administered after leukapheresis.
  • the anti-CD22 antibody-drug conjugate may be selected from Inotuzumab ozogamicin (Besponsa), inotuzumab, and epratuzumab.
  • the anti-CD22 antibody-drug conjugate may be Inotuzumab ozogamicin.
  • the B-cell malignancy may be selected from the group consisting of acute lymphoblastic leukemia (ALL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Burkitt lymphoma, lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia or WM), cutaneous B-cell lymphoma (CBCL), diffuse large B-cell lymphoma (DLBCL), and anaplastic large cell lymphoma (ALCL).
  • ALL acute lymphoblastic leukemia
  • FL follicular lymphoma
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • MCL mantle cell lymphoma
  • MZL marginal zone lymphoma
  • Burkitt lymphoma lymphoplasmacytic lymphoma
  • the CAR T cells may be specific to CD 19 or CD20.
  • the CAR-T cells may be specific to CD 19.
  • the anti-CD19 CAR may be a CAR as described in the context of chimeric antigen receptors (CARs) in previous sections, and its definitions and embodiments apply equally to this aspect of the invention.
  • CARs chimeric antigen receptors
  • the anti-CD19 CAR may comprise: a) a heavy chain variable region (VH) having complementarity determining regions (CDRs) with the following sequences:
  • CDR3 - SLLYGDYLDY (SEQ ID No. 3); and b) a light chain variable region (VL) having CDRs with the following sequences: CDR1 - SASSSVSYMH (SEQ ID No. 4);
  • the anti-CD19 CAR may comprise: a) a heavy chain variable region (VH) having CDRs with the following sequences: CDR1 - GVSLPDYG (SEQ ID NO: 25);
  • CDR2 - IWGSETT (SEQ ID NO: 26) CDR3 - AKHYYYGGSYAMDY (SEQ ID NO: 27); and b) a light chain variable region (VL) having CDRs with the following sequences: CDR1 - QDISKY (SEQ ID NO: 28);
  • the present invention also provides a method for treating a B-cell malignancy in a subject which comprises the step of using anti-CD22 antibody-drug conjugate as bridging therapy prior to treatment with anti-CD19 CAR-T cells, wherein the CAR comprises: a) a heavy chain variable region (VH) having complementarity determining regions (CDRs) with the following sequences:
  • VH heavy chain variable region
  • CDRs complementarity determining regions
  • CDR3 - SLLYGDYLDY (SEQ ID No. 3); and b) a light chain variable region (VL) having CDRs with the following sequences: CDR1 - SASSSVSYMH (SEQ ID No. 4);
  • This aspect of the invention may be formulated as an anti-CD22 antibody-drug conjugate for use in the treatment of a B-cell malignancy in a subject, wherein the anti-CD22 antibody-drug conjugate is used as bridging therapy prior to treatment with anti-CD19 CAR-T cells, wherein the CAR comprises: a) a heavy chain variable region (VH) having complementarity determining regions (CDRs) with the following sequences:
  • VH heavy chain variable region
  • CDRs complementarity determining regions
  • CDR3 - SLLYGDYLDY (SEQ ID No. 3); and b) a light chain variable region (VL) having CDRs with the following sequences: CDR1 - SASSSVSYMH (SEQ ID No. 4);
  • This aspect of the invention may be formulated as use of an anti-CD22 antibody-drug conjugate in the manufacture of a medicament for the treatment of a B-cell malignancy in a subject, wherein the anti-CD22 antibody-drug conjugate is used as bridging therapy prior to treatment with anti-CD19 CAR-T cells, wherein the CAR comprises: a) a heavy chain variable region (VH) having complementarity determining regions (CDRs) with the following sequences:
  • VH heavy chain variable region
  • CDRs complementarity determining regions
  • CDR3 - SLLYGDYLDY (SEQ ID No. 3); and b) a light chain variable region (VL) having CDRs with the following sequences: CDR1 - SASSSVSYMH (SEQ ID No. 4);
  • the method for treating a B-cell malignancy may comprise the following steps: i) administering the anti-CD22 antibody-drug conjugate to the patient after leukapheresis; ii) pre-conditioning the patient; and iii) administering anti CD- 19 CAR-T cells to the patient.
  • the method for treating a B-cell malignancy may comprise the following steps: i) leukapheresis of the patient to obtain a T cell composition for preparation of the anti-CD19 CAR-T cells; ii) administering the anti-CD22 antibody-drug conjugate to the patient; iii) pre-conditioning the patient; and iv) administering the anti CD-19 CAR-T cells to the patient.
  • the anti-CD19 CAR may be a CAR as described in the context of chimeric antigen receptors (CARs) in previous sections, and its definitions and embodiments apply equally to this aspect of the invention.
  • CARs chimeric antigen receptors
  • the anti-CD19 CAR may comprise: a) a heavy chain variable region (VH) having complementarity determining regions (CDRs) with the following sequences:
  • CDR3 - SLLYGDYLDY (SEQ ID No. 3); and b) a light chain variable region (VL) having CDRs with the following sequences: CDR1 - SASSSVSYMH (SEQ ID No. 4);
  • the patient may be of Caucasian, Black, Latino or Hispanic, Asian or any other ethnicity.
  • the patient may be Latino or Hispanic.
  • the patient may have a complex karyotype.
  • Complex karyotype refers to cytogenetic risks of hematologic malignancies associated with a poor prognosis that are well known in the art.
  • the patient may have received at least one prior line of therapy.
  • the patient may have received at least two prior lines of therapy.
  • the patient may have received at least three prior lines of therapy.
  • the patient may have received at least four prior lines of therapy.
  • the patient may have received at least five prior lines of therapy.
  • the patient may have received at least six prior lines of therapy.
  • the at least one prior line of therapy may have been inotuzumab ozogamicin and/or blinatumomab.
  • the patient may have received an allogeneic hematopoietic stem cell transplant (allo- HSCT or allo-SCT).
  • allo- HSCT allogeneic hematopoietic stem cell transplant
  • the patient may present extramedullary disease at screening.
  • the patient may present > 20% blasts in the BM at screening.
  • the patient may present > 50% blasts in the BM at screening.
  • the patient may present > 75% blasts in the BM at screening.
  • the anti-CD22 antibody-drug conjugate may be administered at least 1 week before the administration of the lymphodepleting therapy.
  • the anti-CD22 antibody-drug conjugate may be administered at least 2 weeks before the administration of the lymphodepleting or pre-conditioning therapy.
  • the patient may receive a lymphodepleting pre-conditioning treatment before CD 19 CAR- T cell infusion.
  • the patient may be administered a preconditioning regimen comprising 120 mg/m 2 fludarabine (Flu) and 1000 mg/m 2 cyclophosphamide (Cy). This preconditioning regimen may be administered prior to CAR-T cell administration.
  • Fludarabine may be administered at 30 mg/m2 on Day -6, Day -5, Day -4, and Day -3 prior to being administered the first dose of CAR-T cells (i.e. Day 0). Fludarabine may be administered intravenously. Fludarabine may be administered over 30 min.
  • Cyclophosphamide may be administered at 500 mg/m 2 on Day -6, and Day -5 prior to being administered the first dose of CAR-T cells (i.e. Day 0). Cyclophosphamide may be administered intravenously. Cyclophosphamide may be administered over 30 min.
  • the population of CAR T cells specific for a B-cell malignancy may be autologous.
  • the anti-CD22 antibody-drug conjugate may be administered after leukapheresis.
  • the anti-CD22 antibody-drug conjugate may be selected from Inotuzumab ozogamicin (Besponsa), inotuzumab, and epratuzumab.
  • the anti-CD22 antibody-drug conjugate may be Inotuzumab ozogamicin.
  • the B-cell malignancy may be selected from the group consisting of acute lymphoblastic leukemia (ALL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Burkitt lymphoma, lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia or WM), cutaneous B-cell lymphoma (CBCL), diffuse large B-cell lymphoma (DLBCL), and anaplastic large cell lymphoma (ALCL).
  • ALL acute lymphoblastic leukemia
  • FL follicular lymphoma
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • MCL mantle cell lymphoma
  • MZL marginal zone lymphoma
  • Burkitt lymphoma lymphoplasmacytic lymphoma
  • the invention also contemplates a method for treating a B-cell malignancy in a subject which comprises the step of using anti-CD22 antibody-drug conjugate as bridging therapy prior to treatment with anti-CD19 CAR-T cells, wherein the CAR comprises: a) a heavy chain variable region (VH) having CDRs with the following sequences: CDR1 - GVSLPDYG (SEQ ID NO: 25);
  • CDR3 - AKHYYYGGSYAMDY (SEQ ID NO: 27); and b) a light chain variable region (VL) having CDRs with the following sequences: CDR1 - QDISKY (SEQ ID NO: 28);
  • This aspect of the invention may be formulated as an anti-CD22 antibody-drug conjugate for use in the treatment of a B-cell malignancy in a subject, wherein the anti-CD22 antibody-drug conjugate is used as bridging therapy prior to treatment with anti-CD19 CAR-T cells, wherein the CAR comprises: a) a heavy chain variable region (VH) having CDRs with the following sequences: CDR1 - GVSLPDYG (SEQ ID NO: 25);
  • CDR3 - AKHYYYGGSYAMDY (SEQ ID NO: 27); and b) a light chain variable region (VL) having CDRs with the following sequences: CDR1 - QDISKY (SEQ ID NO: 28);
  • This aspect of the invention may be formulated as use of an anti-CD22 antibody-drug conjugate in the manufacture of a medicament for the treatment of a B-cell malignancy in a subject, wherein the anti-CD22 antibody-drug conjugate is used as bridging therapy prior to treatment with anti-CD19 CAR-T cells, wherein the CAR comprises: a) a heavy chain variable region (VH) having CDRs with the following sequences: CDR1 - GVSLPDYG (SEQ ID NO: 25);
  • CDR3 - AKHYYYGGSYAMDY (SEQ ID NO: 27); and b) a light chain variable region (VL) having CDRs with the following sequences: CDR1 - QDISKY (SEQ ID NO: 28);
  • the method for treating a B-cell malignancy may comprise the following steps: i) administering the anti-CD22 antibody-drug conjugate to the patient after leukapheresis; ii) pre-conditioning the patient; and iii) administering anti CD- 19 CAR-T cells to the patient.
  • the method for treating a B-cell malignancy may comprise the following steps: i) leukapheresis of the patient to obtain a T cell composition for preparation of the anti-CD19 CAR-T cells; ii) administering the anti-CD22 antibody-drug conjugate to the patient; iii) pre-conditioning the patient; and iv) administering the anti CD-19 CAR-T cells to the patient.
  • the anti-CD19 CAR may be a CAR as described in the context of chimeric antigen receptors (CARs) in previous sections, and its definitions and embodiments apply equally to this aspect of the invention.
  • CARs chimeric antigen receptors
  • the anti-CD19 CAR may comprise: a) a heavy chain variable region (VH) having CDRs with the following sequences: CDR1 - GVSLPDYG (SEQ ID NO: 25);
  • CDR3 - AKHYYYGGSYAMDY (SEQ ID NO: 27); and b) a light chain variable region (VL) having CDRs with the following sequences: CDR1 - QDISKY (SEQ ID NO: 28);
  • the patient may be of Caucasian, Black, Latino or Hispanic, Asian or any other ethnicity.
  • the patient may be Latino or Hispanic.
  • the patient may have a complex karyotype.
  • Complex karyotype refers to cytogenetic risks of hematologic malignancies associated with a poor prognosis that are well known in the art.
  • the patient may have received at least one prior line of therapy.
  • the patient may have received at least two prior lines of therapy.
  • the patient may have received at least three prior lines of therapy.
  • the patient may have received at least four prior lines of therapy.
  • the patient may have received at least five prior lines of therapy.
  • the patient may have received at least six prior lines of therapy.
  • the at least one prior line of therapy may have been inotuzumab ozogamicin and/or blinatumomab.
  • the patient may have received an allogeneic hematopoietic stem cell transplant (allo- HSCT or allo-SCT).
  • allo- HSCT allogeneic hematopoietic stem cell transplant
  • the patient may present extramedullary disease at screening.
  • the patient may present > 20% blasts in the BM at screening.
  • the patient may present > 50% blasts in the BM at screening.
  • the patient may present > 75% blasts in the BM at screening.
  • the anti-CD22 antibody-drug conjugate may be administered at least 1 week before the administration of the lymphodepleting therapy.
  • the anti-CD22 antibody-drug conjugate may be administered at least 2 weeks before the administration of the lymphodepleting or pre-conditioning therapy.
  • the patient may receive a lymphodepleting pre-conditioning treatment before CD 19 CAR- T cell infusion.
  • the patient may be administered a preconditioning regimen comprising 120 mg/m 2 fludarabine (Flu) and 1000 mg/m 2 cyclophosphamide (Cy). This preconditioning regimen may be administered prior to CAR-T cell administration.
  • Fludarabine may be administered at 30 mg/m2 on Day -6, Day -5, Day -4, and Day -3 prior to being administered the first dose of CAR-T cells (i.e. Day 0). Fludarabine may be administered intravenously. Fludarabine may be administered over 30 min.
  • Cyclophosphamide may be administered at 500 mg/m 2 on Day -6, and Day -5 prior to being administered the first dose of CAR-T cells (i.e. Day 0). Cyclophosphamide may be administered intravenously. Cyclophosphamide may be administered over 30 min.
  • the population of CAR T cells specific for a B-cell malignancy may be autologous.
  • the anti-CD22 antibody-drug conjugate may be administered after leukapheresis.
  • the anti-CD22 antibody-drug conjugate may be selected from Inotuzumab ozogamicin (Besponsa), inotuzumab, and epratuzumab.
  • the anti-CD22 antibody-drug conjugate may be Inotuzumab ozogamicin.
  • the B-cell malignancy may be selected from the group consisting of acute lymphoblastic leukemia (ALL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Burkitt lymphoma, lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia or WM), cutaneous B-cell lymphoma (CBCL), diffuse large B-cell lymphoma (DLBCL), and anaplastic large cell lymphoma (ALCL).
  • ALL acute lymphoblastic leukemia
  • FL follicular lymphoma
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • MCL mantle cell lymphoma
  • MZL marginal zone lymphoma
  • Burkitt lymphoma lymphoplasmacytic lymphoma
  • Example 1 Generation of a CD19 CAR-T cell composition
  • CAT was chosen as a binding domain as it showed a substantially lower affinity to CD 19 (>40-fold) than FMC63 scFv, a binder used in already marketed CAR T-cell therapies
  • Lentiviral vectors were generated expressing a second-generation CD 19 CAR (SEQ ID NO: 51) (CD19CAT CAR described in W02016/139487, otherwise referred to herein as CAT CAR or AUTO1) which comprises an anti-CD19 antigen-binding domain, a CD8 stalk spacer and transmembrane domain, and a compound 4-1BB-CD3 endodomain, under the control of a PGK promoter (pCCL.PGK.aCD19cat-CD8STK-41BBZ. See Figure 1 A- B and Figure 14.
  • AUTO1 was generated by ex vivo transduction of activated peripheral blood mononuclear cells (PBMCs) using an engineered HIV derived lentiviral vector containing the CD 19 CAR expression cassette.
  • PBMCs peripheral blood mononuclear cells
  • the lentiviral vector was produced under Good Manufacturing Practice (GMP) conditions by four-plasmid co-transfection of HEK293T cells and subsequent harvest and purification of the culture supernatant.
  • GMP Good Manufacturing Practice
  • cells from the leukapheresate starting material were stimulated with mitogenic ligands and cytokines.
  • cells were transduced with the lentiviral vector.
  • Post-transduction cells were expanded (drug substance) to produce the desired dose.
  • the cells were then washed and formulated with a phosphate buffered saline (PBS) / ethylenediaminetetraacetic acid (EDTA) / human serum albumin (HSA) / dimethyl sulfoxide (DMSO) buffer and filled into final packaging and cryopreserved (drug product).
  • PBS phosphate buffered saline
  • EDTA ethylenediaminetetraacetic acid
  • HSA human serum albumin
  • DMSO dimethyl sulfoxide
  • the AUTO1 product consisted of transduced and non-transduced T cells.
  • the dose given to patients was expressed as the total number of CD 19 CAR-positive T cells (the active substance).
  • Binding kinetics of the CAR binding domains CAT scFv (used in AUTO1) and FMC63 scFv (used in axicabtagene ciloleucel and tisagenlecleucel) with recombinant CD 19 were investigated using surface plasmon resonance.
  • Equilibrium dissociation constants (KD) of 14.4 nM for CAT and 0.328 nM for FMC63 were determined, when the data were fitted to a 1 : 1 Langmuir binding model.
  • Table 4 Summary of Binding Kinetics of the CAR Binding Domains CAT scFv and FMC63 scFv.
  • CAR chimeric antigen receptor
  • ka association constant
  • kd dissociation constant
  • KD affinity, equilibrium dissociation constant
  • scFv small chain variable fragment.
  • CD 19 (CAT) CAR T cell proliferation was greater than CD 19 (FMC63) CAR T cells when co-cultured with Raji and NALM-6 cells ( Figure 2).
  • the enhanced proliferation was not a result of increased IL-2 production suggesting an IL-2 independent mechanism.
  • CAT CD 19
  • FMC63 CD 19
  • Raji cells a Burkitt’s lymphoma cell line that expresses CD19
  • pro-inflammatory cytokines were analysed in the supernatant at 48 hours.
  • T cells transduced to express CD19 (CAT) CAR or CD19 (FMC63) CAR were incubated with CD 19-negative and CD 19 expressing targets ( Figure 4A and Figure 4B, respectively).
  • Cell killing was significantly greater for CD 19 (CAT) CAR T cells than for CD 19 (FMC63) CAR T cells, particularly at low effectortarget ratios.
  • NALM-6 non-obese diabetic/severe combined immunodeficiency/gamma
  • NSG mice are immunodeficient, lack mature T cells, B cells and natural killer cells, and are deficient in multiple cytokine signalling pathways. They permit the engraftment of a wide variety of primary human cells.
  • CD 19 (CAT) CAR T cells and CD 19 (FMC63) CAR T cells were assessed in the NALM-6 NSG-mouse xenograft model and compared. In control mice receiving non-transduced T cells, rapid, disseminated tumour infiltration was observed ( Figure 5). CD 19 (FMC63) CAR T cells slowed but did not prevent growth of the tumour. In contrast, equivalent numbers of CD 19 (CAT) CAR T cells resulted in tumour regression.
  • CD 19 (CAT) CAR T cells 1.1 x 10 8 to 9.3 x 10 7 photons/second/cm2/steradian
  • CD 19 (CAT) CAR enables transduced T cells to proliferate, secrete cytokines in response to CD 19-positive targets and specifically lyse CD 19-positive cell lines in vitro with greater cytotoxicity compared to CD 19 (FMC63) CAR T cells.
  • CD 19 (CAT) CAR T cells also showed better anti -tumour efficacy and engraftment versus CD 19 (FMC63) CAR T cells in an NSG NALM-6 mouse model of leukaemia.
  • CD 19 (CAT) CAR T cells can effectively eliminate CD19-expressing tumour cells with greater efficacy compared to CD 19 (FMC63) CAR T cells.
  • Non-clinical studies suggested that no off-target toxicity was anticipated.
  • BM bone marrow
  • CAR chimeric antigen receptor
  • CD cluster of differentiation.
  • the dosing schedule shown in Table 5 defines the day on which the first dose of CD 19 CAR-T cells is administered as Day 1 and the second dose as Day 10.
  • the number of days passed between the first dose and the second dose was 9 days ⁇ 2 days and there is no Day 0. Therefore, the time of administration of the first dose can be considered as Day 0 and the time of administration of the second dose can be considered as Day 9 ⁇ 2 days.
  • Phase lb Primary Cohort IA: Presence of >5% blasts in BM at screening;
  • Phase lb Exploratory Cohort IB: MRD-positive defined as > IE-4 and ⁇ 5% blasts in the BM at screening;
  • Phase IL Primary Cohort IIA Presence of >5% blasts in BM at screening
  • Phase IL Cohort IIB >2nd CR or CRi with MRD-positive defined as >lE-3 by central ClonoSEQ® NGS testing and ⁇ 5% blasts in the BM at screening;
  • Phase lb (Cohort IA and Cohort IB) and Phase II (Cohort IIA and Cohort IIB) B- ALL with isolated EM disease;
  • HIV Human Immunodeficiency Virus
  • HTLV-1 Human Immunodeficiency Virus
  • HTLV-2 Human Immunodeficiency Virus
  • Prior CD 19 targeted therapy other than blinatumomab. Patients who have experienced Grade 3 or higher neurotoxicity following blinatumomab.
  • ORR defined as proportion of patients achieving CR or CRi by central assessment.
  • Phase II - Response to AUT01 treatment measured as duration of remission (DOR) [Time Frame: Up to 24 months]
  • Phase II - Response to AUT01 measured as progression-free survival (PFS). [Time Frame: Up to 24 months]
  • IRRC Independent Response Review Committee
  • the ORR was achieved in 76% of infused patients, with 54.3% achieving CR and 21.3% achieving CRi ( Figure 10). Furthermore, 97% of responders with evaluable samples were MRD negative at 10' 4 level by flow cytometry.
  • the duration of remission was followed up (Figure 11). With a median follow-up of 9.5 months, 61% responders in ongoing remission without subsequent anti-cancer therapies. Response to AUTO1 treatment measured as the median of the duration of remission (DOR) was 14.1 months. The number of events was 18. Of note, 13% of responders who proceeded to stem cell transplant (SCT) while in remission were censored at the time of SCT.
  • SCT stem cell transplant
  • Figure 12 shows the analysis of ORR by patient subgroup.
  • the patient population includes high-risk subgroups, such as extramedullary disease (EMD) and high bone marrow (BM) blasts at pre-conditioning.
  • EMD extramedullary disease
  • BM bone marrow
  • AUC area under the curve
  • CV coefficient of variation
  • Geo geometric
  • PCR polymerase chain reaction
  • SE standard error.
  • Example 4 Pooled analysis of all r/r B-ALL patients treated with CD19 CAT CAR T- cell product (AUTO1) in the Phase Ib/II study
  • BM bone marrow
  • EMD extramedullary disease
  • SCT stem cell transplant
  • the data cut-off date is 13 th September 2023.
  • the results shown in Figure 17 demonstrated a robust and rapid manufacturing, despite variable and challenging starting material.
  • the starting material for manufacture - the patient pheresis - was of variable quality with many pheresis having low or very low T cell content, which is unsurprisingly given the complex treatment history and disease burden in these patients.
  • AUTO1 was released for 95% of patients, with a median time from vein-to- release of 22 days. Consistent manufacturing was observed, despite leukapheresis from patients with multiple lines of prior therapy (many with prior allogeneic SCT) and high leukemic burden. Despite this, the closed system manufacture resulted in highly consistent manufacture (e.g. see transduction efficiency and cell viability). Importantly median vein- to-release time was 22 days trending towards 20 days towards the end of the study.
  • the event free survival estimate (EFS) at 12-months was 50% across all patients ( Figure 20).
  • the median follow-up time was 16.6 months (range: 3.7-36.6 months). 17/99 (17%) responders proceeded to SCT while in remission.
  • AUC area under the curve
  • Cmax maximum concentration
  • CV coefficient of variation
  • d day
  • D day
  • Geo geometric
  • M month
  • PB peripheral blood
  • Tmax time to maximum concentration
  • Severe toxicity mostly limited to patients with high leukemic burden at lymphodepletion;
  • AUTO1 is effective treatment for R/R adult B-ALL, with better outcomes observed in patients with lower leukemic burden at lymphodepletion.
  • bridging therapy chemotherapy with or without INO or tyrosine kinase inhibitors [TKI], single-agent INO, single-agent TKI, steroids, or rituximab
  • Patients then underwent lymphodepletion (fludarabine, 4> ⁇ 30mg/m 2 ; cyclophosphamide, 2> ⁇ 500mg/m 2 ), followed by AUTO1 split dose infusions on Days 1 and 10 based on pre-lymphodepletion leukemic burden, to a target dose of 410* 10 6 CAR-T cells.
  • bridging therapy with INO with or without chemotherapy
  • bridging therapy without INO including chemotherapy, TKI, chemotherapy with TKI, steroids, or rituximab
  • no bridging therapy were described.
  • BM blast percentage at screening was numerically higher in patients who received bridging with INO vs bridging without INO vs no bridging therapy (73%, 34%, and 20%, respectively), and INO bridging led to an effective reduction of BM blasts at pre-conditioning (2%, 51%, and 30%, respectively).
  • the number of patients achieving complete response (CR) or CR with incomplete hematologic recovery (CRi) to AUTO1 was 15/18 (83%), 75/100 (75%), and 9/9 (100%) in patients who received bridging with INO vs bridging without INO vs no bridging therapy, respectively.
  • Table 16 shows data from the 94 patients treated with AUTO1 in Cohort A. Patients with a numerical higher blast % at screening used bridging with INO and these patients experienced a large decrease of blast % after INO bridging therapy.
  • INO-containing bridging therapies were effective in reducing disease burden and, despite higher baseline BM blast percentage, did not appear to have any negative efficacy impacts.
  • Example 5 To analyse the impact of bridging therapy with and without inotuzumab ozogamicin (INO) on clinical outcomes with AUTO1 in the Phase Ib/II study described in Examples 3 and 4. This Example describes results with a longer follow-up than Example 5.
  • INO inotuzumab ozogamicin
  • the clinical study is an open-label, multi-center, global, single-arm, phase Ib/II study evaluating the safety and efficacy of AUTO1 in patients aged >18 years with R/R B-ALL.
  • BT bridging therapy
  • Table 17 Baseline characteristics by type of bridging therapy (BT).
  • Allo-SCT allogeneic stem cell transplant
  • BM bone marrow
  • BT bridging therapy
  • INO inotuzumab ozogamicin
  • INO BT led to a notable reduction in BM blasts (BM blast %) at lymphodepletion while BT without INO or no BT did not (Figure 27).
  • INO BT also led to a greater reduction in extramedullary disease (EMD) status at lymphodepletion (38.9% to 33.3%) compared with BT without INO (20.0% to 19.0%), while there was no change for the no BT group (22.2%).
  • EMD extramedullary disease
  • EFS Median event- free survival
  • the 18-month EFS probability estimates (95% CI) were 57.4% (30.2-77.3), 34.4% (23.2-45.9), and 80.0% (20.4-96.9).
  • Rates of Grade >3 cytokine release syndrome (CRS) were 5.6%, 2.0%, and 0% (Table 18).
  • ICANS immune effector cell-associated neurotoxicity syndrome
  • Rates of Grade >3 hepatobiliary disorders were 5.6%, 6.0%, and 11.1% (Table 18).
  • Table 18 Summary of TEAEs by type of BT.
  • BT bridging therapy
  • CRS cytokine release syndrome
  • ICANS immune effector cell- associated neurotoxicity syndrome
  • INO inotuzumab ozogamicin
  • TEAE treatment- emergent adverse event
  • w/o without.
  • INO-containing BTs were effective in reducing BM disease prior to lymphodepletion and administration of AUTO1.
  • Example 7 AUTO1 for treating R/R B-ALL in a Phase Ib/II study: The Impact of Bridging Therapy on CAR T-cell expansion and persistence. Longer follow-up
  • AUC area under the curve
  • BT bridging therapy
  • CAR chimeric antigen receptor
  • Cmax maximal expansion of transgene/CAR positive T-cells
  • CV% coefficient of variation
  • INO inotuzumab ozogamicin
  • Tmax time to maximal expansion.

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Abstract

La présente invention concerne des procédés de sélection d'une thérapie de pontage pour un patient ayant une malignité des lymphocytes B qui est sur le point de recevoir un traitement avec des cellules CAR-T.
PCT/GB2025/050755 2024-04-09 2025-04-09 Procédé Pending WO2025215360A1 (fr)

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US7052906B1 (en) 1999-04-16 2006-05-30 Celltech R & D Limited Synthetic transmembrane components
WO2016102965A1 (fr) 2014-12-24 2016-06-30 Ucl Business Plc Cellule
WO2016139487A1 (fr) 2015-03-05 2016-09-09 Ucl Business Plc Récepteur d'antigène chimère (car) comprenant un domaine de liaison à cd19
US20180044417A1 (en) 2015-03-05 2018-02-15 Ucl Business Plc Chimeric Antigen Receptor (CAR) Comprising a CD19-Binding Domain

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