TW201909915A - 治療癌症的方法 - Google Patents
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Abstract
揭露一種用於在一有需要之個體中治療癌症的方法，包含對該個體投予一抗PD-1藥劑，其與一種或多種抗癌藥劑組合投予，其中該抗PD-1藥劑與該一種或多種抗癌藥劑每一者係以單獨投予對治療癌症無效的量投予，以提供對治療癌症的不可預期的協同作用。
Description
本發明係關於一種用於治療癌症的方法。
以程序性細胞死亡 1(programmed cell death，PD-1)受體與其配體為標的的抗體已在包括泌尿上皮細胞癌(urothelial carcinoma，UC)等多種腫瘤中顯示其抗腫瘤能力。這些抗體對於器官移植患者的療效與安全性因為移植物排斥作用的風險而缺乏研究。
本發明提供一種用於在一有需要之個體中治療癌症的方法，包含對該個體投予一抗PD-1藥劑，其與一種或多種抗癌藥劑組合投予。
在本發明的部分具體實施例中，該抗PD-1藥劑為一抗PD-1抗體。在一具體實施例中，該抗PD-1抗體為吉舒達（pembrolizumab）。
在本發明的部分具體實施例中，該一種或多種抗癌藥劑包含癌思停（bevacizumab）、順鉑（cisplatin）與健擇（gemcitabine）。
根據本發明的部分具體實施例，該抗PD-1藥劑與該一種或多種抗癌藥劑每一者係以會產生治療癌症的協同作用之量投予。
在本發明的部分具體實施例中，該癌症為泌尿上皮細胞癌。
在本發明的部分具體實施例中，該個體為接受異體移植者。根據本發明的部分具體實施例，該抗PD-1藥劑與該一種或多種抗癌藥劑係以不會造成異體移植排斥作用的量投予。
應理解的是，前面的一般性描述與下面的詳細描述均僅為例示性及解釋性的，而不是對本發明的限制。
本發明提供一種用於在一有需要之個體中治療癌症的方法，包含對該個體投予一抗PD-1藥劑，其與一種或多種抗癌藥劑組合投予。
在本發明的部分具體實施例中，該抗PD-1藥劑為抗PD-1抗體。在一具體實施例中，該抗PD-1抗體為吉舒達。
在本發明的部分具體實施例中，該一種或多種抗癌藥劑包含癌思停、順鉑及健擇。
根據本發明的部分具體實施例，該抗PD-1藥劑與該一種或多種抗癌藥劑每一者係以會產生治療癌症的協同作用之量投予。
在本發明的部分具體實施例中，該癌症為泌尿上皮細胞癌。
在本發明的部分具體實施例中，該個體為接受異體移植者。根據本發明的部分具體實施例，該抗PD-1藥劑與該一種或多種抗癌藥劑係以不會造成異體移植排斥作用的量投予。
藉由以下實例進一步說明本發明，這些實例是為了說明而非限制的目的而提供。
實例
實例1：在不改變免疫抑制劑的劑量下，合併抗PD-1免疫療法可使腫瘤退行與保持移植體功能
一名患有末期腎臟病之61歲婦人於2008年四月進行死體腎臟移植。其患有糖尿病與高血壓等重大疾病。移植手術後其移植體在免疫抑制藥劑普賴蘇濃（prednisolone）、普樂可復（tacrolimus）與山喜多（mycophenolate mofetil）作用下維持穩定狀態。2009年六月中斷普賴蘇濃給藥。
她在2013年五月進行左側腎輸尿管切除與膀胱袖口切除後，被診斷出在左側輸尿管下三分之一處罹患UC。在2013年九月至2016年三月間，她因復發性膀胱癌接受了多次的經尿道膀胱腫瘤切除術，並自膀胱內灌注泛艾黴素（pharmarubicin）、排多癌注射劑（mitomycin C）與卡介苗（bacillus Calmette-Guerin）。2016年七月，她的病歷上記載排尿困難及陰道小量出血。正子電腦斷層造影與子宮頸活檢顯示復發性UC侵入移植的腎盂、膀胱、子宮頸及陰道（圖1
，(A)）。
2016年八月她接受了靜脈注射一抗PD-1單株抗體（吉舒達[1 mg/kg] ）與抗癌藥劑（癌思停[4 mg/kg]、順鉑[50 mg/m2
]及健擇[500 mg/m2
] ）。4個療程後，於2016年十月的正子電腦斷層造影顯示了顯著的腫瘤退行（圖1
，(B)）。2017年三月，正子電腦斷層造影證實11個療程後仍有持續性部分有效反應。在抗PD-1免疫療法治療後，以固定山喜多劑量（1 g/天），以及緩慢地自9 g/天增加至10 g/天，使血液中普樂可復濃度維持在5至10 ng/mL的治療下，移植體維持穩定的功能（圖1
，(C)）。該婦人出現因免疫引起的斑性丘狀發疹，但在抗組織胺治療下可完全消除。
以免疫檢察點抑制劑對抗惡性細胞與表現外來抗原的細胞（如異體移植） 促使的免疫細胞活化，已知與細胞及抗體介導排斥作用有關[2，3]。現有文獻中，除了患有轉移性十二指腸腺癌的腎臟移植患者外，已廣泛地報導抗PD-1藥劑治療後引發異體移植排斥作用。在保疾伏（nivolumab）治療後逐漸減少康速龍錠（Prednisolone）劑量，以及以斥消靈錠（sirolimus）取代以普樂可復治療，可維持異種移植體的功能與使腫瘤退行[4]。本發明所載之患者，在不改變免疫抑制劑的劑量下，合併使用抗PD-1藥劑與抗癌藥劑可順利地維持異體移植體的功能與降低腫瘤負荷。近來研究結果顯示化學療法可透過消除免疫抑制細胞（例如骨髓來源抑制細胞或調節T細胞），與健擇或鉑類藥物一起使用達到增強抗癌療效[5]。此外，抗血管新生劑可以藉由使腫瘤新生血管正常化提升內源的免疫抗腫瘤反應[5]。因此，結合抗PD-1藥劑與抗癌藥劑可產生良好的療效且不會增加免疫引起的移植排斥作用。
本領域中的通常知識者將理解，可以對上述具體實施例進行改變而不脫離其廣泛的發明構思。因此，應當理解，本發明不限於所揭露的特定具體實施例，而是旨在涵蓋由所附的申請專利範圍所界定的本發明的精神及範圍內的修改。
參考文獻 1. Bellmunt J, de Wit R, Vaughn DJ et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017; 376: 1015-1026. 2. Lipson EJ, Bagnasco SM, Moore J, Jr. et al. Tumor Regression and Allograft Rejection after Administration of Anti-PD-1. N Engl J Med 2016; 374: 896-898. 3. Boils CL, Aljadir DN, Cantafio AW. Use of the PD-1 Pathway Inhibitor Nivolumab in a Renal Transplant Patient With Malignancy. Am J Transplant 2016; 16: 2496-2497. 4. Barnett R, Barta VS, Jhaveri KD. Preserved Renal-Allograft Function and the PD-1 Pathway Inhibitor Nivolumab. N Engl J Med 2017; 376: 191-192. 5. Apetoh L, Ladoire S, Coukos G, Ghiringhelli F. Combining immunotherapy and anticancer agents: the right path to achieve cancer cure? Ann Oncol 2015; 26: 1813-1823.
當結合圖式閱讀時，將更佳地理解前述發明內容以及以下對本發明的詳細描述。為了說明本發明的目的，在圖式中顯示目前較佳的具體實施例。
圖式中：
圖1顯示治療前後的正子電腦斷層造影、隨時間的血清肌酸酐與普樂可復（tacrolimus；FK506）濃度以及尿蛋白/肌酸酐比值。 (A) 在治療開始前，移植的腎盂、膀胱、子宮頸及陰道出現代謝亢進。(B) 治療3個月後，代謝亢進顯著的消除。(C) 穩定的血清肌酸酐與普樂可復（FK506）濃度，以及尿蛋白/肌酸酐比值。
Claims (11)
- 一種用於在一有需要之個體中治療癌症的方法，包含對該個體投予一抗PD-1藥劑，其與一種或多種抗癌藥劑組合投予，其中該抗PD-1藥劑與該一種或多種抗癌藥劑每一者係以單獨投予對治療癌症無效的量投予，以提供對治療癌症的不可預期的協同作用。
- 如請求項1之方法，其中該抗PD-1藥劑為一抗PD-1抗體。
- 如請求項2之方法，其中該抗PD-1抗體為吉舒達（pembrolizumab）。
- 如請求項1之方法，其中該一種或多種抗癌藥劑包含癌思停（bevacizumab）、順鉑（cisplatin）及健擇（gemcitabine）。
- 如請求項1之方法，其中，針對一人類個體，該抗PD-1藥劑係以低於2 mg/kg的量投予。
- 如請求項4之方法，其中，針對一人類個體，癌思停係以低於10 mg/kg的量投予。
- 如請求項4之方法，其中，針對一人類個體，順鉑係以低於100 mg/m2 的量投予。
- 如請求項4之方法，其中，針對一人類個體，健擇係以低於1000 mg/m2 的量投予。
- 如請求項1至8中任一項之方法，其中該癌症為泌尿上皮細胞癌(urothelial carcinoma)。
- 如請求項1至9中任一項之方法，其中該個體為接受異體移植者。
- 如請求項10之方法，其中該抗PD-1藥劑與該一種或多種抗癌藥劑係以不會造成異體移植排斥作用的量投予。
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