Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients
Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients
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DOI：
10.1073/pnas.0712237105
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发表时间：
2008-02-26
影响因子：
11.1
通讯作者：
Dranoff, Glenn
中科院分区：
文献类型：
--
作者：
Hodi, F. Stephen;Butler, Marcus;Dranoff, Glenn
细胞毒性T淋巴细胞相关抗原4（CTLA-4）作为内源性和疫苗诱导的抗肿瘤免疫的负调节剂发挥作用。向晚期癌症患者施用全人抗CTLA-4阻断性单克隆抗体增加了一些受试者中免疫介导的肿瘤破坏。尽管如此，有反应的患者也经常表现出严重的炎症病理，这增加了CTLA-4阻断的治疗和毒性作用可能相关的可能性。在这里，我们表明，在大多数转移性黑色素瘤患者中，用经辐照的、经工程改造以分泌GM-CSF（GVAX）的自体肿瘤细胞接种疫苗后定期输注抗CTLA-4抗体产生临床上有意义的抗肿瘤免疫，而没有3级或4级毒性。这种序贯免疫疗法在晚期卵巢癌患者中的应用还表明，肿瘤破坏和严重的炎症病理可能是分离的，尽管需要进一步改进以增加临床反应并最大限度地减少该人群的毒性。治疗诱导的肿瘤坏死程度与治疗后活检组织中肿瘤内CD 8（+）效应T细胞与FoxP 3（+）调节T细胞（T细胞）比率的自然对数呈线性相关。总之，这些发现有助于澄清CTLA-4抗体阻断在先前接种疫苗的患者中的免疫学和临床效果，并提高了选择性靶向抗肿瘤TcB可能构成联合治疗的补充策略的可能性。
Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) functions as a negative regulator of endogenous and vaccine-induced antitumor immunity. The administration of fully human anti-CTLA-4 blocking monoclonal antibodies to advanced-cancer patients increases immune-mediated tumor destruction in some subjects. Nonetheless, patients that respond also frequently manifest serious inflammatory pathologies, raising the possibility that the therapeutic and toxic effects of CTLA-4 blockade might be linked. Here we show that periodic infusions of anti-CTLA-4 antibodies after vaccination with irradiated, autologous tumor cells engineered to secrete GM-CSF (GVAX) generate clinically meaningful antitumor immunity without grade 3 or 4 toxicity in a majority of metastatic melanoma patients. The application of this sequential immunotherapy to advanced ovarian carcinoma patients also revealed that tumor destruction and severe inflammatory pathology could be dissociated, although further refinements are required to increase clinical responses and to minimize toxicity in this population. The extent of therapy-induced tumor necrosis was linearly related to the natural logarithm of the ratio of intratumoral CD8(+) effector T cells to FoxP3(+) regulatory T cells (Tregs) in posttreatment biopsies. Together, these findings help clarify the immunologic and clinical effects of CTLA-4 antibody blockade in previously vaccinated patients and raise the possibility that selective targeting of antitumor Tregs may constitute a complementary strategy for combination therapy.