Elucidating immunologic mechanisms of PROSTVAC cancer immunotherapy.
Elucidating immunologic mechanisms of PROSTVAC cancer immunotherapy.
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DOI：
10.1186/s40425-014-0034-0
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发表时间：
2014
影响因子：
10.9
通讯作者：
Franzusoff A
中科院分区：
文献类型：
--
作者：
Mandl SJ;Rountree RB;Dela Cruz TB;Foy SP;Cote JJ;Gordon EJ;Trent E;Delcayre A;Franzusoff A
PROSTVAC®是一种目前正在研究的用于治疗转移性去势抵抗性前列腺癌（mCRPC）的主动免疫疗法，由两种不同的痘病毒载体组成，以激发针对前列腺特异性抗原（PSA）作为靶肿瘤抗原的生产免疫应答。一项PROSTVAC免疫疗法的2期研究显示，中位总生存期显著提高了8.5个月，目前正在一项全球3期研究中进行验证（PROSPECT; NCT01322490）。本研究探索临床前模型，研究PROSTVAC免疫治疗抗肿瘤疗效的作用机制和免疫特征，目的是确定临床获益的潜在免疫相关因素。研究prostvac诱导的BALB/c雄性小鼠的免疫应答和抗肿瘤效果。通过干扰素γ (IFNγ) ELISPOT、细胞毒脱颗粒、多细胞因子细胞内染色和体内T细胞耗损来表征诱导T细胞反应的功能。采用流式细胞术对肿瘤浸润淋巴细胞（til）进行表型分析。与同源的单载体方案相比，两种PROSTVAC载体的异源启动-增强方案显著提高了活化的psa特异性CD4和CD8 T细胞反应的大小和质量。通过激活标记物的表达、多种细胞因子的产生和细胞毒性T细胞活性的增强，证明prostvac激活的CD4和CD8 T细胞具有高度的功能。重要的是，PROSTVAC免疫疗法在可移植前列腺癌小鼠模型中产生了显著的抗肿瘤效果。抗原扩散发生在prostvac治疗的动物中，这些动物排斥了表达psa的肿瘤，随后排斥了psa阴性的肿瘤。体内CD4和CD8的消耗表明，这两种T细胞亚群都有助于抗肿瘤疗效。TILs的表征表明，PROSTVAC免疫治疗大大增加了肿瘤内活化效应T细胞与调节性T细胞的比例。PROSTVAC免疫疗法通过免疫介导的抗原扩散激活广泛的、高功能的T细胞对PSA和内源性肿瘤抗原的免疫。这些临床前结果进一步阐明了PROSTVAC免疫治疗的作用模式及其与PROSTVAC二期研究中观察到的延长总生存期的潜在因果关系。该临床验证正在PROSPECT iii期临床研究中进行。本文的在线版本（doi:10.1186/s40425-014-0034-0）包含补充材料，仅供授权用户使用。
PROSTVAC®, an active immunotherapy currently studied for the treatment of metastatic castration-resistant prostate cancer (mCRPC), consists of a heterologous prime-boost regimen with two different poxvirus-based vectors to provoke productive immune responses against prostate specific antigen (PSA) as the target tumor antigen. A Phase 2 study of PROSTVAC immunotherapy showed significantly improved median overall survival by 8.5 months and is currently being validated in a global Phase 3 study (PROSPECT; NCT01322490). Here, preclinical models were explored to investigate the mechanism of action and immune signatures of anti-tumor efficacy with PROSTVAC immunotherapy with the goal to identify potential immune correlates of clinical benefit. PROSTVAC-induced immune responses and anti-tumor efficacy were studied in male BALB/c mice. Functionality of the induced T cell response was characterized by interferon-gamma (IFNγ) ELISPOT, cytotoxic degranulation, multi-cytokine intracellular staining, and in vivo T cell depletion. Tumor infiltrating lymphocytes (TILs) were evaluated phenotypically by flow cytometry. The heterologous prime-boost regimen of the two PROSTVAC vectors significantly enhanced the magnitude and quality of activated PSA-specific CD4 and CD8 T cell responses compared to homologous, single vector regimens. PROSTVAC-activated CD4 and CD8 T cells were highly functional as evidenced by expression of activation markers, production of multiple cytokines, and amplified cytotoxic T cell activity. Importantly, PROSTVAC immunotherapy resulted in significant anti-tumor efficacy in a transplantable prostate cancer mouse model. Antigen-spreading occurred in PROSTVAC-treated animals that rejected PSA-expressing tumors, as shown by subsequent rejection of PSA-negative tumors. In vivo CD4 and CD8 depletion revealed that both T cell subsets contributed to anti-tumor efficacy. Characterization of TILs demonstrated that PROSTVAC immunotherapy greatly increased the intra-tumoral ratio of activated effector to regulatory T cells. PROSTVAC immunotherapy activates broad, highly functional T cell immunity to PSA and to endogenous tumor antigens via immune-mediated antigen spreading. These preclinical results further elucidate the mode of action of PROSTVAC immunotherapy and its potential causal relationship to extended overall survival as observed in the PROSTVAC Phase 2 study. The clinical validation is ongoing in the PROSPECT Phase 3 clinical study. The online version of this article (doi:10.1186/s40425-014-0034-0) contains supplementary material, which is available to authorized users.