Clinical trials employing cancer vaccine combination therapies

在最近针对癌症的大型对照免疫疗法研究中，一个反复出现的发现是总生存期（OS）得到改善，但中位无进展生存期（PFS）没有改善。这为及时完成概念验证疗效研究提供了障碍。PFS的改善与最终OS改善的缺乏可能是由于给予免疫治疗与临床显着的免疫介导的肿瘤生长速度减慢之间的时间差。首个治疗性癌症疫苗的批准，使增强新型实验性治疗性疫苗与其他疗法的免疫效果的努力获得了更高的优先权。仔细的临床前研究强调了标准疗法的能力：a)以免疫相关的方式杀死细胞；b)改变存活细胞的表型，使它们更容易受到免疫介导的识别和杀死。这导致合理设计研究，将治疗性癌症疫苗与标准疗法结合起来。这些最近的临床前和临床研究表明，尽管采用标准疗法（如化疗），疫苗仍能产生免疫反应。这些联合研究为测试联合策略对更传统的2期终点（如PFS）的影响能力提供了一个平台。如果上述关于生长速率的假设是正确的，那么它表明，如果人们能够合理地将治疗性疫苗（与延迟效应相关）与标准疗法（与肿瘤体积早期但短暂的减少相关）结合起来，而不降低免疫反应，那么人们可能能够使用诸如PFS之类的事件来区分标准治疗方案和联合方案。两项正在进行的前列腺癌试验和一项乳腺癌研究的初步数据支持这一假设。前列腺癌试验表明，联合治疗可改善进展时间（TTP）的有Quadramet +/- PROSTVAC疫苗（2.1个月vs 3.9个月，n=32）和氟他胺+/- PROSTVAC疫苗（84天vs 161天，n=26）；乳腺癌试验比较了多西他赛+/- PANVAC疫苗与初步数据支持联合（2.9个月vs 8.0个月，n=21）。因此，合理设计的联合研究有可能显著加快概念验证疗效研究（二期）的疗效分析。这种方法可能特别适用于影响OS的可用治疗方法越来越多的肿瘤，以及在病程较早的生存随访较远的肿瘤。对正在进行的研究的最终分析可能最终有助于确定这种方法的效用。单克隆抗体已与疫苗联合用于治疗各种类型的肿瘤。在前列腺癌中，已对人细胞毒性t淋巴细胞抗原-4 （CTLA-4）单克隆抗体与疫苗联合进行了测试。CTLA-4是一种t细胞表面糖蛋白，在t细胞激活后上调以抑制免疫反应。它的主要功能是通过调节机体的免疫活动来预防自身免疫。T细胞在其细胞表面表达两种拮抗受体CD28和CTLA-4。两者都与apc表面相同的配体或共刺激分子（B7.1和B7.2，也称为CD80和CD86）结合。这些共刺激分子与CD28结合激活T细胞，而与CTLA-4相互作用抑制T细胞刺激。用中和抗体阻断CTLA-4已被证明可以维持和增强免疫反应。ipilimumab（一种抗ctla -4单克隆抗体）和GVAX在16例转移性前列腺癌患者中的I期研究表明，免疫相关不良事件与免疫反应之间存在相关性。另一项即将公布结果的I期试验，将ipilimumab和PSA-TRICOM疫苗联合用于转移性前列腺癌患者。一项中期分析显示，在11名患者中，10 mg/kg剂量的PSA倍增时间显著增加（从研究前的2.6个月增加到研究后的11.4个月，p = 0.01）。Gulley博士及其在NCI肿瘤免疫学和生物学实验室（LTIB）和癌症研究中心（CCR）医学肿瘤学分部（MOB）的同事在NCI临床中心正在进行或最近于2010 -11财年完成了以下联合疫苗临床试验。一项随机II期试验，在男性雄激素不敏感的非转移性（D0.5）前列腺癌、MOB、CCR、NCI患者中，联合疫苗治疗PROSTVAC/TRICOM和氟他胺与氟他胺单独治疗。这是首个在D0.5前列腺癌患者中结合疫苗和二线激素治疗的随机试验。一项基于PSA的疫苗和抗ctla -4抗体在转移性雄激素非依赖型前列腺癌患者中的I期试验该试验是首个结合抗ctla -4抗体和基于载体的前列腺癌疫苗的临床试验。本研究的手稿已提交发表。153Sm-EDTMP （Quadramet）联合或不联合PSA/TRICOM疫苗在男性雄激素不敏感转移性前列腺癌、MOB、CCR、NCI患者中的随机2.5期研究该试验是首个将疫苗与寻骨放射性核素结合用于雄激素非依赖性前列腺癌患者的临床试验。一项多西他赛单独或联合PANVAC-V（牛痘）和PANVAC-F（鸡痘）治疗转移性乳腺癌的随机II期试验研究。Mob, ccr, nci。这是首个将疫苗与多西他赛联合应用于乳腺癌患者群体的随机试验。与外部癌症中心的合作试验：在CEA表达癌患者中连续接种水痘-CEA(6D)-TRICOM和牛痘-CEA(6D)-TRICOM，联合GM-CSF和干扰素- α - 2b的I期研究。（俄亥俄州立综合癌症中心）转移性去势抵抗性前列腺癌患者接种疫苗后进行标准化疗与标准化疗的II期研究。（东部肿瘤合作组）。我们目前正在与RTOG讨论一个多中心合作小组研究Alpharadin和PSA-TRICOM对骨转移患者的治疗，该研究基于Quadramet有或没有疫苗研究的初步结果。

One recurrent finding in recent large controlled immunotherapies studies for cancer has been improved overall survival (OS) without an improvement in median progression free survival (PFS). This provides a hurdle for timely completion of proof-of-concept efficacy studies. This lack of improvement in PFS with eventual demonstration of improved OS may be due to the time-lag between administering the immunotherapy and a clinically significant immune-mediated slowing of the growth-rate of the tumor. Approval of the first therapeutic cancer vaccine has conferred higher priority on the effort to augment the immunologic impact of novel experimental therapeutic vaccines with other therapies. Careful preclinical studies have highlighted the ability of standard therapies to a) kill cells in an immunologically relevant manner and b) change the phenotype of surviving cells to make them more susceptible to immune mediated recognition and killing. This has led to rationally designed studies combining therapeutic cancer vaccines with standard therapies. These recent preclinical and clinical studies have demonstrated the ability to mount immune responses to vaccine despite standard therapies (e.g., chemotherapy). These combination studies provide a platform for testing the ability of combination strategies to impact more traditional phase 2 endpoints such as PFS. If the above hypothesis on growth rate is correct, it suggests that if one could rationally combine therapeutic vaccines (associated with delayed effects) with standard therapies (associated with early but transient decrease in tumor volume) in a manner that doesnt decrease the immune responses, then one might be able to use events such as PFS to discriminate between standard of care and combination regimens. Vaccine plus standard of care therapies Preliminary data from 2 ongoing prostate cancer trials and a breast cancer study support this hypothesis. The prostate cancer trials suggesting an improvement in time to progression (TTP) for the combination are Quadramet +/- PROSTVAC vaccine (2.1 vs 3.9 months, n=32) and flutamide +/- PROSTVAC vaccine (84 vs 161 days, n=26); and the breast cancer trial compares docetaxel +/- PANVAC vaccine with preliminary data favoring the combination (2.9 vs 8.0 months, n=21). Thus rationally designed combination studies have the potential to significantly speed up efficacy analysis in proof-of-concept efficacy studies (phase 2). This approach may be especially useful in tumors with an increasing number of therapies available that impact OS, and earlier in the disease course when follow-up for survival is more remote. Final analysis of ongoing studies may ultimately help determine the utility of this approach. Vaccine plus experimental therapies Monoclonal antibodies have been combined with vaccines for the treatment of various tumor types. In prostate cancer, a human cytotoxic T-lymphocyte antigen-4 (CTLA-4) mono-clonal antibody has been tested in combination with vaccines. CTLA-4 is a T-cell surface glycoprotein that is upregulated following T-cell activation to inhibit the immune response. Its main function is to prevent autoimmunity by regulating the bodys immune activity. T cells express two counteracting receptors on their cell surface CD28 and CTLA-4. Both bind to the same ligands or costimulatory molecules on the surface of APCs (B7.1 and B7.2, also known as CD80 and CD86). Binding of these costimulatory molecules to CD28 activates T cells, while interacting with CTLA-4 inhibits T-cell stimulation. Blocking CTLA-4 with a neutralizing antibody has been shown to sustain and potentiate immune responses. A Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, and GVAX in 16 patients with metastatic prostate cancer suggested a correlation between immune-related adverse events and immune response . Another Phase I trial, with results soon to be published, combined ipilimumab and PSA-TRICOM vaccine in metastatic prostate cancer patients. An interim analysis demonstrated a significant increase in PSA doubling time (from 2.6 months pre-study to 11.4 months post-study; p = 0.01) in 11 patients at a dose of 10 mg/kg. Dr. Gulley and his colleagues in the Laboratory of Tumor Immunology and Biology (LTIB) and the Medical Oncology Branch (MOB), Center for Cancer Research (CCR), NCI, have ongoing or recently completed in FY10-11 the following combination vaccine clinical trials at the NCI Clinical Center. A randomized Phase II trial combining vaccine therapy with PROSTVAC/TRICOM and Flutamide, vs. Flutamide alone in men with androgen insensitive non metastatic (D0.5) prostate cancer, MOB, CCR, NCI. This was the first randomized trial to combine a vaccine with this second-line hormone therapy in D0.5 prostate cancer patients. A phase I Trial of a PSA based vaccine and an anti-CTLA-4 antibody in patients with Metastatic Androgen Independent Prostate Cancer. This trial is the first clinical trial to combine an anti-CTLA-4 antibody and a vector-based vaccine in prostate cancer. A manuscript on this study has been submitted for publication. A randomized phase 2.5 study of 153Sm-EDTMP (Quadramet) with or without a PSA/TRICOM vaccine in men with androgen-insensitive metastatic prostate cancer, MOB, CCR, NCI. This trial is the first clinical trial to combine vaccine with a bone seeking radionuclide for use in patients with androgen independent prostate cancer. A randomized Pilot Phase II study of Docetaxel alone or in combination with PANVAC-V (vaccinia) and PANVAC-F (fowlpox) in adults with metastatic breast cancer. MOB, CCR, NCI. This is the first randomized trial to combine vaccine with Docetaxel in this breast cancer patient population. Collaborative Trials with Extramural Cancer Centers A Phase I study of sequential vaccinations with fowlpox-CEA(6D)-TRICOM and vaccinia-CEA(6D)-TRICOM, in combination with GM-CSF and Interferon-Alfa-2B in patients with CEA expressing carcinomas. (Ohio State Comprehensive Cancer Center) A phase II study of vaccine followed by standard chemotherapy vs. standard chemotherapy in patients with metastatic castration-resistant prostate cancer. (Eastern Cooperative Oncology Group). We are currently in discussions with the RTOG on a multi-center cooperative group study of Alpharadin and PSA-TRICOM for patients with bone metastasis based on the preliminary results of the Quadramet with or without vaccine study.