Combination therapies involving novel cancer vaccines

涉及新型癌症疫苗的联合疗法

基本信息

批准号：
8763430
负责人：
Ravi Madan
金额：
$ 12.58万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8763430
关键词：
ARI brand of 153Sm-EDTMP Androgens CCR Cancer Patient Cancer Vaccines Castration Cell Death Cells Clinical Clinical Research Clinical Trials Collaborations Colorectal Cancer Combined Modality Therapy Combined Vaccines Data Disease Event Flutamide Growth Human Immune Immune response Immunologics Immunotherapy Investigational Therapies Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of prostate Mediating Patients Pharmaceutical Preparations Phase Phase II Clinical Trials Phenotype Progression-Free Survivals Radiation Radiation therapy Radiopharmaceuticals Randomized Recombinant Vaccines Recombinants Recurrence Regimen Research Design Speed Testing Therapeutic Time Tumor Volume Vaccine Therapy Vaccines base castration resistant prostate cancer cell killing chemotherapy clinically significant cytokine design docetaxel follow-up high risk hormone therapy immunogenic improved inhibitor/antagonist killings malignant breast neoplasm men novel phase 2 study pre-clinical preclinical study randomized trial response standard of care therapeutic vaccine trial comparing tumor vaccine efficacy

项目摘要

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 (immunogenic cell death) and b) change the phenotype of surviving cells to make them more susceptible to immune mediated recognition and killing (immunogenic cell modulation). 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 (52 vs 107 days, n=37) and flutamide +/- PROSTVAC vaccine (108 vs 192 days, n=41); and the breast cancer trial compares docetaxel +/- PANVAC vaccine with preliminary data favoring the combination (120 vs 192 days, n=48). 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. Current Trials Evaluating Vaccine Combination Strategies within the project include: 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. Combining a vaccine targeting muc-1 (l-BLP 25) and combining that with standard radiation and hormonal therapy for high risk prostate cancer. This is a broad collaboration involving MOB, LTIB, UOB, ROB, and MIP. The primary endpoint of this trial will evaluate immunologic response to this vaccine combination. Additional combination trials are being planned using PSA-TRICOM with emerging hormonal therapies and radiopharmaceuticals in prostate cancer. Enzalutamide +/- PROSTVAC is currently being evaluated in 2 clinical trials based on preclinical data which suggest these therapies may have synergistic immune effects. One trial is in non-metastatic castration sensitive prostate cancer and the other is in metastatic castration resistant prostate cancer. Both of these trials will investigate how vaccine can potentially alter the growth rates in patients treated with enzalutamide and how such changes could potentially enhance clinical benefit for patients.

最近针对癌症的大型对照免疫疗法研究中反复出现的一项发现是总生存期 (OS) 得到改善，而中位无进展生存期 (PFS) 却没有改善。这为及时完成概念验证功效研究提供了障碍。 PFS 缺乏改善，但最终证明 OS 有所改善，可能是由于免疫治疗与临床上显着的免疫介导的肿瘤生长速度减慢之间存在时间滞后。第一个治疗性癌症疫苗的批准赋予了我们更加优先的努力，以增强新型实验性治疗性疫苗与其他疗法的免疫学影响。仔细的临床前研究强调了标准疗法的能力：a）以免疫相关方式杀死细胞（免疫原性细胞死亡）和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（免疫原性细胞调节）。这导致了将治疗性癌症疫苗与标准疗法相结合的合理设计的研究。这些最近的临床前和临床研究表明，尽管采用标准疗法（例如化疗），疫苗仍能够增强免疫反应。这些联合研究提供了一个平台，用于测试联合策略影响更传统的 2 期终点（例如 PFS）的能力。如果上述关于生长速度的假设是正确的，则表明如果人们能够以一种不降低免疫反应的方式合理地将治疗性疫苗（与延迟效应相关）与标准疗法（与肿瘤体积的早期但短暂的减少相关）结合起来，那么人们也许能够利用 PFS 等事件来区分标准护理和联合治疗方案。疫苗加标准护理疗法来自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，Quadramet +/- PROSTVAC 疫苗（52 天与 107 天，n=37）和氟他胺 +/- PROSTVAC 疫苗（108 天与 192 天，n=41）联合用药可改善疾病进展时间 (TTP) ）；乳腺癌试验将多西紫杉醇 +/- PANVAC 疫苗与支持联合用药的初步数据进行了比较（120 天与 192 天，n=48）。因此，合理设计的组合研究有可能显着加快概念验证功效研究（第二阶段）中的功效分析。这种方法可能对影响 OS 的可用疗法越来越多的肿瘤特别有用，并且在病程早期（此时生存随访时间更遥远）尤其有用。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实用性。目前评估该项目内疫苗组合策略的试验包括：一项随机 II 期试验，将疫苗疗法与 PROSTVAC/TRICOM 和氟他胺相结合，与单独使用氟他胺治疗雄激素不敏感的非转移性 (D0.5) 前列腺癌、MOB、CCR、NCI 男性患者进行比较。这是第一个在 D0.5 前列腺癌患者中将疫苗与二线激素疗法相结合的随机试验。结合针对 muc-1 (l-BLP 25) 的疫苗，并将其与标准放射和激素疗法相结合，治疗高风险前列腺癌。这是一项涉及 MOB、LTIB、UOB、ROB 和 MIP 的广泛合作。该试验的主要终点将评估对该疫苗组合的免疫反应。正在计划使用 PSA-TRICOM 与新兴激素疗法和放射性药物治疗前列腺癌进行更多联合试验。 Enzalutamide +/- PROSTVAC 目前正在 2 项基于临床前数据的临床试验中进行评估，这些数据表明这些疗法可能具有协同免疫作用。一项试验针对非转移性去势敏感型前列腺癌，另一项试验针对转移性去势抵抗性前列腺癌。这两项试验将研究疫苗如何可能改变接受恩杂鲁胺治疗的患者的生长速度，以及这些变化如何可能提高患者的临床获益。