Clinical trials employing cancer vaccine combination therapies

采用癌症疫苗联合疗法的临床试验

• 批准号: 8763277
• 负责人: James L. Gulley
• 金额: $ 76.72万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 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/8763277
• 关键词: ARI brand of 153Sm-EDTMP; Adverse event; American Society of Clinical Oncology; Androgen Receptor; Androgens; Antibodies; Autoimmunity; Binding; CD28 gene; CD80 gene; Cancer Center; Cancer Patient; Cancer Vaccines; Carcinoma; Cell Death; Cell surface; Cells; Clinical; Clinical Research; Clinical Trials; Colorectal Cancer; Combined Modality Therapy; Combined Vaccines; Comprehensive Cancer Center; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Disease; Event; External Beam Radiation Therapy; Extramural Activities; Flutamide; Fowlpox; Fowlpox-CEA(D609)-MUC1(L93)-Tricom Vaccine; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Human; Immune; Immune response; Immunologics; Immunotherapy; Interferon Alfa-2b; Investigational Therapies; Laboratories; Ligands; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Manuscripts; Mediating; Medical Oncology; Membrane Glycoproteins; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Mono-S; Monoclonal Antibodies; NCI Center for Cancer Research; Nomograms; Ohio; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phenotype; Progression-Free Survivals; Protocols documentation; Publications; Publishing; Radiation; Radiation Therapy Oncology Group; Radioisotopes; Randomized; Recombinant Vaccines; Recombinants; Recurrence; Regimen; Reporting; Research Design; Samarium SM 153 lexidronam; Specific qualifier value; Speed; Surface; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Time; Tumor Biology; Tumor Volume; Vaccination; Vaccine Clinical Trial; Vaccine Therapy; Vaccines; Vaccinia; Vaccinia-TRICOM Vaccine; Vaccinium; Writing; androgen independent prostate cancer; anticancer research; base; bone; castration resistant prostate cancer; cell killing; chemotherapy; clinically significant; collaborative trial; cytokine; design; docetaxel; follow-up; hormone therapy; immunogenic; improved; inhibitor/antagonist; killings; malignant breast neoplasm; men; neutralizing antibody; novel; patient population; phase 1 study; phase 2 study; preclinical study; prevent; rVaccinia-CEA(D609)/MUC1(L93)/TRICOM Vaccine; randomized trial; receptor; research study; safety study; standard of care; therapeutic vaccine; trial comparing; tumor; tumor immunology; vaccine efficacy; vector-based vaccine

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. 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. We have recently completed a safety study of PROSTVAC combined with ipilimumab, which blocks negative costimulation. Up to 10 mg/kg of ipilimumab was safely administered with a vaccine that enhances positive costimulation. Immune-related adverse events were similar in proportion and gradeto those previously reported with ipilimumab alone. Furthermore, while the median predicted survival was about 18 months based on a validated nomogram, actual median OS exceeded 34 months in this phase I study. 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 FY11-12 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 published. 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. Formal protocol specified interim analysis presented at ASCO 2012 and is being written up for publication. A randomized Pilot Phase II study of Docetaxel alone or in combination with PANVAC-V (vaccinia) and PANVAC-F (fowlpox) in with metastatic breast cancer. MOB, CCR, NCI. This is the first randomized trial to combine vaccine with Docetaxel in this breast cancer patient population. This trial recently completed accrual and results are being written for publication. Long-term follow-up of prostate cancer patients treated with vaccine and definitive radiation therapy. (recently published) Two studies have recently been started combining a newly approved androgen receptor inhibitor (enzaulatamide) with or without PSA-TRICOM vaccine in patients with either rising PSA but no radiographic evidence of disease, or patients with metastatic castration resistant prostate cancer. 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) This trial recently completed accrual. 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.

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。疫苗加实验疗法 单克隆抗体已与疫苗结合用于治疗各种肿瘤类型。在前列腺癌中，人类细胞毒性 T 淋巴细胞抗原 4 (CTLA-4) 单克隆抗体已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。其主要功能是通过调节机体免疫活性来预防自身免疫性疾病。 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 表面上的相同配体或共刺激分子结合（B7.1 和 B7.2，也称为 CD80 和 CD86）。这些共刺激分子与 CD28 结合可激活 T 细胞，而与 CTLA-4 相互作用则可抑制 T 细胞刺激。使用中和抗体阻断 CTLA-4 已被证明可以维持和增强免疫反应。我们最近完成了一项 PROSTVAC 联合 ipilimumab 的安全性研究，该研究可阻断负性共刺激。高达 10 mg/kg 的易普利姆玛 (ipilimumab) 与可增强正向共刺激的疫苗一起安全施用。免疫相关不良事件的比例和等级与之前单独使用伊匹单抗报告的不良事件相似。此外，虽然根据经过验证的列线图，预测生存期中位数约为 18 个月，但在本 I 期研究中，实际中位 OS 超过 34 个月。 Gulley 博士及其在 NCI 癌症研究中心 (CCR) 肿瘤免疫学和生物学实验室 (LTIB) 以及肿瘤内科肿瘤学分部 (MOB) 的同事正在进行或最近在 2011-12 财年完成了以下联合疫苗临床在 NCI 临床中心进行的试验。一项针对雄激素不敏感非转移性 (D0.5) 前列腺癌、MOB、CCR、NCI 男性的随机 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。在转移性雄激素非依赖性前列腺癌患者中进行基于 PSA 的疫苗和抗 CTLA-4 抗体的 I 期试验。该试验是第一个将抗 CTLA-4 抗体和基于载体的疫苗结合治疗前列腺癌的临床试验。这项研究的手稿已发表。一项在患有雄激素不敏感的转移性前列腺癌、MOB、CCR、NCI 的男性中进行的 153Sm-EDTMP (Quadramet) 联合或不联合 PSA/TRICOM 疫苗的随机 2.5 期研究。该试验是第一个将疫苗与骨寻找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。正式方案指定了在 ASCO 2012 上提出的中期分析，目前正在编写出版。一项单独使用多西紫杉醇或联合 PANVAC-V（牛痘）和 PANVAC-F（鸡痘）治疗转移性乳腺癌的随机试点 II 期研究。 MOB、CCR、NCI。这是第一个在乳腺癌患者群体中将疫苗与多西紫杉醇联合使用的随机试验。该试验最近完成了应计，结果正在撰写中以供发布。对接受疫苗和根治性放射治疗的前列腺癌患者进行长期随访。 （最近发表）最近开始了两项研究，将新批准的雄激素受体抑制剂（enzaulatamide）与或不与 PSA-TRICOM 疫苗相结合，用于治疗 PSA 升高但无疾病放射学证据的患者，或患有转移性去势抵抗性前列腺癌的患者。与校外癌症中心的合作试验 在表达 CEA 的癌症患者中序贯接种鸡痘-CEA(6D)-TRICOM 和痘苗-CEA(6D)-TRICOM 联合 GM-CSF 和干扰素-Alfa-2B 的 I 期研究。 （俄亥俄州立综合癌症中心）这项试验最近完成了应计。我们目前正在与 RTOG 讨论基于 Quadramet 有或无疫苗研究的初步结果，进行 Alpharadin 和 PSA-TRICOM 用于骨转移患者的多中心合作小组研究。