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.

在最近的大型受控免疫疗法研究中，对癌症的一份反复发现已改善总体存活率（OS），而没有改善中值无进展生存期（PFS）。这为及时完成概念验证效力研究提供了一个障碍。 PFS缺乏改善，最终证明OS的改善可能是由于给予免疫疗法和临床上显着的免疫介导的肿瘤生长速率放慢速度之间的时间段。批准第一种治疗性癌症疫苗已授予更高的优先级，以增强新型实验治疗疫苗对其他疗法的免疫学影响。仔细的临床前研究突出了标准疗法对A）以免疫学相关的方式杀死细胞的能力（免疫原性死亡），b）更改幸存细胞的表型，使其更容易受到免疫介导的识别和杀伤（免疫原性调节）。这导致了合理设计的研究，将治疗性癌症疫苗与标准疗法相结合。这些最近的临床前和临床研究表明，尽管有标准疗法（例如，化学疗法），具有对疫苗免疫反应的能力。这些组合研究提供了一个平台，用于测试组合策略影响更传统的第2阶段终点（例如PFS）的能力。如果上述关于生长速率的假设是正确的，则表明，如果可以合理地将治疗疫苗（与延迟作用相关）与标准疗法（与早期但短暂的肿瘤量相关），以不降低免疫反应的方式，那么可能会使用诸如PFS（例如PFS）（例如Chiminals Carriminate of Carryments of Carrymens and Commimensens and Commimensens and commins and and and肿瘤反应）。疫苗和护理标准疗法的初步数据来自2项正在进行的前列腺癌试验和一项乳腺癌研究，这支持了这一假设。前列腺癌试验表明，组合的进展时间有所改善（TTP）是Quadramet +/- ProstVac疫苗（52 vs 107天，n = 37）和氟丁酰胺+/- PROSTVAC疫苗（108 vs 192天，n = 41）;乳腺癌试验将多西他赛+/- PANVAC疫苗与有利于组合的初步数据进行了比较（120 vs 192天，n = 48）。因此，理性设计的组合研究有可能显着加快概念验证疗效研究的疗效分析（第2阶段）。这种方法在肿瘤中可能特别有用，这些肿瘤越来越多地影响OS，并且在随访的生存过程更遥远时，在疾病过程中早些时候。对正在进行的研究的最终分析最终可能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使用，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）单链抗体已与疫苗结合进行了测试。 CTLA-4是T细胞表面糖蛋白，在T细胞激活后被上调以抑制免疫反应。它的主要功能是通过调节身体免疫活性来防止自身免疫性。 T细胞在其细胞表面CD28和CTLA-4上表达两个应对受体。两者都与APC表面（B7.1和B7.2，也称为CD80和CD86）的同一配体或共刺激分子结合。这些共刺激分子与CD28的结合激活T细胞，而与CTLA-4相互作用抑制了T细胞刺激。用中和抗体阻断CTLA-4可以维持和增强免疫反应。我们最近完成了对Prostvac和ipilimumab结合的安全研究，该研究阻碍了负面刺激。使用可增强阳性共刺激的疫苗安全施用高达10 mg/kg的ipilimumab。与免疫相关的不良事件的比例相似，而grenteto先前仅用ipilimumab报告的grenteto。此外，尽管基于经过验证的诺夫图的中位数预测生存率约为18个月，但在本I阶段的研究中，实际中位OS超过34个月。 Gulley博士及其在NCI癌症研究中心（CCR）的肿瘤免疫学和生物学实验室（LTIB）和医学肿瘤学分支（MOB）的同事在NCI临床中心的以下组合疫苗临床试验中持续或最近完成。在患有雄激素不敏感的非转移性（D0.5）前列腺癌（D0.5）前列腺癌的男性中，一项将疫苗疗法与前列腺剂和氟丁酰胺相结合的随机II期试验，仅与氟丁二胺相结合。这是在D0.5前列腺癌患者中首次将疫苗与这种二线激素治疗相结合的随机试验。在转移性雄激素独立前列腺癌患者中，基于PSA的疫苗和抗CTLA-4抗体的I期试验。该试验是第一个在前列腺癌中结合抗CTLA-4抗体和基于载体的疫苗的临床试验。这项研究的手稿已发表。对患有雄激素不敏感的转移性前列腺癌男性中有或没有PSA/Tricom疫苗的153SM-EDTMP（Quadramet）的随机2.5研究。该试验是首次将疫苗与寻求放射性核素的骨骼合并用于雄激素独立前列腺癌患者的临床试验。正式协议指定的临时分析在ASCO 2012上提出，并正在编写供出版。与转移性乳腺癌一起进行的单独或与Panvac-V（Vaccinia）和Panvac-F（Fowlpox）结合的随机试验性II期研究。暴民，CCR，NCI。这是在该乳腺癌患者人群中首次将疫苗与多西他赛相结合的随机试验。该试验最近完成了应计，结果正在供出版。接受疫苗和明确放射治疗治疗的前列腺癌患者的长期随访。 （最近发表的）最近开始两项研究，在PSA升高但不存在的放射线疗法的患者或转移性世界范围的患者中，新的雄激素受体抑制剂（Enzaulatamide）具有或不使用PSA-TRICOM疫苗，有或没有PSA-TriCOM疫苗。与外癌外癌的合作试验中心对fowlpox-CEA（6D） - 三晶和疫苗 - CEA（6D） - 三核治疗的顺序疫苗进行了I期研究，并与GM-CSF和Interferon-Alfa-2b结合使用CEA表达CARCINOMAS的患者。 （俄亥俄州立大学综合癌症中心）该试验最近完成了应计。目前，我们正在与RTOG讨论α-骨转移患者的多中心合作小组研究，该研究基于Quadramet的初步结果，对有或没有疫苗研究的骨转移的初步结果。