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: 7965861
• 负责人: James L. Gulley
• 金额: $ 86.37万
• 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/7965861
• 关键词: ARI brand of 153Sm-EDTMP; Active Immunotherapy; Adjuvant; Adult; Amendment; Androgens; Antibodies; Autologous Dendritic Cells; Biological; Biology; Cancer Center; Cancer Institute of New Jersey; Cancer Patient; Cancer Vaccines; Carcinoma; Castration; Clinical; Clinical Trials; Collaborations; Colorectal; Combined Modality Therapy; Combined Vaccines; Comprehensive Cancer Center; Cystectomy; Data; Denileukin Diftitox; Disease; Dose; Drops; Duke Comprehensive Cancer Center; Eastern Cooperative Oncology Group; Engineering; Enrollment; Exhibits; External Beam Radiation Therapy; Extramural Activities; Flutamide; Fowlpox; Fowlpox vector; Fowlpox-CEA(D609)-MUC1(L93)-Tricom Vaccine; Genetic Crossing Over; Gleason Grade for Prostate Cancer; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; HLA-A2 Antigen; Hormones; Human; Immune response; Immunologics; Indolent; Interferon Alfa-2b; Interleukin-2; Laboratories; Local Therapy; Lung; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Medical Oncology; Metastatic Adenocarcinoma; Metastatic Prostate Cancer; NCI Center for Cancer Research; Neoplasm Metastasis; Nilutamide; Nonmetastatic; Ohio; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Pilot Projects; Poxviridae; Prostate; Prostate Cancer Vaccine; Prostate-Specific Antigen; Radiation; Radiation therapy; Radioisotopes; Randomized; Randomized Controlled Clinical Trials; Recombinant Fowlpox-GM-CSF Vaccine; Recombinant Vaccines; Recombinants; Reporting; Resistance; Role; Safety; Samarium SM 153 lexidronam; Schedule; Secondary Immunization; Serum; Stable Disease; Structure of base of prostate; Subgroup; Survival Analysis; T-Cell Depletion; T-Lymphocyte; Time; Toxic effect; Transgenes; Treatment Protocols; Tumor Antigens; Upper arm; Vaccination; Vaccine Clinical Trial; Vaccine Therapy; Vaccines; Vaccinia; Vaccinia virus; Vaccinia-TRICOM Vaccine; androgen independent prostate cancer; anticancer research; base; bladder Carcinoma; bone; breast cancer vaccine; chemotherapy; collaborative trial; cytokine; design; docetaxel; follow-up; hormone therapy; improved; malignant breast neoplasm; men; novel; open label; patient population; rVaccinia-CEA(D609)/MUC1(L93)/TRICOM Vaccine; reconstitution; research study; response; sargramostim; standard of care; trend; tumor immunology; vaccine efficacy; vector; vector-based vaccine

We reported previously the first randomized study of any kind in patients with nonmetastatic, castrate-resistant prostate cancer. The study employed vaccine, the hormone nilutamide, and the combined therapy (crossover for each arm) with an endpoint of time to progression. We now report survival analyses at 6.5 years from the initiation of therapy with a median potential follow-up of 4.4 years. Forty-two patients were randomized to receive either a poxvirus-based prostate-specific antigen (PSA) vaccine or nilutamide. Patients in either arm who developed increasing PSA without radiographic evidence of metastasis could cross over to receive the combined therapies. Median survival among all patients was 4.4 years from date of enrollment. Median survival exhibited a trend toward improvement for patients initially randomized to the vaccine arm (median, 5.1 versus 3.4 years; P = 0.13). Starting from the on-study date, the retrospectively determined subset of 12 patients who initially received vaccine and then later received nilutamide suggested improved survival compared with the 8 patients who began with nilutamide and subsequently were treated with vaccine (median, 6.2 versus 3.7 years; P = 0.045). A subgroup analysis of patients randomized to the vaccine arm versus the nilutamide arm showed substantial improvements in survival if at baseline patients had a Gleason score <7 (P = 0.033) and PSA <20 ng/dL (P = 0.013) or who had prior radiation therapy (P = 0.018). These data indicate that patients with nonmetastatic castration-resistant prostate cancer (D0.5) who receive vaccine before second-line hormone therapy may potentially result in improved survival compared with patients who received hormone therapy and then vaccine. These data also suggest that patients with more indolent disease may derive greater clinical benefit from vaccine alone or vaccine before second-line hormone therapy compared with hormone therapy alone or hormone therapy followed by vaccine. These findings have potential implications for both the design and endpoint analysis of larger vaccine combination therapy trials. We hypothesized that a metronomic dose of IL-2 as a biological adjuvant would cause less toxicity while maintaining immunologic response. Eighteen patients with localized prostate cancer were treated in a single arm trial using previously established doses of vaccine and radiation therapy. The vaccine used was a recombinant vaccinia virus engineered to encode PSA admixed with a recombinant vaccinia encoding the costimulatory molecule B7.1, followed by booster vaccinations with a recombinant fowlpox vector expressing PSA. Patients received a total of eight planned vaccination cycles, once every 4 weeks, with granulocyte-macrophage colony-stimulating factor given on days 1to 4 and IL-2 at a dose of 0.6MIU/M2 given from days 8 to 21 after each vaccination. Definitive external beam radiation therapy was initiated after the third vaccination cycle. Patients were evaluated for safety and immunologic response. Toxicity and immunologic activity were compared with the previously reported regimen containing a higher dose of IL-2. Seventeen of 18 patients received all eight cycles of vaccine with IL-2. Five of eight HLA-A2+ patients evaluated had an increase in PSA-specific T cells of ≥3-fold. Toxicities were generally mild, with only seven vaccination cycles of 140 given resulting in grade 3 toxicities possibly attributable to IL-2. Metronomic-dose IL-2 in combination with vaccine and radiation therapy is safe, can induce prostate-specific immune responses, and has immunologic activity similar to low-dose IL-2, with markedly reduced toxicities. 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 FY08-09 the following collaborative vaccine clinical trials at the NCI Clinical Center. A Phase I/II pilot study of sequential vaccinations with rFowlpox-PSA (L155)-TRICOM (PROSTVAC-F/TRICOM) alone, or in combination with rVaccinia-PSA (L155)-TRICOM (PROSTVAC-V/TRICOM), and the role of GM-CSF, in patients with prostate cancer, MOB, CCR, NCI. This is the first trial involving the use of a vaccine for prostate cancer containing transgenes for three costimulatory molecules. The study showed evidence of significant drops in serum PSA, objective response, prolonged stable disease and survival in patients with advanced prostate cancer which correlated with immunologic responses. This trial also provided evidence for a more appropriate prostate cancer patient population for vaccine therapy trials. 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. 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 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. A Phase I-II study of tumor vaccine following chemotherapy in patients with previously untreated metastatic breast cancer: Vaccine-induced bias of T-cell repertoire reconstitution after T-cell Reinfusion. (Collaboration with Dr. Sportes) MOB, CCR, NCI. This trial combines the concepts of T-cell repertoire reconstitution with vaccine therapy. An open label pilot study to evaluate the safety and tolerability of PANVAC-V (Vaccinia) and PANVAC-F (Fowlpox) in combination with Sargramostim (GM-CSF) in patients with metastatic adenocarcinoma, MOB, CCR, NCI. This trial employed vectors with transgenes of both multiple tumor antigens and multiple costimulatory molecules. A recent amendment allowed additional patients to further analyze the efficacy of the vaccine. Collaborative Trials with Extramural Cancer Centers A phase II study of PROSTVAC-V(Vaccinia)/TRICOM and PROSTVAC-F(fowlpox)/TRICOM with GM-CSF in patients with PSA progression after local therapy for prostate cancer. (Eastern Cooperative Oncology Group) 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 I study of regulatory T cell depletion with Denileukin Diftitox followed by active immunotherapy with autologous dendritic cells infected with CEA-6D expressing fowlpox-TRICOM in patients with advanced or metastatic malignancies expressing CEA (Duke Comprehensive Cancer Center) Phase I study of intravessical recombinant fowlpox-GM-CSF and or recombinant fowlpox-TRICOM in patients with bladder carcinoma scheduled for cystectomy (Cancer Institute of New Jersey, CINJ)

我们以前报道了对非转移性，耐Castrate前列腺癌患者的任何类型的首次随机研究。该研究采用了疫苗，尼罗二酰胺激素和联合治疗（每个臂的交叉），并具有进展的终点。现在，我们报告从开始治疗后6。5年进行生存分析，中位潜在随访4。4年。将42例患者随机分配，以接受基于痘病毒的前列腺特异性抗原（PSA）疫苗或尼罗二酰胺。在没有放射学的转移证据的情况下，任何一个臂中的患者都可以跨越综合疗法。自入学日期以来，所有患者的中位生存期为4.4年。中位存活率显示出最初随机与疫苗组随机分配的患者的趋势（中位数为5.1 v.4岁； p = 0.13）。从研究日期开始，最初接受疫苗然后后来接受尼罗塔米德的12例患者的追溯确定的子集表明，与尼罗丁酰胺启动并随后用疫苗治疗的8例患者（6.2 vs 3.7年对3.7岁； p = 0.045）。如果在基线患者的Gleason评分<7（P = 0.033）和PSA <20 ng/dL（P = 0.013）或患有先前的放射治疗（P = 0.018）的情况下（P = 0.018），对随机分配给疫苗组与NILUTAMIDE ARM的患者的亚组分析显示出了很大的提高。这些数据表明，与接受激素治疗和疫苗的患者相比，在二线激素治疗之前接受疫苗的非转移性cast割前列腺癌（D0.5）患者可能会提高存活率。这些数据还表明，与单独的激素治疗或激素治疗相比，二线激素治疗之前，单独使用疫苗或疫苗的患者可能会从疫苗或疫苗中获得更大的临床益处，然后再获得疫苗。这些发现对较大疫苗组合治疗试验的设计和终点分析具有潜在的影响。我们假设，IL-2作为生物辅助物的分析剂量在保持免疫学反应的同时会引起较小的毒性。 使用先前确定的疫苗和放射疗法的局部前列腺癌患者进行了18例局部前列腺癌。所使用的疫苗是一种重组疫苗病毒，该病毒设计用于编码用编码共同刺激分子B7.1的重组疫苗混合的PSA，然后是带有重组的Fowlpox载体的增强疫苗，表达PSA。患者每4周一次接受八个计划的疫苗接种周期，每次疫苗后第8至21天给出的粒细胞巨噬细胞刺激性刺激因子和IL-2给予0.6miu/m2的剂量。第三次疫苗接种周期后开始确定的外束辐射疗法。评估患者的安全性和免疫反应。将毒性和免疫活性与先前报道的含有更高剂量的IL-2的方案进行了比较。 18例患者中有17名接受了IL-2的所有八个疫苗周期。在评估的八名HLA-A2+患者中，有5例PSA特异性T细胞增加了3倍。毒性通常是轻度的，只有七个疫苗接种周期为140个，导致3级毒性可能归因于IL-2。与疫苗和放射治疗结合使用的监测剂量IL-2是安全的，可以诱导前列腺特异性免疫反应，并且具有类似于低剂量IL-2的免疫学活性，并且显着降低了毒性。 Gulley博士及其同事在肿瘤免疫学和生物学实验室（LTIB）和NCI癌症研究中心（CCR）的医学肿瘤学分支机构（MOB）已在NCI临床中心进行了以下或最近在08-09完成的或最近在08-09完成。 A Phase I/II pilot study of sequential vaccinations with rFowlpox-PSA (L155)-TRICOM (PROSTVAC-F/TRICOM) alone, or in combination with rVaccinia-PSA (L155)-TRICOM (PROSTVAC-V/TRICOM), and the role of GM-CSF, in patients with prostate cancer, MOB, CCR, NCI. 这是涉及将疫苗用于三个共刺激分子的转基因的第一次试验。这项研究表明，血清PSA的显着下降，客观反应，长期稳定疾病和晚期前列腺癌患者的存活率显着下降，这与免疫反应有关。该试验还提供了更合适的前列腺癌患者人群进行疫苗治疗试验的证据。 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。该试验是第一次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。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。在转移性乳腺癌的成年人中，单独或与PANVAC-V（Vaccinia）和Panvac-F（Fowlpox）结合多西他赛的随机试点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。化学疗法后肿瘤疫苗的I-II期研究对先前未经治疗的转移性乳腺癌患者：疫苗诱导的T细胞再灌注后T细胞库库偏置的偏差。 （与Sportes博士合作）Mob，CCR，NCI。该试验将T细胞曲目重建的概念与疫苗疗法结合在一起。一项开放式标签试验研究，用于评估Panvac-V（Vaccinia）和Panvac-F（Fowlpox）与Sargramostim（GM-CSF）在转移性腺癌，MOB，MOB，CCR，CCR，NCI中的安全性和耐受性。该试验使用多种肿瘤抗原和多种共刺激分子的转基因载体。最近的一项修正案允许其他患者进一步分析疫苗的功效。与校外癌的合作试验中心，对前列腺癌治疗后PSA进展的患者对ProstVAC-V（Vaccinia）/Tricom和Prostvac-F（FowlPox）/Tricom的II期研究。 （东部协作肿瘤学组）I期研究与GM-CSF和Interferon-Alfa-2b结合使用Fowlpox-CEA（6D） - TICOM和VECCINIA-CEA（6D）-CEA（6D） - TICOM。 (Ohio State Comprehensive Cancer Center) A Phase I study of regulatory T cell depletion with Denileukin Diftitox followed by active immunotherapy with autologous dendritic cells infected with CEA-6D expressing fowlpox-TRICOM in patients with advanced or metastatic malignancies expressing CEA (Duke Comprehensive Cancer Center) Phase I study of intravessical recombinant fowlpox-GM-CSF and or计划进行膀胱癌患者的重组禽晶状体（新泽西州癌症研究所，CINJ）