Clinical trials employing cancer vaccine combination therapies

我们之前报道了第一项针对非转移性、去势抵抗性前列腺癌患者的随机研究。该研究采用疫苗、激素尼鲁胺和联合治疗（每组交叉），终点为进展时间。我们现在报告了开始治疗后6.5年的生存分析，中位潜在随访时间为4.4年。42名患者随机接受基于痘病毒的前列腺特异性抗原（PSA）疫苗或尼鲁胺。在任何一组中，没有放射学证据证明PSA升高的患者都可以交叉接受联合治疗。从入组之日起，所有患者的中位生存期为4.4年。最初随机分配到疫苗组的患者的中位生存期有改善的趋势（中位，5.1年对3.4年；P = 0.13）。从研究日期开始，回顾性确定的12例最初接受疫苗，后来接受尼鲁胺治疗的患者的亚组显示，与8例开始接受尼鲁胺治疗，随后接受疫苗治疗的患者相比，生存率提高（中位数，6.2年对3.7年；P = 0.045）。随机分配到疫苗组和尼鲁胺组的患者的亚组分析显示，基线时Gleason评分为7 （P = 0.033）和PSA为20 ng/dL （P = 0.013）或既往接受过放射治疗（P = 0.018）的患者的生存率显著提高。这些数据表明，与接受激素治疗后再接种疫苗的患者相比，非转移性去势抵抗性前列腺癌（D0.5）患者在接受二线激素治疗前接种疫苗可能会提高生存率。这些数据还表明，与单独接受激素治疗或激素治疗后再接受疫苗治疗相比，单纯接种疫苗或先接种疫苗后接受二线激素治疗的患者可获得更大的临床获益。这些发现对大型疫苗联合治疗试验的设计和终点分析具有潜在的意义。我们假设一定剂量的IL-2作为生物佐剂，在维持免疫应答的同时，毒性更小。在一项单组试验中，18名局部前列腺癌患者使用先前确定的疫苗剂量和放射治疗进行治疗。使用的疫苗是编码PSA的重组痘苗病毒与编码共刺激分子B7.1的重组痘苗混合，然后用表达PSA的重组鸡痘载体加强接种。患者共接受8个计划接种周期，每4周接种1次，接种后第1 - 4天接种粒细胞-巨噬细胞集落刺激因子，第8 - 21天接种剂量为0.6MIU/M2的IL-2。在第三个接种周期后开始进行最终的外束放射治疗。评估患者的安全性和免疫反应。毒性和免疫活性与先前报道的含有较高剂量IL-2的方案进行了比较。18例患者中有17例接受了所有8个周期的IL-2疫苗。评估的8名HLA-A2+患者中有5名psa特异性T细胞增加了3倍。毒性一般较轻，仅接种7次疫苗，每接种140次，导致可能由IL-2引起的3级毒性。节拍剂量IL-2与疫苗和放射治疗联合使用是安全的，可以诱导前列腺特异性免疫反应，并且具有与低剂量IL-2相似的免疫活性，毒性明显降低。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完成了以下合作疫苗临床试验。在前列腺癌、MOB、CCR、NCI患者中，rFowlpox-PSA (L155)-TRICOM （PROSTVAC-F/TRICOM）单独或联合r痘痘- psa (L155)-TRICOM （PROSTVAC-V/TRICOM）序贯接种，以及GM-CSF的作用的I/II期试点研究。这是首次使用含有三种共刺激分子转基因的前列腺癌疫苗进行试验。研究表明，晚期前列腺癌患者血清PSA显著下降、客观反应、疾病稳定期延长和生存与免疫应答相关。该试验还为更合适的前列腺癌患者人群进行疫苗治疗试验提供了证据。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。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。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。一项I-II期肿瘤疫苗在既往未治疗的转移性乳腺癌患者化疗后的研究：疫苗诱导的t细胞再输注后t细胞库重建的偏倚（与Sportes博士合作）MOB， CCR， NCI。这项试验结合了t细胞库重组和疫苗治疗的概念。一项开放标签试点研究，评估PANVAC-V（痘苗）和PANVAC-F（鸡痘）联合Sargramostim （GM-CSF）治疗转移性腺癌、MOB、CCR、NCI患者的安全性和耐受性。本试验采用了多种肿瘤抗原和多种共刺激分子的转基因载体。最近的一项修订允许更多的患者进一步分析疫苗的功效。前列腺癌局部治疗后PSA进展的患者中PROSTVAC-V（痘苗）/TRICOM和PROSTVAC-F（禽痘）/TRICOM联合GM-CSF的II期研究（Eastern Cooperative Oncology Group）在CEA表达癌患者中顺序接种水痘-CEA(6D)-TRICOM和牛痘-CEA(6D)-TRICOM联合GM-CSF和干扰素- α - 2b的I期研究。（杜克大学综合癌症中心）一项I期研究，在晚期或转移性恶性肿瘤中表达CEA的患者中，使用Denileukin Diftitox进行调控性T细胞消耗，随后使用自体树突状细胞感染表达fowlpox-TRICOM的CEA- 6d进行主动免疫治疗（杜克大学综合癌症中心）（新泽西癌症研究所，CINJ）

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)