Cancer Therapy Clinical Trials Using Novel Recombinant Vaccines

治疗前列腺癌的psa靶向痘病毒疫苗耐受良好。在一项随机、对照、盲法II期研究中，评估了PROSTVAC-VF治疗的安全性、延长无进展生存期（PFS）和总生存期。125名患者被随机分配到疫苗系列的多中心试验中。符合条件的患者有最小症状去势抵抗性转移性前列腺癌（mCRPC）。PROSTVAC-VF包括2个重组病毒载体，每个载体编码前列腺特异性抗原（PSA）的转基因和3个免疫共刺激分子（B7.1、ICAM-1和LFA3: TRICOM）。以牛痘为基础的载体用于启动，随后计划进行6次以禽流感为基础的载体增强。患者按2:1分配到PROSTVAC-VF + GM-CSF组，对照空载体+生理盐水注射组。2例接受PROSTVAC-VF治疗，40例接受对照载体治疗。患者特征相似。主要终点为PFS，两组相似（P=0.6）。然而，在研究后3年，PROSTVAC-VF患者的总生存率为25/82(30%)，而对照组为7/40（17%）。中位生存期延长8.5个月（疫苗组24.5个月，对照组16个月）；估计风险比0.56 (95% CI 0.37-0.85)；分层对数秩P=0.0061。PROSTVAC-VF免疫治疗耐受性良好，与mCRPC患者死亡率降低44%和中位生存期改善8.5个月相关。这些令人振奋的数据为临床意义的益处提供了初步证据，但需要在更大的III期研究中得到证实。一项采用重组痘病毒疫苗的多中心随机II期试验提供了转移性去势抵抗性前列腺癌（mCRPC）患者中位总生存期（OS）提高（p=0.0061）的证据。本研究采用相同疫苗接种mCRPC，探讨GM-CSF与疫苗的影响，以及免疫和预后因素对中位生存期的影响。32例患者接种含有前列腺特异性抗原（PSA）转基因和3种人共刺激分子（B7.1、ICAM-1和LFA-3，简称TRICOM）的重组痘苗1次。患者接受了含有相同四种转基因的重组鸡痘强化疫苗。12/32的患者显示血清PSA下降，2/12的患者显示可评估的指数病变下降。中位OS为26.6个月。具有更高psa特异性t细胞反应的患者表现出提高生存率的趋势（p=0.055）。在接受GM-CSF与未接受GM-CSF的患者队列中，t细胞反应或生存率没有差异。Halabi患者预测生存期为18个月（预测为12.3个月），实际中位生存期为14.6个月，而Halabi患者预测生存期为8805个月；18个月（预测生存期20.9个月）达到或超过37.3个月，其中12/15患者的生存期超过预测（p=0.035）。Treg抑制功能在存活时间长于预期的患者中下降，而在存活时间短于预期的患者中增加。这些研究提供的证据表明，mCRPC症状较轻的患者（Halabi预测生存期为18个月）可能从疫苗治疗中获益最多。转移癌患者接种重组CEA-MUC-1-TRICOM痘病毒疫苗的初步研究痘病毒载体具有被证实的安全记录，可用于合并多种转基因。先前的痘病毒疫苗临床试验表明，对自身抗原的免疫耐受可以被打破。癌胚抗原（CEA）和MUC-1（乳腺癌相关上皮粘蛋白）在相当大比例的常见实体癌中过表达。该研究的主要终点是疫苗安全性，次要终点是免疫和临床反应。我们在此报告了一项对25名患者进行的初步研究，该研究采用了由CEA和MUC-1基因组成的痘病毒疫苗方案，以及由B7.1、ICAM-1和LFA-3组成的三联共刺激分子（TRICOM，由B7.1、ICAM-1和LFA-3组成）工程改造成牛痘（PANVAC-V）作为初级疫苗，并工程改造成鸡痘（PANVAC-F）作为加强疫苗。这种疫苗耐受性良好。除注射部位反应外，无等级&amp；#8805；在超过2%的循环中发现毒性。在16例接受测试的患者中，有9例在接种疫苗后出现对muc -1和/或CEA的免疫应答。一名透明细胞卵巢癌合并症状性腹水的患者在放射学和生化方面有持久的临床反应（18个月），一名乳腺癌患者证实大肝转移灶的大小减少了20%。这种疫苗策略似乎是安全的，与CD8和CD4免疫反应相关，并已显示出临床活性的证据。该药物的进一步试验，无论是单独使用还是与免疫增强剂和其他治疗药物联合使用，都是有必要的。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。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。一项开放标签I期研究，评估一种疫苗（GI-6207）的安全性和耐受性，该疫苗由完整的、热灭活的重组酵母（酵母）组成，经基因修饰后可在表达CEA的转移性癌成人中表达CEA蛋白。这是该疫苗的首次人体试验。一项开放标签试点研究，评估talactoferrin对成人非小细胞肺癌（NSCLC）免疫系统的影响。对该药物的免疫应答是主要终点。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）

Therapeutic PSA-targeted poxviral vaccines for prostate cancer have been well tolerated. PROSTVAC-VF treatment was evaluated for safety, prolongation of progression free of survival (PFS), and overall survival, in a randomized, controlled, and blinded phase II study. 125 patients were randomized in a multi-center trial of vaccination series. Eligible patients had minimally symptomatic castration resistant metastatic prostate cancer (mCRPC). PROSTVAC-VF comprises 2 recombinant viral vectors, each encoding transgenes for prostate specific antigen (PSA) and 3 immune costimulatory molecules (B7.1, ICAM-1, and LFA3: TRICOM). Vaccinia-based vector was used for priming followed by 6 planned Fowlpox-based vector boosts. Patients were allocated (2:1) to PROSTVAC-VF + GM-CSF, versus Control empty vectors + saline injections. 2 patients received PROSTVAC-VF and 40 received Control vectors. Patient characteristics were similar. The primary endpoint was PFS, which was similar in the two groups (P=0.6). However, at 3 years post study, PROSTVAC-VF patients had a better overall survival with 25/82 (30%) alive, versus 7/40 (17%) Controls. There was a longer median survival by 8.5 months (24.5 months for vaccine versus 16 months Controls);and estimated hazard ratio 0.56 (95% CI 0.37-0.85); stratified log rank P=0.0061. PROSTVAC-VF immunotherapy was well tolerated and associated with a 44% reduction in the death rate and an 8.5 month improvement in median OS in men with mCRPC. These provocative data provide preliminary evidence of clinically meaningful benefit, but need to be confirmed in a larger Phase III study. A concurrent multicenter, randomized Phase II trial employing a recombinant poxviral vaccine provided evidence of enhanced median overall survival (OS) (p=0.0061) in patients with metastatic castrate-resistant prostate cancer (mCRPC). This study employed the identical vaccine in mCRPC to investigate the influence of GM-CSF with vaccine, and the influence of immunologic and prognostic factors on median OS. 32 patients were vaccinated once with recombinant vaccinia containing the transgenes for prostate-specific antigen (PSA) and three human costimulatory molecules (B7.1, ICAM-1 and LFA-3, designated as TRICOM). Patients received booster vaccines with recombinant fowlpox containing the same four transgenes. 12/32 patients showed declines in serum PSA and 2/12 showed evaluable decrease in index lesions. Median OS was 26.6 months. Patients with greater PSA-specific T-cell responses showed a trend (p=0.055) toward enhanced survival. There was no difference in T-cell responses or survival in cohorts of patients receiving GM-CSF vs no GM-CSF. Patients with a Halabi predicted survival of < 18 months (predicted 12.3 months) had an actual median OS of 14.6 months, while those with a Halabi predicted survival of ≥ 18 months (predicted survival 20.9 months) will meet or exceed 37.3 months, with 12/15 patients living longer than predicted (p=0.035). Treg suppressive function was shown to decrease in patients surviving longer than predicted and increase in patients surviving less than predicted. These studies provide evidence that patients with more indolent mCRPC (Halabi predicted survival ≥ 18 months) may best benefit from vaccine therapy. Pilot study of vaccination with recombinant CEA-MUC-1-TRICOM poxviral-based vaccines in patients with metastatic carcinoma. Poxviral vectors have a proven safety record and can be used to incorporate multiple transgenes. Prior clinical trials with poxviral vaccines have shown that immunologic tolerance to self-antigens can be broken. Carcinoembryonic antigen (CEA) and MUC-1 (breast cancer associated epithelial mucin) are overexpressed in a substantial proportion of common solid carcinomas. The primary end point of this study was vaccine safety, with immunologic and clinical responses as secondary end points. We report here a pilot study of 25 patients treated with a poxviral vaccine regimen consisting of the genes for CEA and MUC-1, along with a triad of costimulatory molecules (TRICOM; composed of B7.1, ICAM-1, and LFA-3) engineered into vaccinia (PANVAC-V) as a prime vaccination and into fowlpox (PANVAC-F) as a booster vaccination. The vaccine was well tolerated. Apart from injection-site reaction, no grade ≥2 toxicity was seen in more than 2% of the cycles. Immune responses to MUC-1and/or CEA were seen following vaccination in 9 of 16 patients tested. A patient with clear cell ovarian cancer and symptomatic ascites had a durable (18-month) clinical response radiographically and biochemically, and one breast cancer patient had a confirmed decrease of >20% in the size of large liver metastasis. This vaccine strategy seems to be safe, is associated with both CD8 and CD4 immune responses, and has shown evidence of clinical activity. Further trials with this agent, either alone or in combination with immunopotentiating and other therapeutic agents, are warranted. 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 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. An open label phase I study to evaluate the safety and tolerability of a vaccine (GI-6207) consisting of whole, heat-killed recombinant Saccharomyces cerevisiae (yeast) genetically modified to express CEA protein in adults with metastatic CEA-expressing carcinoma. This is a first in humans trial for this vaccine. An open label pilot study to evaluate the effect on the immune system of talactoferrin in adults with non-small cell lung cancer (NSCLC). Immunologic response to this agent is the primary endpoint. 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)