Bifunctional T cell receptor based immunotherapeutics

描述（由申请人提供）：该项目的长期目标是开发一种肿瘤靶向TCR-IL2融合蛋白ALT-801，作为治疗p53阳性癌症的免疫疗法。该融合蛋白的TCR部分对HLA- A2.1中肿瘤相关蛋白p53衍生的肽具有特异性。这种高亲和力的TCR旨在引导已批准的抗癌药物白介素-2 （IL-2）到达肿瘤部位，以增强IL-2的抗肿瘤活性，并最大限度地减少与IL-2治疗相关的毒性。在许多异种移植肿瘤模型中，ALT-801抑制了人类p53+/HLA-2.1癌细胞衍生的原发肿瘤的生长或引起肿瘤消退，并表现出明显优于重组人IL-2的抗肿瘤活性。作用机制研究表明，融合蛋白与免疫细胞结合并引导这些细胞到达肿瘤部位，介导其抗肿瘤活性。基于这些结果，ALT-801已被作为治疗局部晚期或转移性p53阳性恶性肿瘤的临床候选药物，以评估其安全性、免疫原性、药代动力学特征和建立最大耐受剂量水平（MTD）。融合蛋白刺激免疫细胞和抗肿瘤活性的能力也被测量。患者被纳入三个不同剂量水平的队列，并确定了MTD。ALT-801在MTD水平上耐受性良好。来自治疗患者的数据还表明，ALT-801的血清半衰期（约3.3小时）比重组人IL-2长得多，并达到相应的靶向血清水平。ALT-801治疗可提高患者血清中INF3浓度，但不诱导患者血清中TNF1，并刺激外周血单个核细胞，提示免疫细胞激活可能在抗肿瘤反应中发挥作用。肿瘤评估显示约50%的治疗患者病情稳定，部分患者肿瘤缩小。基于这些发现，ALT-801进入II期临床试验是必要的。根据该提案，将进行IIa期试验，以继续评估ALT-801在I期试验中观察到肿瘤反应的目标适应症中的有效性和安全性。将追求以下具体目标：1)产生足够的ALT-801临床材料以支持II期人体临床研究；2)进行II期人体临床试验，以评估MTD剂量水平下ALT-801在难治性转移性黑色素瘤、肾细胞癌、头颈癌和前列腺癌患者中的疗效和安全性。本研究提出的临床终点的实现将促使适当适应症的招募扩大，为ALT-801进入FDA批准的关键临床试验提供必要的数据。

DESCRIPTION (provided by applicant): The long-term objective of this project is to develop a tumor-targeted TCR-IL2 fusion protein, ALT-801, as an immunotherapeutic for treatment of p53-positive cancers. The TCR portion of this fusion protein is specific for a peptide derived from the tumor-associated protein p53 presented in the context of HLA- A2.1. This high-affinity TCR is designed to guide the approved anti-cancer drug, interleukin-2 (IL-2), to the tumor site to enhance the IL-2 anti-tumor activity and to minimize toxicity associated with IL-2 treatment. In a number of xenograft tumor models, ALT-801 inhibited the growth or caused regression of primary tumors derived from human p53+/HLA-2.1 cancer cells and exhibited significantly better anti- tumor activity than recombinant human IL-2 alone. Mechanism-of-action studies suggest that the fusion protein binds to immune cells and guides these cells to the tumor site where they mediate their anti- tumor activities. Based on these results, ALT-801 has been advanced as a clinical candidate for the treatment of cancer patients with locally advanced or metastatic p53-positive malignancies to evaluate the safety, immunogenicity, pharmacokinetic profile and to establish the maximum tolerated dose level (MTD). The fusion protein's ability to stimulate immune cells and anti-tumor activity was also measured. Patients have been enrolled in three different dose level cohorts and the MTD has been determined. ALT-801 is well tolerated at the MTD level. Data from the treated patients also indicate that ALT-801 has a substantial longer serum half-life (i.e. ~ 3.3 hr) than that of recombinant human IL-2 and achieves the corresponding targeted serum levels. ALT-801 treatment increases serum INF3 concentration without inducing TNF1 in the patients' sera and stimulates peripheral blood mononuclear cells, indicating immune cell activation that may play a role in antitumor responses. Tumor assessment showed stable disease in approximately 50% of the treated patients with tumor shrinkage observed in some patients. Based on these findings, advancement of ALT-801 into Phase II clinical testing is warranted. Under this proposal, a Phase IIa trial will be conducted to continue the evaluation of ALT-801's efficacy and safety in the target indications where tumor responses were observed in the Phase I trial. The following specific aims will be pursued: 1) generate sufficient ALT-801 clinical material to support Phase II human clinical studies, and 2) conduct a Phase IIa human clinical trial to evaluate the efficacy and safety of ALT-801 in subjects with refractory metastatic melanoma, renal cell carcinoma, head and neck cancer and prostate cancer at the MTD dose level. Achievement of clinical endpoints proposed by this study will prompt an expansion of enrollment in the appropriate indications to provide data necessary for advancement of ALT-801 into pivotal clinical trials for FDA approval. PUBLIC HEALTH RELEVANCE: The goal of the proposed research is to examine the safety and efficacy of a novel tumor-targeted immunotherapeutic in patients with refractory metastatic melanoma, renal cell carcinomas, head and neck cancer and prostate cancer. This is a second phase of a human trial of the immunotherapeutic which has shown to provide clinical benefits for patients having these cancers. This may lead to a safe and effective approach to treat patients with refractory, metastatic cancer.