Phase I Study of ALT-801 in Metastatic Melanoma/Kidney Cancer Patients

描述（由申请人提供）： 本项目的长期目标是开发肿瘤靶向的T细胞受体-白细胞介素-2（TCR-IL-2）融合蛋白ALT-801，作为治疗黑色素瘤和肾癌的免疫剂。 该融合蛋白的TCR部分对衍生自在人白细胞抗原背景下呈递的肿瘤相关蛋白p53的肽具有特异性。（HLA）-A2.1这种高亲和力TCR被设计用于将批准的抗癌药物白细胞介素-2（IL-2）引导至肿瘤部位，并将与IL-2治疗相关的毒性降至最低。 基于在黑色素瘤和肾癌中观察到的20%至50%的p53过表达频率和约45%的HLA-A2.1的估计频率，使用ALT-801作为本文提出的用于最终死亡的那些亚群的治疗可能针对至多几千例美国年度病例。 在许多异种移植肿瘤模型中，TCR-IL-2融合蛋白抑制源自人黑素瘤（和其它人肿瘤细胞）的原发性肿瘤的生长，并且表现出比单独的重组人IL-2显著更好的抗肿瘤活性。 TCR-IL 2融合蛋白在HLA-A2转基因小鼠中也表现出有利的药代动力学和毒性特征。基于这些结果，嵌合形式的TCR-IL 2融合体（ALT-801）已被提出作为治疗癌症患者的临床候选物。 对于本提案中描述的ALT-801的临床开发，将在局部晚期或转移性恶性肿瘤患者中进行临床试验，以评价ALT-801的安全性、最大耐受剂量和药代动力学特征。 ALT-801的安全性和抗肿瘤反应将在扩大的黑色素瘤或肾癌患者队列中进一步评估。 （1）在进行性转移性恶性肿瘤患者中进行1期剂量递增试验，以检查ALT-801治疗的剂量限制性毒性、最大耐受剂量、药代动力学和抗肿瘤反应;（二）扩大最大耐受剂量队列中黑色素瘤或肾癌患者的数量，以进一步评估治疗的安全性和抗肿瘤反应ALT- 801由于p53在约50%的所有肿瘤中过表达，因此证明ALT-801在治疗黑色素瘤和肾癌孤儿适应症中的安全性和有效性可能对经历许多其他类型罕见癌症的患者人群有很大益处。

DESCRIPTION (provided by applicant): The long-term objective of this project is to develop a tumor-targeted T-Cell Receptor-Interleukin-2 (TCR-IL2) fusion protein, ALT-801, as an immunotherapeutic for treatment of melanoma and kidney 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 human leukocyte antigen. (HLA)-A2.1 This high affinity TCR is designed to guide the approved anti-cancer drug, interleukin-2 (IL-2), to the tumor site and minimize toxicity associated with IL-2 treatment. Based on the observed frequency of p53 overexpression in melanoma and kidney cancer of 20% to 50% and an estimated frequency of HLA-A2.1 of about 45%, use of ALT-801 as a treatment proposed here for a subpopulation of those with eventual mortality would likely target at most a few thousand annual U.S. cases. In a number of xenograft tumor models, the TCR-IL2 fusion protein inhibited the growth of primary tumors derived from human melanoma (and other human tumor cells) and exhibits significantly better antitumor activity than recombinant human IL-2 alone. The TCR-IL2 fusion protein also exhibits favorable pharmacokinetics and toxicity profiles in HLA-A2 transgenic mice. Based on these results, a chimeric form of the TCR-IL2 fusion (ALT-801) has been advanced as a clinical candidate for the treatment of cancer patients. For clinical development of ALT-801 described under this proposal, a clinical trial will be carried out in patients with locally advanced or metastatic malignancies to evaluate the safety, maximum-tolerated dose and pharmacokinetic profile of ALT-801. The safety profile and antitumor response of ALT-801 will be further assessed in an expanded cohort of patients with melanoma or kidney cancer. The following specific aims will be pursued: (1) conduct a Phase 1 dose-escalation trial in patients with progressive metastatic malignancies to examine the dose limiting toxicity, maximum tolerated dose, pharmacokinetics and antitumor response of treatment with ALT-801; (2) expand the number of patients with melanoma or kidney cancer in the maximum tolerated dose cohort to further assess safety and antitumor response of treatment with ALT- 801. Since p53 is overexpressed on around 50% of all tumors, demonstration of the safety and efficacy of ALT-801 in the treatment of melanoma and kidney cancer orphan indications could be of great benefit to the patient population experiencing many other types of rare cancers.