Immuno-Targeted Therapy for Melanoma

 描述(申请人提供)：PD-1或PD-L1阻断的免疫疗法正在改变癌症治疗的格局，最好的证据是在黑色素瘤患者中有持续的肿瘤反应，导致FDA首次批准了抗PD-1疗法。我们一直在研究对这种疗法的反应和抵抗，现在我们能够提出机制研究，旨在提供对PD-1阻断的反应、先天和获得性抵抗的分子理解。在第一个主题中，我建议表征通过在患者来源的样本中阻断PD-1而释放的T细胞反应。这将包括肿瘤浸润性淋巴细胞(TIL)的表型和功能研究，以及对治疗性T细胞的精细抗原特异性的分析。随着对接受PD-1阻断抗体pembrolizumab治疗的患者最初队列的长期随访，我们现在看到了在长时间的客观肿瘤反应后肿瘤进展延迟的病例。我们将通过分析T细胞功能、抗原处理机制的变化和突变变化来研究获得性耐药的机制，这些变化导致新的表位因免疫编辑而丢失。第二个主题集中在研究上，这在我的实验室里一直是一个长期的主题，现在正在成为临床现实。我们曾假设靶向治疗可以使癌细胞对免疫治疗敏感，这导致我的团队致力于BRAF抑制剂的临床开发，并研究耐药的分子机制。但目标始终是将它们与免疫疗法结合使用。BRAF抑制剂具有一系列性质，使它们成为非常好的组合候选者，但显然，转换努力需要足够的临床前建模和患者的机制理解。第三个主题基于我15年来在研究人员发起的基于细胞疗法的癌症免疫疗法临床试验中的经验。我们从树突状细胞疫苗开始，既有多肽冲击的，也有基因修饰的，并意识到益处仅限于偶尔出现长期反应的患者。这使得我的团队做出了一大笔投资，建立了T细胞受体(TCR)工程收养细胞转移(ACT)计划，这是世界上极少数的计划之一。我们现在正在将TCR工程的ACT与检查点封锁疗法结合起来，我建议在资助期间继续这项研究。总之，我们的建议是基于假设驱动的床边床后机制研究，目标是以患者为中心在黑色素瘤的肿瘤免疫治疗方面取得进展。

 DESCRIPTION (provided by applicant): Immunotherapy with PD-1 or PD-L1 blockade is changing the landscape of cancer therapy, as best evidenced in melanoma with sustained tumor responses in a significant number of patients leading to the first approval of an anti-PD-1 therapy by the FDA. We have been studying response and resistance to this therapy and we are now in the position to propose mechanistic studies aimed at providing a molecular understanding of response, innate and acquired resistance to PD-1 blockade. In the 1st theme I propose to characterize the T cell responses unleashed by blocking PD-1 in patient-derived samples. This will include phenotypic and functional studies in tumor infiltrating lymphocytes (TIL), as well as analyses of the fine antigen specificity of the therapeutic T cells. With the lon term follow up of the initial cohorts of patients treated with the PD-1 blocking antibody pembrolizumab we are now seeing cases of delayed tumor progression after a long period of objective tumor response. We will study the mechanisms of acquired resistance by analyzing changes in T cell function, antigen processing machinery and mutational changes, leading to the loss off neoepitopes due to immune editing. The 2nd theme is centered in research that has been a longstanding theme in my laboratory and that now is becoming a clinical reality. We had hypothesized that targeted therapies could sensitize cancer cells to immunotherapy, and this led my group to work on the clinical development of BRAF inhibitors and study the molecular mechanisms of resistance. But the goal was always to use them in combination with immunotherapy. BRAF inhibitors have a series of properties that make them very good candidates for combination, but it is evident that the translational efforts require adequate preclinical modeling and mechanistic understanding in patients. The 3rd theme builds on my 15 year experience in investigator-initiated cell therapy-based cancer immunotherapy clinical trials. We started with dendritic cell vaccines, both peptide pulsed and genetically modified, and realized that the benefit was restricted to occasional patients with long-term responses. This brought my group to make a big investment in setting up a T cell receptor (TCR) engineered adoptive cell transfer (ACT) program, which is one of the very few in the world. We are now combining TCR engineered ACT with checkpoint blockade therapy and I propose to pursue this research during the funding period. In conclusion, our proposal is based on hypothesis-driven bench-to-bedside-and-back mechanistic studies with the goal of patient-centric advances in tumor immunotherapy for melanoma.