Novel therapeutic approaches for enhancing anti-tumor immunity in SCLC

项目总结 小细胞肺癌(SCLC)是一种高度致命的恶性肿瘤，新的治疗策略是 迫切需要。一个有希望的途径是使用免疫治疗(IMT)药物，如PD-1/PD-L1 途径抑制剂。然而，尽管它的突变负担很高，我们小组和其他人的数据表明 自相矛盾的是，小细胞肺癌的免疫抑制表型与浸润性T细胞水平相对较低， 减少了抗原提呈，增加了CD47的水平，CD47是髓系功能的抑制因子。此外， 初步临床测试表明，大多数小细胞肺癌通常表达低水平或极低水平的PD-L1，并且未能 对PD-1抑制剂单一治疗有反应；在有反应的肿瘤中也不可避免地出现IMT耐药，通过 尚未确定其特征的机制。因此，PD以外的免疫抑制机制-- 1/PD-L1通路可能在小细胞肺癌中发挥重要作用，以及新的治疗方法和组合 要实现小细胞肺癌IMT的潜力，需要进行治疗。 这项提议的目标是通过确定新的IMT目标和新的组合来解决这个问题 治疗方案，并迅速将其转化为临床。我们的团队已经有了很有希望的线索。首先，我们 发现小细胞肺癌对靶向DNA损伤修复(DDR)的药物高度敏感，包括PARP和 Chk1抑制剂，这一发现现在得到了早期临床结果的支持。我们的初步数据进一步表明，复员方案 抑制可能会增加PD-L1的表达，并通过增加肿瘤相关新抗原的产生 (TAA)，可能使肿瘤对IMT敏感。在目标1中，我们将测试DDR抑制剂是否能增加该基因的表达 并增强PD-1/PD-L1抑制剂的疗效。第二，我们开发了一种新的战略来 通过使用CDK4/6抑制剂保护免疫细胞免受化疗的细胞毒效应，CDK4/6抑制剂可以 用于保护免疫细胞，但不能保护缺乏Rb的小细胞肺癌细胞。在目标2中，我们将测试CDK4/6 抑制可以通过保护免疫细胞免受化疗诱导的影响来增强免疫细胞的抗肿瘤效果 可提高小细胞肺癌患者的细胞毒性，改善化疗/IMT联合治疗。第三，我们已经确定了 “不要吃我”信号CD47成为小细胞肺癌新的IMT靶点；阻断CD47有效地促进了 巨噬细胞吞噬小细胞肺癌细胞，抑制肿瘤生长。在目标3中，我们将测试目标是否 此CD47髓系检查点可增强抗肿瘤免疫和PD-1/PD-L1阻断的疗效 小细胞肺癌模型的体内化疗。 这里检验的总体假设是，通过靶向所有这些因素，小细胞肺癌患者的抗肿瘤免疫能力可以得到增强。 过程，导致更有效的IMT联合方案。这些研究将通过小说来促进 我们和一个多学科团队开发的具有免疫能力的小鼠临床前小细胞肺癌模型 包括临床和实验室调查人员、免疫学家、病理学家和其他有 在小细胞肺癌和IMT方面的创新，以及将实验室结果转化为临床的记录。

PROJECT SUMMARY Small cell lung cancer (SCLC) is a highly lethal malignancy for which new therapeutic strategies are desperately needed. One promising avenue is the use of immunotherapy (IMT) agents such as PD-1/PD-L1 pathway inhibitors. Despite its high mutation burden, however, data from our group and others indicate that SCLC paradoxically has an immunosuppressed phenotype with relatively low levels of infiltrating T-cells, reduced antigen presentation, and increased levels of CD47, a suppressor of myeloid function. Furthermore, initial clinical testing suggests that most SCLC tumors often express low or very low levels of PD-L1 and fail to respond to PD-1 inhibitor monotherapy; IMT resistance also inevitably emerges in responding tumors by mechanisms that have not yet been characterized. Thus, immunosuppressive mechanisms other than the PD- 1/PD-L1 pathway are likely to play a major role in SCLC, and novel therapeutic approaches and combination therapies are needed to realize the potential of IMT in SCLC. The goal of this proposal is to address this issue by identifying new IMT targets and novel combination regimens, and to rapidly translate them into the clinic. Our team already has promising leads. First, we identified that SCLC is highly vulnerable to drugs targeting DNA damage repair (DDR) including PARP and Chk1 inhibitors, a finding now supported by early clinical results. Our preliminary data further suggest that DDR inhibition may increase PD-L1 expression and, by increasing the production of tumor-associated neoantigens (TAA), may sensitize tumors to IMT. In Aim 1, we will test whether DDR inhibitors can increase the expression of TAAs, and enhance the efficacy of PD-1/PD-L1 inhibitors. Second, we have developed a novel strategy for protecting immune cells from the cytotoxic effects of chemotherapy by using inhibitors of CDK4/6, which can be used to protect immune cells, but not RB-deficient SCLC cells. In Aim 2, we will test whether CDK4/6 inhibition can enhance the anti-tumor effects of immune cells by protecting them from chemotherapy-induced cytotoxicity and enable improved chemotherapy/IMT combinations in SCLC. Third, we have identified the “don't-eat-me” signal CD47 as a novel IMT target for SCLC; blockade of CD47 effectively promotes the phagocytosis of SCLC cells by macrophages and inhibits tumor growth. In Aim 3, we will test whether targeting this CD47 myeloid checkpoint can enhance antitumor immunity and the efficacy of PD-1/PD-L1 blockade and chemotherapy in vivo in SCLC models. The overall hypothesis tested here is that antitumor immunity can be enhanced in SCLC by targeting all these processes, leading to more effective IMT combination regimens. These studies will be facilitated by novel immune-competent pre-clinical murine SCLC models that we have developed and by a multidisciplinary team including clinical and laboratory investigators, immunologists, pathologists, and others with a record of innovation in SCLC and IMT and a track record of translating laboratory findings into the clinic.