Novel therapeutic approaches for enhancing anti-tumor immunity in SCLC

项目摘要 小细胞肺癌（SCLC）是一种高度致命的恶性肿瘤， 迫切需要的。一个有希望的途径是使用免疫治疗（IMT）剂，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， SCLC矛盾地具有免疫抑制表型，浸润T细胞水平相对较低， 抗原呈递减少，髓系功能抑制因子CD 47水平升高。此外，委员会认为， 最初的临床试验表明，大多数SCLC肿瘤通常表达低水平或极低水平的PD-L1， 对PD-1抑制剂单药治疗有反应; IMT耐药性也不可避免地出现在反应性肿瘤中， 尚未被描述的机制。因此，除了PD-1以外的免疫抑制机制 1/PD-L1通路可能在SCLC中发挥重要作用，以及新的治疗方法和组合 需要新的治疗方法来实现SCLC中IMT的潜力。 该提案的目标是通过确定新的IMT靶点和新的组合来解决这一问题 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。一是 发现SCLC对靶向DNA损伤修复（DDR）的药物（包括PARP）非常脆弱， Chk 1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， 抑制可增加PD-L1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抑制剂是否可以增加 TAA的作用，并增强PD-1/PD-L1抑制剂的疗效。第二，我们制定了一项新的战略， 通过使用CDK 4/6抑制剂保护免疫细胞免受化疗的细胞毒性作用， 可用于保护免疫细胞，但不能保护RB缺陷的SCLC细胞。在目标2中，我们将测试CDK 4/6是否 抑制可以通过保护免疫细胞免受化疗诱导的肿瘤抑制而增强免疫细胞的抗肿瘤作用。 细胞毒性和能够改善SCLC中的化疗/IMT组合。第三，我们确定了 “不要吃我”信号CD 47作为SCLC的新IMT靶点;阻断CD 47可有效促进 通过巨噬细胞吞噬SCLC细胞并抑制肿瘤生长。在目标3中，我们将测试是否瞄准 这种CD 47骨髓检查点可以增强抗肿瘤免疫和PD-1/PD-L1阻断的功效， 在SCLC模型中进行体内化疗。 这里测试的总体假设是，通过靶向所有这些靶点，可以增强SCLC的抗肿瘤免疫力。 过程，导致更有效的IMT组合方案。这些研究将通过新的 免疫能力的临床前小鼠SCLC模型，我们已经开发，并由一个多学科的团队 包括临床和实验室研究人员、免疫学家、病理学家和其他有以下记录的人： SCLC和IMT的创新以及将实验室发现转化为临床的记录。

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.