Phase 1 Evaluation of Enhanced Natural Killer Cells as a Treatment Strategy in Non-Small cell Lung Cancer Patients Refractory to PD-1/PD-L1 Immune Checkpoint Inhibitors

增强型自然杀伤细胞作为对 PD-1/PD-L1 免疫检查点抑制剂耐药的非小细胞肺癌患者的治疗策略的 1 期评估

• 批准号: 10680537
• 负责人: MIGUEL A VILLALONA-CALERO
• 金额: $ 61.26万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-09 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680537
• 关键词: A549; Acute Myelocytic Leukemia; Aftercare; Allogenic; Animals; Antigens; Biological; Blood; Cancer Etiology; Cancer Patient; Cell Line; Cell physiology; Cells; Cessation of life; Clinical; Clinical Trials; Combined Modality Therapy; Cytolysis; Data; Dependence; Disease; Dose; Engraftment; Epithelium; Gene Modified; Growth Factor Receptors; HLA Antigens; Human; IL18 gene; Immune; Immune checkpoint inhibitor; Immunotherapy; In Vitro; Interleukin-12; Interleukin-15; Interleukin-2; K-562; K562 Cells; Knock-out; Leukemic Cell; Lymphocyte Depletion; Malignant Neoplasms; Malignant neoplasm of lung; Messenger RNA; Monoclonal Antibody Therapy; Mus; Myeloid Leukemia; NK Cell Activation; Natural Killer Cells; Non-Small-Cell Lung Carcinoma; PDL1 inhibitors; Patients; Placebos; Proteins; Proto-Oncogene Proteins c-akt; Recurrent tumor; Refractory; Resistance; Role; Safety; Signal Transduction; Testing; Therapeutic; Time; Toxic effect; Tumor Antigens; Tumor Burden; Tumor Tissue; Tumor Volume; Umbilical Cord Blood; Umbilical cord structure; United States; Up-Regulation; Woman; anti-PD-L1; antibody-dependent cell cytotoxicity; cancer cell; cell killing; checkpoint inhibition; chimeric antigen receptor; cytokine; cytotoxicity; efficacy evaluation; efficacy study; experience; first-in-human; improved; in vivo; lung cancer cell; men; mouse model; myeloid leukemia cell; peripheral blood; phase 1 study; phase 1 testing; programmed cell death ligand 1; programmed cell death protein 1; retroviral transduction; safety and feasibility; safety study; treatment strategy; tumor; tumor progression

PROJECT SUMMARY: Lung cancer (LC), the most frequent cause of cancer deaths for men and women, is estimated to lead to 228,820 new cases and 135,720 deaths in the United States in 2020. In recent years inhibition of immune checkpoints, such as programmed cell death-1 (PD-1) and programmed cell death ligand- 1 (PD-L1), has been shown to provide survival benefits to patients with LC. However, most patients demonstrate either primary resistance or experience tumor recurrence and die of their disease. Our group has demonstrated that cancer cells upregulate PD-L1 on natural killer (NK) cells, immune cells that can target malignancies without the necessity of chimeric antigen receptors or prior antigen exposure and do not require matching to recipient's human leukocyte antigen for potential activity. Upregulation of PD- L1resulted in enhanced NK-cell function. Furthermore, the PD-L1 inhibitor atezolizumab (AZ) resulted in enhanced leukemic cell killing against myeloid leukemia lacking PD-L1 expression, and mice treated with selective cytokines (IL-12, IL-15, and IL-18) in combination with AZ showed a significant improvement in survival even in the absence of PD-L1 expression in their tumor tissue. We were able to express soluble IL-15 (sIL-15) tagged with a truncated epithelial growth factor receptor in umbilical cord NK cells in vitro, while upregulating endogenous PD-L1 expression on the NK cells. These transduced NK cells maintained greater than 30% antigen-specific tumor lysis compared to mock-transduced NK cells and demonstrated cytotoxicity against A549 Non-Small-Cell LC (NSCLC) cells. Human A549 NSCLC cells were subsequently injected in non-syngeneic mice and followed with treatment with these “enhanced” cordon blood CB NK cells. In comparison to treatment with mock-transduced NK cells, or NK cells expressing sIL-15 (sIL-15-NK) but without ex vivo activation, the enhanced CB NK cells induced substantial reduction in tumor volume. We also performed safety/toxicity in vivo studies of this approach and compared with AZ alone. Our data suggest that anti-PD-L1 mAb therapy has a unique therapeutic role in treating PD-L1 negative cancer, acting through PD-L1(+) NK cells. This activity is achieved independent of PD-1 activity and in the presence of NK-activating cytokines. We hypothesize that cytokine “enhanced” NK cells will provide clinical benefit to NSCLC patients and that the antitumor activity of this approach will be further enhanced by co- administration of AZ. To test this hypothesis and document the safety of this strategy, we propose additional in vivo safety and efficacy studies followed by a phase 1 study in which CB NK cells, genetically modified to express sIL-15, followed by ex-vivo expansion in the presence of IL-2, IL-18, and IL-12 will be administered either by themselves or combined with AZ, following lymphocyte depletion, to NSCLC patients whose tumor has previously progressed on or after treatment with PD-1/PD-L1 inhibitors.

项目摘要：肺癌（LC）是男性和女性癌症死亡最常见的原因，是 估计在2020年在美国导致228,820例新病例和135,720例死亡。 抑制免疫定位点，例如程序性细胞死亡-1（PD-1）和程序性细胞死亡配体 1（PD-L1）已显示为LC患者提供生存益处。但是，大多数患者 表现出一级抗性或经历肿瘤复发并死于其疾病。 我们的小组表明，癌细胞上调自然杀伤（NK）细胞的PD-L1，免疫细胞，这些细胞是 无需嵌合抗原受体或先前的抗原暴露，可以靶向恶性肿瘤 不需要与接受者的人类白细胞抗原匹配以进行潜在活性。 PD的上调 在增强的NK细胞函数中被L1sUlted。此外，PD-L1抑制剂Atezolizumab（AZ）导致 对缺乏PD-L1表达的髓样白血病的增强的白血病细胞杀死，用小鼠治疗的小鼠 选择性细胞因子（IL-12，IL-15和IL-18）与AZ结合显示出显着改善 即使在其肿瘤组织中没有PD-L1表达的情况下，生存也是如此。 我们能够表达用截短的上皮生长因子受体标记的固体IL-15（SIL-15） 脐带NK细胞体外，同时上调NK细胞上的内源性PD-L1表达。这些 与模拟转导的抗原特异性肿瘤裂解相比 NK细胞并显示针对A549非小细胞LC（NSCLC）细胞的细胞毒性。人A549 NSCLC 随后将细胞注入非合成小鼠，然后对这些“增强”进行处理 Cordon血液CB NK细胞。与模拟转导的NK细胞或表达的NK细胞的处理相比 SIL-15（SIL-15-NK），但没有离体激活，增强的CB NK细胞会大幅度降低 肿瘤体积。我们还对这种方法进行了安全/毒性，并与仅AZ进行了比较。 我们的数据表明，抗PD-L1 MAB疗法在治疗PD-L1阴性方面具有独特的治疗作用 癌症，通过PD-L1（+）NK细胞作用。该活性独立于PD-1活动和 NK激活细胞因子的存在。我们假设细胞因子“增强” NK细胞将提供临床 对NSCLC患者的益处，这种方法的抗肿瘤活性将通过共同提高 AZ的管理。为了检验这一假设并记录此策略的安全性，我们提出了其他 体内安全性和效率研究随后进行了1期研究，其中CB NK细胞在基因上修改为 Express SIL-15，然后在存在IL-2，IL-18和IL-12的情况下进行EX-VIVO扩展 通过淋巴细胞部署后，单独或与AZ结合给NSCLC患者的肿瘤患者 以前在用PD-1/PD-L1抑制剂治疗后或之后进展。