Development of a tumor-retentive immunostimulant as adjunct therapy for solid tumor cancers

开发肿瘤保留免疫刺激剂作为实体瘤癌症的辅助治疗

基本信息

批准号：
10602219
负责人：
Marcus Laird Forrest
金额：
$ 39.56万
依托单位：
KINIMMUNE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-07 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10602219
关键词：
Abscopal effect Breast Melanoma CD8B1 gene CT26 CXCL1 gene Caliber Cancer Patient Cations Cells Charge Clinical Clinical Trials Complex Data Development Diagnosis Diffusion Dose Event Exhibits Extracellular Matrix Formulation Future Goals Head and Neck Neoplasms Head and neck structure Hour ITGAM gene Image Immune Immune checkpoint inhibitor Immune response Immune system Immunologic Adjuvants Immunologics Immunotherapy Infiltration Injectable Injections Interferon Type II Interleukin-2 Interleukin-6 Legal patent Malignant Neoplasms Maximum Tolerated Dose Metastatic Neoplasm to the Lung Modeling Molecular Multiple Sclerosis Mus Necrosis Outcome Palpable Patients Peptides Pharmacologic Substance Phase Phase I Clinical Trials Positioning Attribute Preparation Property Publishing Refractory Resistance Safety Sampling Serum Signal Transduction Site Small Business Technology Transfer Research Solid Neoplasm Structure Suspensions TNF gene Testing Toxic effect Tumor Burden Tumor Tissue Tumor-infiltrating immune cells Unresectable absorption anti-PD-1 cancer cell cancer immunotherapy checkpoint therapy copolymer 1 cytokine cytokine release syndrome design draining lymph node immune activation immune-related adverse events improved improved outcome innovation molecular size mouse model nanoparticle novel particle recruit self assembly side effect standard care subcutaneous success synergism tumor tumor growth tumor microenvironment uptake water solubility zeta potential

项目摘要

PROJECT SUMMARY/ABSTRACT Cancer immunotherapy activates the host immune system to seek and destroy cancer cells. Checkpoint inhibitors block immunosuppressive signals, thereby ‘releasing the brakes’ of the immune system. Solid tumors, however, typically do not respond well to checkpoint inhibitors. They are only effective in the 20-30% patients with an already immunologically ‘hot’ tumor. Thus, novel immunostimulant therapies aim to recruit immune cells to tumor tissue, turning cold tumors hot and working synergistically with checkpoint inhibitors. Immunostimulants that induce local immune-cell infiltration may induce an Abscopal effect and may increase responsiveness in patients that are resistant to checkpoint inhibitors. Unfortunately, immunostimulants often induce systemic immune-related adverse events (e.g., cytokine release syndrome), even when administered locally to tumor tissue. Most immunostimulants exhibit molecular properties promoting diffusion and systemic absorption (e.g., small molecular size, negative charge, high water solubility), This presents a major limitation as it leads to limited immune activation in the target tumor tissue after administration and immune-related adverse events. In this project, we will advance KIN-001 – a tumor-retentive formulation of the immunostimulant CpG designed to persist in tumor tissue thereby mitigating systemic immune-related adverse events and potentiating immune activity in the tumor microenvironment and draining lymph nodes. KIN-001 is a small volume nanosuspension for intratumoral injection comprised of commercially available glatiramer acetate (GA) (Copaxone®, approved for multiple sclerosis) complexed with CpG (immunostimulant). Through preliminary studies of KIN-001, our group has demonstrated its efficacy in recruiting immune cells to the tumor without inducing significant systemic cytokines, and we have identified the optimal mass ratio of GA to CpG. This Phase I STTR study has three Specific Aims: In Specific Aim 1, we will complete an in-use stability study of different formulations of KIN-001 to demonstrate that KIN-001 is a stable composition and quality is maintained between preparation and injection into the tumor under anticipated conditions of use. Specific Aim 2 will focus on identifying the maximum tolerated dose of KIN-001 compared to CpG in a predominant immunotherapy mouse model. In Specific Aim 3, we will establish proof of mechanism by elucidating KIN-001’s tumor retention and synergy potential when combined with anti-PD1, a checkpoint inhibitor. The long-term goal of this project is to commercialize KIN-001 as the first and only tumor-retentive immunostimulant with low toxicity for cancer patients that have palpable (i.e., injectable) solid tumors and are refractory to checkpoint inhibitors. KIN-001 will improve efficacy of standard treatment (e.g., checkpoint inhibitors) with minimal side effects, leading to improved outcomes and survival.

项目概要/摘要癌症免疫疗法激活宿主免疫系统来寻找并摧毁癌细胞。抑制剂阻断免疫抑制信号，从而“释放免疫系统的刹车”，然而，通常对检查点抑制剂反应不佳，它们仅对 20-30% 的患者有效。因此，新的免疫刺激疗法旨在招募免疫细胞。作用于肿瘤组织，使冷肿瘤变热并与检查点抑制剂协同作用。诱导局部免疫细胞浸润的免疫刺激剂可能会诱导远隔效应，并可能增加不幸的是，免疫刺激剂常常对检查点抑制剂产生耐药性。即使给药，也会诱发全身免疫相关的不良事件（例如细胞因子释放综合征）大多数免疫刺激剂表现出促进扩散和全身性的分子特性。吸收（例如，小分子尺寸、负电荷、高水溶性），这是一个主要限制因为它导致给药后靶肿瘤组织中的免疫激活有限，并且与免疫相关在这个项目中，我们将推进 KIN-001——一种免疫刺激剂的肿瘤保留制剂。 CpG 旨在持续存在于肿瘤组织中，从而减轻全身免疫相关的不良事件和 KIN-001 是一种小型药物，可增强肿瘤微环境和引流淋巴结中的免疫活性。用于肿瘤内注射的体积纳米混悬液，由市售的醋酸格拉替雷 (GA) 组成（Copaxone®，已批准用于多发性硬化症）与 CpG（免疫刺激剂）复合通过初步测试。在KIN-001的研究中，我们的团队已经证明了其在无需诱导显着的全身细胞因子，并且我们已经确定了此阶段 GA 与 CpG 的最佳质量比。 I STTR 研究有三个具体目标：在具体目标 1 中，我们将完成不同材料的使用中稳定性研究。 KIN-001 的配方，以证明 KIN-001 是一种稳定的组合物，并且质量保持在具体目标 2 将重点关注在预期使用条件下的制备和注射到肿瘤中。与主要免疫治疗小鼠中的 CpG 相比，确定 KIN-001 的最大耐受剂量在具体目标 3 中，我们将通过阐明 KIN-001 的肿瘤保留和作用来建立机制证明。与检查点抑制剂抗 PD1 联合使用时的协同潜力该项目的长期目标是将 KIN-001 商业化，作为第一个也是唯一一个对癌症低毒性的肿瘤保留免疫刺激剂患有可触及（即可注射）实体瘤且对 KIN-001 无效的患者。将提高标准治疗（例如检查点抑制剂）的疗效，同时副作用最小，从而改善结果和生存。