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

• 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
• 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

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.

项目摘要/摘要 癌症免疫疗法激活宿主免疫系统，寻找并摧毁癌细胞。检查点 抑制物可阻断免疫抑制信号，从而为免疫系统“松开刹车”。实体瘤， 然而，通常对检查点抑制剂反应不佳。它们只对20%-30%的患者有效 患有免疫学上已经很“热”的肿瘤。因此，新的免疫刺激疗法旨在招募免疫细胞。 到肿瘤组织，使冷肿瘤变热，并与检查点抑制剂协同工作。 诱导局部免疫细胞渗透的免疫刺激剂可能会引起非局部性效应，并可能增加 对检查点抑制剂耐药的患者的反应性。不幸的是，免疫刺激剂通常 诱发与全身免疫相关的不良事件(例如，细胞因子释放综合征)，即使在注射时也是如此 局部转移到肿瘤组织。大多数免疫刺激剂表现出促进扩散和全身反应的分子特性 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区肿瘤组织的免疫激活有限，与免疫相关 不良事件。在这个项目中，我们将推进KIN-001--一种保持肿瘤的免疫刺激剂的配方 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 增强肿瘤微环境中的免疫活性，引流淋巴结。KIN-001是一款小型 用于瘤内注射的体积纳米混悬剂，由市售醋酸格雷聚体(GA)组成 (Copaxone®，批准用于多发性硬化症)与CpG(免疫刺激剂)复合。通过初选 在对KIN-001的研究中，我们的小组已经证明了它在没有 诱导显著的全身性细胞因子，我们已经确定了GA和CpG的最佳质量比。这一阶段 在具体目标1中，我们将完成不同型号的汽车在用稳定性研究。 KIN-001的处方证明KIN-001是一种稳定的成分，质量保持在 在预期的使用条件下制备和注射到肿瘤内。《特定目标2》将专注于 在主要免疫治疗小鼠中确定KIN-001与CpG的最大耐受量 模特。在具体目标3中，我们将通过阐明KIN-001‘S肿瘤滞留和 当与检查点抑制剂抗PD1结合时，具有协同作用。这个项目的长期目标是 将KIN-001商业化为第一种也是唯一一种对癌症低毒的肿瘤保留性免疫刺激剂 可触及(即可注射)实体肿瘤且对检查点抑制剂无效的患者。KIN-001 将以最小的副作用提高标准治疗(例如，检查点抑制剂)的疗效，导致 改善结果和存活率。