Development of a novel checkpoint inhibitor-TGF beta combination therapy to reverse immune suppression and increase survival rates in advanced colorectal cancer patients

开发新型检查点抑制剂-TGFβ联合疗法以逆转免疫抑制并提高晚期结直肠癌患者的生存率

• 批准号: 10393306
• 负责人: Dori A Thomas-Karyat
• 金额: $ 5.61万
• 依托单位: SYNTHIS THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393306
• 关键词: Development; novel; checkpoint; inhibitor; TGF

SYNTHIS SBIR Ph I PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) is the 3rd most common cancer and the 2nd leading cause of cancer deaths in the US. Approximately 15-20% of CRC patients have high microsatellite instability (MSI-H). Although the FDA- approved immune checkpoint, anti-PD1 antibodies, nivolumab and pembrolizumab are effective in MSI-H CRCs, patient response rates are a modest 28-35%. The remaining 80% of CRC patients that are microsatellite stable (MSS) do not respond to anti-PD1/PDL1. With considerable room to improve in both populations, new combination IO treatments should 1) boost responses in MSI-H patients, and/or 2) offer new treatment options for the majority of checkpoint-resistant CRC patients with immunosuppressed “cold” tumors. TGF-β is an immuno-suppressive cytokine, with elevated levels in late stage CRC patients that cripple the adaptive immune system and decrease survival rates. In murine colon cancer models, blockade of the PD1 pathway led to a compensatory increase in TGF-β signaling, while blockade of both pathways led to tumor regression. Because historically systemic TGF-β blockade cause an array of significant issues, including host toxicity, novel TGF-β therapies are required to convert IO therapy-resistant “cold” CRCs into immunogenic “hot” tumors to drive tumor clearance. At Synthis, we are developing a novel, more aggressive checkpoint therapy combined with TGF-β inhibition (named: PTA) to eradicate CRC. In Aim 1, we will demonstrate that PTA reverses immune-suppression in vitro, and restores pathways critical for tumor clearance, such as IFN-γ expression and cytotoxic T cell mediated tumor killing. In Aim 2, we will test PTA in colon cancer models in vivo, using the humanized HuGEMM PD1 mouse model, which expresses human PD1 on T cells. PTA will be tested in an in vivo PD assay to establish the appropriate dose range to use in efficacy studies. We will then test PTA for efficacy in the MC38 colon cancer model in vivo, as well as harvest tumor infiltrating lymphocytes (TILs) to investigate the effect of PTA on immune cell infiltration and/or activation. The ultimate goal of PTA is to convert “cold” CRC tumors into immune infiltrated “hot” tumors and increase patient survival rates. New combination studies with anti-PD1 plus IO therapies are in high demand. Because CRC patients are resistant to single anti-PD1 therapies, a novel, more aggressive IO approach is required. With a predicted CRC global market size of $11B in 2022, PTA will be positioned as a single IO therapy that will eliminate two validated immuno-suppressive pathways to treat CRC patients and increase patient survival.

Synthis Sbir PH I项目摘要/摘要 结直肠癌（CRC）是美国第三大癌症，也是美国癌症死亡的第二大原因。 大约15-20％的CRC患者具有较高的微卫星不稳定性（MSI-H）。虽然FDA- 批准的免疫切除点，抗PD1抗体，Nivolumab和Pembrolizumab在MSI-H中有效 CRC，患者反应率为28-35％。其余80％的CRC患者是 微卫星稳定（MSS）对抗PD1/PDL1无反应。都有可考虑的空间可以改善两者 种群，新组合IO治疗应1）增强MSI-H患者的反应，/或2）提供新的 大多数具有免疫抑制“冷”肿瘤的耐检查点的CRC患者的治疗选择。 TGF-β是一种免疫抑制性细胞因子，在晚期CRC患者中升高，密码学是 自适应免疫系统并降低存活率。在鼠结肠癌模型中，PD1的封锁 途径导致TGF-β信号的补偿性增加，而两种途径的阻塞导致肿瘤 回归。因为历史上系统性的TGF-β封锁引起了一系列重大问题，包括宿主 毒性，需要新颖的TGF-β疗法将抗IO治疗的“冷” CRC转化为免疫原性 “热”肿瘤以驱动肿瘤清除。在Synthis，我们正在开发一个小说，更具侵略性的检查站 治疗与TGF-β抑制作用（命名：PTA）结合使用，以放射性CRC。在AIM 1中，我们将证明 PTA在体外逆转免疫抑制，并恢复对肿瘤清除至关重要的途径，例如IFN-γ 表达和细胞毒性T细胞介导的肿瘤杀死。在AIM 2中，我们将在结肠癌模型中测试PTA Vivo，使用人源化的Hugemm PD1小鼠模型，该模型在T细胞上表达人PD1。 PTA会 在体内PD测定中测试，以建立适当的剂量范围以用于效率研究。然后我们会 测试PTA在体内MC38结肠癌模型的效率，以及收获肿瘤浸润淋巴细胞 （TIL）研究PTA对免疫细胞浸润和/或激活的影响。 PTA的最终目标是 将“冷” CRC肿瘤转化为免疫浸润的“热”肿瘤并提高患者的存活率。新的 使用抗PD1加IO疗法的组合研究需求很高。因为CRC患者具有抵抗力 对于单一抗PD1疗法，需要一种新颖，更具侵略性的IO方法。具有预测的CRC全球 2022年的市场规模为$ 11B，PTA将被定位为一种IO疗法，将消除两种经过验证 治疗CRC患者并增加患者存活率的免疫抑制途径。