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.

SYNTHS SBIR I期项目总结/摘要 结直肠癌（CRC）是美国第三大常见癌症，也是癌症死亡的第二大原因。 大约15-20%的CRC患者具有高微卫星不稳定性（MSI-H）。尽管FDA- 获批的免疫检查点、抗PD 1抗体、nivolumab和pembrolizumab在MSI-H中有效 在CRC中，患者有效率为28- 35%。其余80%的CRC患者 微卫星稳定（MSS）不响应抗PD 1/PDL 1。在这两方面都有相当大的改进空间 新的联合IO治疗应1）促进MSI-H患者的缓解，和/或2）提供新的 为大多数具有免疫抑制“冷”肿瘤的检查点耐药CRC患者提供治疗选择。 TGF-β是一种免疫抑制细胞因子，在晚期CRC患者中水平升高， 适应性免疫系统和降低生存率。在鼠结肠癌模型中，阻断PD 1 通路导致TGF-β信号传导的代偿性增加，而阻断这两条通路导致肿瘤发生。 回归分析由于历史上全身性TGF-β阻断会导致一系列重大问题，包括宿主 由于其毒性，需要新的TGF-β疗法将IO疗法抗性的“冷”CRC转化为免疫原性CRC， “热”肿瘤驱动肿瘤清除。在Synthis，我们正在开发一种新颖的，更具侵略性的检查点 联合TGF-β抑制剂（命名为PTA）治疗以根除CRC。在目标1中，我们将证明， PTA在体外逆转免疫抑制，并恢复肿瘤清除的关键途径，如IFN-γ 表达和细胞毒性T细胞介导的肿瘤杀伤。在目标2中，我们将在结肠癌模型中测试PTA， 体内，使用人源化HuGEMM PD 1小鼠模型，其在T细胞上表达人PD 1。PTA将 在体内PD试验中进行测试，以确定用于疗效研究的适当剂量范围。然后我们将 测试PTA在体内MC 38结肠癌模型中的功效，以及收获肿瘤浸润淋巴细胞 （TIL）以研究PTA对免疫细胞浸润和/或活化的影响。PTA的最终目标是 将“冷”CRC肿瘤转化为免疫浸润的“热”肿瘤，提高患者存活率。新 抗PD 1加IO疗法的联合研究需求很高。因为CRC患者对 与单一抗PD 1疗法相比，需要一种新的、更具侵略性的IO方法。预测CRC全局 到2022年，PTA的市场规模将达到110亿美元，PTA将被定位为一种单一的IO治疗， 免疫抑制途径来治疗CRC患者并增加患者存活率。