Modulation of cancer induced immune suppression via inhibition of SCD1

项目总结 代谢重编程在癌症的发生中起着关键作用，部分原因是它能够促进免疫。 肿瘤内的抑制特性。目前尚不清楚是否抑制肿瘤中的脂肪酸代谢 会影响它们的免疫原性。我们发现抑制硬脂酰辅酶A去饱和酶1(SCD1)的速率限制 参与脂肪酸合成的酶将饱和酸(SFA)转化为单不饱和脂肪酸 (MUFAs)，增加免疫原性低的肿瘤的免疫原性。我们的结果表明，抑制 致瘤性新生脂肪生成是增强T细胞肿瘤的一种新方法 免疫疗法。在这样做的过程中，我们的新型领先的SCD1抑制剂(MTI-301；又名SSI-4)单独，并与 免疫检查点抑制物(ICIS)在免疫活性小鼠模型中的抗肿瘤协同作用 使肿瘤对ICIS敏感，作为早期临床试验的前奏。我们还将优化疗效，寻求 可用于危重患者的设计和分层的预测性生物反应标志物 第三阶段临床试验。SCD1在侵袭性癌症中普遍上调，并被MTI-301抗肿瘤药物证实 在广泛的癌细胞系和肿瘤小鼠模型中的活性。从机制上讲，MUFA被剥夺 在成瘾的癌细胞中导致内质网(ER)应激，介导细胞凋亡。我们 利用免疫活性小鼠肿瘤模型发现MTI-301激活获得性免疫 通过内质网应激途径的钙网蛋白/PERK臂促进活化的T细胞肿瘤侵袭和 从而促进了抗PD1抗体的治疗。与抗PD1抑制剂联合使用，MTI-301使肿瘤对 免疫检查点抑制剂对小鼠三重阴性乳腺癌和HER2乳腺癌小鼠的作用 模特们。基于这些数据，我们的中心假设是异常的新生脂肪生成与 肿瘤免疫原性减弱。在这一快速通道1/2阶段SBIR提案中提出了三个目标。在……里面 目标1(里程碑1，第一阶段SBIR)，将完成普洛斯狗的毒理学研究，以确定未观察到的- 不良反应水平(NOAEL)允许计算I期临床试验的第一个人体剂量。在AIM 2(里程碑2，第二阶段SBIR)，GMP MTI-301将与提交的 新药(IND)申请FDA第一阶段试验批准的调查。在AIM 3(里程碑3，第二阶段SBIR)中， 将进行一期临床试验和探索性生物标记物，包括鉴定免疫浸润物 进入肿瘤部位的情况将进行评估。总而言之，我们设想scd1将成为广谱抗癌的靶点。 在侵袭性恶性肿瘤中过度表达。在治疗上有用，MTI-301增加了免疫原性 免疫原性差的肿瘤因此对免疫检查点阻断敏感，导致戏剧性的适应性 免疫介导的肿瘤细胞杀伤。这种联合疗法应该会提高患者的应答率，并 患者耐受性良好。

PROJECT SUMMARY Metabolic reprogramming plays a critical role in carcinogenesis, in part due its ability to promote immune suppressive properties within tumors. It remains unclear whether inhibition of fatty acid metabolism in tumors affects their immunogenicity. We show that inhibition of stearoyl CoA desaturase 1 (SCD1), the rate limiting enzyme involved in fatty-acid synthesis converting saturated acids (SFA) to monounsaturated fatty acids (MUFAs), increases the immunogenicity of poorly immunogenic tumors. Our results indicate that inhibition of tumorigenic de novo lipogenesis represents a novel approach to enhance T cell-based cancer immunotherapy. In so doing, our novel lead SCD1 inhibitor (MTI-301; aka SSI-4) singly, and in combination with immune checkpoint inhibitors (ICIs) using immune competent mouse models demonstrates anti-tumor synergy sensitizing tumors to ICIs, as a prelude to an early phase clinical trial. We will also optimize efficacy and seek predictive biomarkers of response that could be useful for the design and stratification of patients in the critical Phase III clinical trial. SCD1 is universally upregulated in aggressive cancers and validated by MTI-301 antitumor activity across a broad range of cancer cell lines and tumor mouse models. Mechanistically, MUFA deprivation in addicted cancer cells leads to endoplasmic reticulum (ER) stress mediating apoptotic cell death. We discovered using immune competent mouse cancer models that MTI-301 activates the adaptive immune response via calreticulin/PERK arm of the ER stress pathway enhancing activated T cell tumor infiltration and thereby promoting anti-PD1 antibody therapy. Combined with anti-PD1 inhibitor, MTI-301 sensitizes tumors to immune checkpoint inhibitors in mouse triple negative breast cancer (TNBC) and HER2 breast cancer mouse models. Based upon these data, our central hypothesis is that aberrant de novo lipogenesis is linked to attenuation of tumor immunogenicity. Three aims are proposed in this fast-track Phase 1/2 SBIR proposal. In Aim 1 (Milestone 1, Phase I SBIR), GLP dog toxicology study will be completed to identify the No-observed- adverse-effect level (NOAEL) enabling calculation of the first in human dose for the phase I clinical trial. In Aim 2 (Milestone 2, Phase II SBIR), GMP MTI-301 will be synthesized and capsulated along with submission of the investigation of new drug (IND) application for FDA Phase I trial approval. In Aim 3 (Milestone 3, Phase II SBIR), a Phase I clinical trial will be performed and exploratory biomarkers including identification of immune infiltrates into the tumor site will be assessed. In summary, we envision SCD1 as a broad-spectrum anti-cancer target overexpressed in aggressive malignancies. Therapeutically useful, MTI-301 increases the immunogenicity of poorly immunogenic tumors thereby sensitizing to immune checkpoint blockade, leading to dramatic adaptive immune mediated tumor cell killing. This combination therapy should enhance patient response rates and be well tolerated in patients.