Modulation of cancer induced immune suppression via inhibition of SCD1

项目摘要 代谢重编程在肿瘤发生中起着关键作用，部分原因是它能够促进免疫反应， 肿瘤内的抑制特性。目前尚不清楚抑制肿瘤中的脂肪酸代谢是否 影响其免疫原性。我们发现，抑制硬脂酰辅酶A去饱和酶1（SCD 1）， 参与脂肪酸合成的酶，将饱和酸（SFA）转化为单不饱和脂肪酸 MUFA增加了免疫原性差的肿瘤的免疫原性。我们的研究结果表明， 致瘤性从头脂肪生成代表了一种新的方法，以提高T细胞为基础的癌症 免疫疗法在此过程中，我们的新型先导SCD 1抑制剂（MTI-301; aka SSI-4）单独使用，以及与 使用免疫活性小鼠模型的免疫检查点抑制剂（ICI）显示出抗肿瘤协同作用 使肿瘤对ICI敏感，作为早期临床试验的前奏。我们还将优化疗效， 反应的预测性生物标志物，可用于设计和分层的患者在关键的 III期临床试验。SCD 1在侵袭性癌症中普遍上调，并通过MTI-301抗肿瘤药物验证 在广泛的癌细胞系和肿瘤小鼠模型中的活性。机械性地剥夺MUFA 在上瘾的癌细胞中，导致内质网（ER）应激介导凋亡性细胞死亡。我们 使用免疫活性小鼠癌症模型发现，MTI-301激活适应性免疫 通过ER应激途径的钙网蛋白/PERK臂的应答增强活化的T细胞肿瘤浸润， 从而促进抗PD 1抗体治疗。MTI-301与抗PD 1抑制剂联合使用可使肿瘤对PD 1敏感 小鼠三阴性乳腺癌（TNBC）和HER 2乳腺癌小鼠中的免疫检查点抑制剂 模型基于这些数据，我们的中心假设是异常的新生脂肪生成与以下因素有关： 肿瘤免疫原性的减弱。在这份快速通道第1/2阶段SBIR提案中提出了三个目标。在 目标1（里程碑1，I期SBIR），将完成GLP犬毒理学研究，以确定未观察到的- 副作用水平（NOAEL），能够计算I期临床试验的首次人体剂量。在Aim中 2（里程碑2，第二阶段SBIR），GMP MTI-301将与提交一起合成和封装 新药（IND）申请FDA I期试验批准的调查。在目标3（里程碑3，第二阶段SBIR）中， 将进行I期临床试验，探索性生物标志物，包括免疫浸润的鉴定 将评估肿瘤部位。总之，我们设想SCD 1作为广谱抗癌靶点， 在侵袭性恶性肿瘤中过度表达。在治疗上有用的是，MTI-301增加了免疫原性。 免疫原性差的肿瘤，从而对免疫检查点阻断敏感，导致显著的适应性免疫缺陷。 免疫介导的肿瘤细胞杀伤。这种联合治疗应该提高患者的反应率， 患者耐受良好。

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.