Exploiting tumor metabolism to optimize T cell therapy

项目摘要/摘要 前列腺癌和乳腺癌分别是男性和女性最常见的恶性肿瘤。MSKCC 正在积极开发新的治疗策略，包括前列腺特异性膜抗原(PSMA) 特异性采用CAR T细胞疗法以及与代谢和免疫调节相关的综合研究 检查点(抗PD1/PDL1/CTLA4)免疫调节疗法。Serganova博士带来独特的体验 以及适用于PET成像的报告系统的专业知识，以监测T细胞的运输、激活和 坚持不懈，非侵入性，这是对MSKCC上述努力的补充。她一直是一名高级研究员 在过去的10年里一直是布拉斯伯格实验室的科学家，一直是许多拨款的关键研究员，从 P50(在活体细胞和分子成像中心，ICMICs)，重复资助3个周期(2000- 2016)。布拉斯伯格实验室一直得到NCI的资助，并专注于“成像免疫调节-- 在嵌合抗原受体(CAR)T细胞治疗中的应用“(Parent R01 CA204924；7/‘16-6/’21)；以及”成像“ 肿瘤和T细胞对代谢和免疫调节治疗的反应“(Parent R01 CA215136；7/‘17-6/’22)。 初步数据显示，LDH-A在肿瘤中的表达对代谢表型和肿瘤有影响 微环境(包括乳腺癌模型中HIF-1活性降低、血管形成和坏死) 和免疫抑制(包括减少肿瘤的内源性TIL和CAR-T细胞，在两者中 乳腺癌和前列腺癌模型)。LDH-A耗尽和检查点封锁增加了大鼠的长期存活率 乳腺癌模型，并加强前列腺癌模型中PSMA导向的CAR T细胞治疗。 有待检验的假说包括：1)LDH-A/乳酸水平、HIF-1、肿瘤 微环境(TME)与免疫反应性；2)LDH-A与HIF-1之间存在相互作用 转录因子，对连接新陈代谢、血管生成和 免疫抑制；3)这种相互作用对TME、T细胞靶向和激活有影响 在肿瘤进展和转移的发展过程中。 研究计划中需要解决的问题包括：1)LDH-A耗竭是否会显著改变HIF-1 活性及其下游靶点(血管内皮生长因子-A)，以及主要影响的信号通路？2)什么 代谢特征(乳酸/LDH-A状态)、TME、免疫反应性、 不同实体瘤中转移的形成？3)LDH-A/乳酸代谢谱 与免疫状况(内源性TIL和CAR-T运输)呈负相关，这与固体有关吗 肿瘤进展和转移发展？4)LDH-A缺失对转化生长因子β1和 NFAT-1通路在已建立的肿瘤模型和免疫细胞(CAR T细胞)中的活性？我的目标是 这个R50应用中的研究计划与两个父R01一致，但他们也带来了新的概念 这可能会发展成新的治疗策略，未来将在MSKCC更全面地探索。

PROJECT SUMMARY/ABSTRACT Prostate and breast cancers remain the most common malignancy in men and women, respectively. MSKCC is actively developing new therapeutic strategies, including Prostate Specific Membrane Antigen (PSMA) specific adoptive CAR T cell therapy and comprehensive studies related to the role of metabolism and checkpoint (anti-PD1/PDL1/CTLA4) immune modulation therapy. Dr. Serganova brings unique experience and expertise in reporter systems suitable for PET imaging to monitoring T cell trafficking, activation and persistence non-invasively that complement the above efforts at MSKCC. She has been a Senior Research Scientist in the Blasberg Lab for the last 10 years and has been a key investigator on many grants, starting with a P50 (In Vivo Cellular and Molecular Imaging Centers,ICMICs), funded repetitively over 3 cycles (2000- 2016). The Blasberg lab has consistently received NCI funding and is focused on “Imaging immune modula- tion in chimeric antigen receptor (CAR) T cell therapy” (parent R01 CA204924; 7/'16-6/'21); and “Imaging tumor and T cell responses to metabolic and immune modulation therapy” (parent R01 CA215136; 7/'17-6/'22). Preliminary data show that LDH-A expression in tumors has an impact on the metabolic phenotype and tumor microenvironment (including diminished HIF-1 activity, vascularization and necrosis in a breast cancer model) and on immune suppression (including reduced tumor infiltration endogenous TILs and CAR-T cells, in both breast and prostate cancer models). LDH-A depletion and checkpoint blockade increases long-term survival in the breast cancer model, and enhances PSMA-directed CAR T cell therapy in the prostate cancer model. Hypotheses to be tested include: 1) there is a “cause/effect link” between LDH-A/lactate level, HIF-1, the tumor microenvironment (TME) and immune responsiveness; 2) there is an interplay between LDH-A and the HIF-1 transcription factor, with significant influences on downstream targets that link metabolism, angiogenesis and immunosuppression; and 3) this interplay has an impact on the TME, and on T cell targeting and activation during tumor progression and development of metastases. Questions to be addressed in the Research Plan include: 1) Does LDH-A depletion significantly change HIF-1 activity and its downstream targets (VEGF-A), and what signaling pathways are primarily affected? 2) What are the relationships between the metabolic profile (lactate/LDH-A status), the TME, immune responsiveness, and the formation of metastases in different solid tumors? 3) Does the LDH-A/lactate metabolic profile correlate inversely with the immune profile (endogenous TILs and CAR-T trafficking), and is this related to solid tumor progression and metastases development? 4) Does LDH-A depletion have an effect on TGFβ1 and NFAT-1 pathway activity in established tumor models and immune cells (CAR T cells)? The goals of my research plan in this R50 application are consistent with the two parent R01s, but they also bring new concepts that could develop into novel therapeutic strategies to be explored at MSKCC more fully in the future.