Exploiting tumor metabolism to optimize T cell therapy

项目总结/摘要 前列腺癌和乳腺癌仍然是男性和女性最常见的恶性肿瘤。MSKCC 积极开发新的治疗策略，包括前列腺特异性膜抗原（PSMA） 特异性过继性CAR T细胞疗法和与代谢和免疫相关的作用相关的全面研究 检查点（抗PD 1/PDL 1/CTLA 4）免疫调节治疗。Serganova博士带来独特的经验 和报告系统的专业知识，适用于PET成像，以监测T细胞运输，激活和 持久性非侵入性，补充上述努力在MSKCC。她一直是高级研究员 在过去的10年里，他一直是Blasberg实验室的科学家，也是许多赠款的主要研究者， 与P50（体内细胞和分子成像中心，ICMIC），重复资助超过3个周期（2000- 2016）。Blasberg实验室一直获得NCI的资助，并专注于“成像免疫模块- 嵌合抗原受体（CAR）T细胞疗法中的作用”（亲本R 01 CA 204924; 7/16 -6/21）;和“成像 肿瘤和T细胞对代谢和免疫调节疗法的应答”（亲本R 01 CA 215136; 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发生有影响。 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（包括减少的肿瘤浸润内源性TIL和CAR-T细胞，在两种情况下， 乳腺癌和前列腺癌模型）。LDH-A耗竭和检查点阻断可增加患者的长期生存率 乳腺癌模型，并增强前列腺癌模型中PSMA指导的CAR T细胞疗法。 有待验证的假设包括：1）LDH-A/乳酸水平、HIF-1、肿瘤细胞增殖和凋亡之间存在“因果联系”。 LDH-A和HIF-1之间存在相互作用， 转录因子，对连接代谢、血管生成和血管生成的下游靶点具有显著影响， 免疫抑制;以及3）这种相互作用对TME以及对T细胞靶向和活化有影响 在肿瘤进展和转移的发展过程中。 研究计划中要解决的问题包括：1）LDH-A耗竭是否显著改变HIF-1 活性及其下游靶点（VEGF-A），以及主要影响哪些信号通路？2)什么 是代谢特征（乳酸/LDH-A状态）、TME、免疫反应性 以及不同实体瘤转移灶的形成？3)LDH-A/乳酸代谢谱是否 与免疫特征（内源性TILs和CAR-T运输）呈负相关，这是否与实体瘤相关？ 肿瘤进展和转移发展？4)LDH-A耗竭是否对TGFβ1和TGF β 2有影响？ 在已建立的肿瘤模型和免疫细胞（CAR T细胞）中的NFAT-1通路活性？我的目标 R50应用程序中的研究计划与两个R 01母公司一致，但它们也带来了新的概念 这可能会发展成为新的治疗策略，在MSKCC更充分地探索在未来。

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.