Exploiting tumor metabolism to optimize T cell therapy

项目总结/文摘

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.