Metabolic regulation of T cell effector function and anti-tumor immunotherapy

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

One critical aspect impacting on T cell proliferation and function is the host environment. The activation and effector functions of adoptively-transferred T lymphocytes are associated with increased energetic and biosynthetic demands, generally secured by augmented nutrient entry and utilization. However, the potential of an engineered anti-tumor T cell (using a chimeric antigen receptor (CAR) or T cell receptor (TCR)) to respond to tumor antigens is often negatively modulated by the metabolic environment of the tumor. This environment is conditioned by nutrient composition, "waste" products, oxygen concentration, pH and physical forces, amongst others. The dysregulated growth of cancer cells can directly influence the extracellular environment and negatively impact on the ensuing immune response. These differences in metabolite environment may account for at least one of the mechanisms modulating the success of CAR-T cells directed against diffuse leukemias (i.e. CD19-CAR) as compared to solid tumors. Indeed, we have found that specific metabolites regulate T cell differentiation and function. We have identified alpha-ketoglutarate, a metabolite derived from glutamine, as a regulator in the balance between effector Th1 vs regulatory T cell (Treg) differentiation; it increases Th1 polarization while significantly inhibiting Treg generation. Consistent with these data, alpha-ketoglutarate promoted the effector profile of Treg-polarized CAR T cells against a tumor antigen. Further studies are evaluating the impact of metabolites on CAR T function with the goal of generating CAR T cells with an optimized persistence and function in the tumor microenvironment. We hypothesize that variability in CAR T cell immunotherapeutic potential is affected by variations in manufacturing platforms (in collaboration with Drs. David Stroncek and Steven Highfill) and can be predicted through evaluation of antigen-dependent CAR T cell activity. We are therefore comparing different CAR selection and production processes and are developing systems wherein the dynamic differentiation features of CAR-T cells can be evaluated as a function of the CAR construct and patient-specific characteristics. To this end, we are using a high throughput Immunotron system for immune monitoring in collaboration with Gregoire Altan-Bonnet's lab, allowing an analysis of CART as a function of the secretion/consumption of 7 cytokines and T cell activation parameters. This computational pipeline is being used to monitor real-time responses of CAR-T cells from patients who have been treated with CD22-CAR and CD19/CD22 CAR vectors at the NIH (PI: Nirali Shah) and comparing these data with CD22-CART generated on a different platform at Stanford (PI: Crystal Mackall). These data are being leveraged to optimize CAR manufacturing, evaluate divergent patient outcomes, and enhance durable responses in pediatric leukemia patients. Using data from a phase I bivalent CD19.22.BBz CAR T-cell trial for pediatric ALL (PI: Nirali Shah), we developed a novel bicistronic CD19.28z/CD22.BBz construct with enhanced dual-targeting efficacy. This CAR is presently being evaluated in a phase 1/2 clinical trial (NCT05442515). Furthermore, as"Ph-like" ALL is a high risk subgroup of B-ALL wherein half of childhood and adult Ph-like ALL cases have rearrangements in cytokine receptor like factor-2 (CRLF2) encoding the thymic stromal lymphopoietin receptor (TSLPR), we are presently investing significant efforts into the development of a clinical trial targeting TSLPR with a TSLPR-specific CAR.