Research in the Fraietta laboratory focuses on the generation of innovative immunotherapy strategies involving T cells and their impact on immunity, tumor biology and the tissue/tumor microenvironment in the setting of translatable preclinical studies. We use primary patient samples, in vitro systems and cutting-edge animal models to 1) understand the factors and mechanisms associated with successful adoptive transfer of T cells, with the goal of improving the functions of both endogenous and gene-modified T cells, 2) develop mechanism-based strategies to enhance the survival, expansion and potency of infused T cell products directed against tumors and viral pathogens, and 3) devise methods to modulate the host immune environment to optimally activate T cells.

The current direction within the laboratory is to address both basic and clinical research questions on the role of human T cells in mediating effective anti-tumor immune responses. Our specific areas of interest are as follows:

Next-generation Synthetic Biology: We use a variety of genetic engineering approaches to redirect T cells to recognize and destroy tumors, while sparing healthy tissues. These efforts include the development of CARs and other synthetic immunoreceptors/signaling systems with more potent effector activity, enhanced durability and improved safety, compared to conventional cellular therapeutics. From these studies we have developed expertise in multiple aspects of genome editing to target the major mechanisms of resistance and toxicity in CAR T cell therapy, with the objective of increasing the efficacy of this already transformational approach.

Epigenetic Modulation of Immune Cell Function: Cell fate determination programs encoded in DNA are interpreted, modified, transmitted and expanded as chromatin. Memory and effector CD8+ T cell differentiation from naive precursors requires broad chromatin changes, leading to global or site-specific reprogramming of gene expression. The diversity of signals encountered by T cells requires a matching capacity for transcriptional outcomes provided by the dynamic nature of the epigenome. Important gaps remain in our understanding of the epigenetic landscape of functional and defective T cells in cancer. In this vein, our goals are to investigate epigenetic variation that influences the efficacy of CAR T cell immunotherapy, use epigenetic therapeutics to overcome resistance, identify genes that can be targeted for stable epigenetic programming and develop methods for modifying these programs to reinvigorate the cells in way that improves their anti-tumor potency. These efforts hold great promise for answering long-standing questions as well as generating the most robust antigen-specific T cells for highly effective adoptive cell transfer therapies.

Biomarkers of Response and Resistance to Cellular Immunotherapy: Our main endeavor in this area is the phenotypic and functional characterization of T cells directly isolated and expanded from cancer patients. We are also interested in determining how tumor antigen-specific lymphocytes in hematological malignancies and solid tumors change following CAR T cell infusion or treatment of patients with immunomodulatory agents. These efforts will elucidate the critical determinants of successful CAR T cell-mediated anti-tumor responses in individuals responding to the therapy, and may reveal several actionable ways to overcome resistance in subjects who do not respond. Such predictive biomarkers can be utilized by physicians to prescribe CAR T cell therapy only to the responding patient population, thus eliminating the unnecessary expense and risk of immune-related adverse events for non-responders. Given the intensive cell manufacturing process required for CAR T cell generation, the potential toxicity, and possible new alternative treatments, the ability to use immunological biomarkers to identify which patients are most likely to respond would greatly benefit these individuals and lead to an optimal personalized approach to therapy. Our investigations will ultimately allow us to intervene and generate maximally active CAR T cell products for most, if not all, future patients.