Research We Fund

This project will identify and engineer strategies to improve the function of chimeric antigen receptor (CAR) T cells in patients with relapsed/refractory large B-cell lymphoma. We will leverage our recent discoveries in lymphoma and CAR T cell therapy to (i) determine if the tumor influences the T cells that are harvested for CAR T manufacture, (ii) engineer T cells to be more resilient to suppressive signals in the tumor, and (iii) engineer T cells to have greater infiltration into tumors.

We have discovered that the tumor cells of the vast majority of follicular lymphoma cases have a unique tumor-specific feature in their major receptor. This is an essential modification that allows lymphoma cells to capture local support from tissue cells. Our investigation will add diagnostic and prognostic value and provide a new target for therapy. We will develop a new antibody approach which will improve the potency of existing treatments.

Follicular lymphoma (FL) affects ~110,000 Americans and is, unfortunately, frequently referred to as incurable, however, that may change in the near future.  Newer immune-based therapies induce remission in a majority of FL patients and the goal of FL therapy in 2024 should be durable remission or cure.  Immune therapies are, generally, more elegant than chemotherapies as they target specific proteins or ‘antigens’ expressed on tumor cells, e.g. the CD19 and CD20 antigens; however, these therapies thus share a common limitation: ‘antigen escape’ whereby rare tumor cells lacking the targeted antigen evade attack and cause relapse.

Richter’s transformation (RT) refers to the development of an aggressive lymphoma in patients with a prior diagnosis of chronic lymphocytic leukemia (CLL) that remains uncured, even with the current T-cell based immunotherapy such as chimeric antigen receptor (CARs) T cells. Fibroblastic reticular cells (FRCs) modulate T cells in secondary lymphoid organs (SLOs) via toll-like receptors (TLR) and promote the expression of PD-L1 and PD-L2 to modulate and suppress T cells especially cytotoxic T cells, however, the role of FRCs is not well defined in CLL or RT. Here, we propose to perform mechanistic and translational studies to understand if and how TLR9 plays a critical role in FRC-modulated suppressive T cell activities, and to determine whether targeting TLR9 in FRCs can reactivate T cell immunity and improve treatment outcome in RT.