CD79b as a novel target for CAR T-cell therapy in B-cell malignancies
Sattva Neelapu
MDThe University of Texas MD Anderson Cancer Center
Project Term: July 1, 2019 - June 30, 2022
Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 induces durable remissions in a significant proportion of patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphomas (NHL). However, relapse or progression occurs in ~60% of patients with majority of them experiencing CD19 loss in their tumors. Here, we will characterize the mechanism of CD19 loss in NHLs and develop CD79b CAR T-cell therapy as a novel approach to overcome CAR T resistance due to CD19 loss.
Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive B-cell non-Hodgkin’s lymphoma (NHL) in the US and worldwide. First-line chemotherapy cures about 60% of patients with DLBCL. However, patients who do not respond to first or second-line therapy have a very poor prognosis with average survival of only about 6 months. Genetically engineered T-cell therapy called chimeric antigen receptor (CAR) T-cell therapy is rapidly emerging as a promising treatment for these patients. Indeed, three large multicenter clinical trials have recently shown that CAR T-cell therapy targeting CD19 on tumor cells in aggressive B-cell NHL can induce durable remissions in approximately 40% of the patients suggesting that this therapy may be potentially curative. Although this novel therapy offers hope for these patients, it is not effective in all. In fact, about 60% develop relapsed disease after CD19 CAR T-cell therapy. These patients currently have no standard treatment options available and there is an urgent need to develop novel therapies. We observed that a major reason for failure to achieve durable remission after CD19 CAR T-cell therapy is loss of the CD19 target on the surface of the tumor cells. In this proposal, we will develop CAR T-cell therapy against an alternate target, CD79b, on tumor cells in DLBCL. In preliminary studies, we found that CD79b CAR T-cells could kill DLBCL tumor cells. We will investigate this further in this project in preclinical models of lymphoma with and without CD19 expression. Our short-term goal is to initiate a clinical trial by year 4 to test the safety and efficacy of this novel CD79b CAR T-cell therapy in patients with DLBCL relapsing after CD19 CAR T-cell therapy. We will also develop and evaluate a novel bi-specific CAR T-cell therapy targeting CD19 and CD79b in preclinical models of DLBCL with the goal of minimizing immune escape due to target loss in the future. In summary, we will use cutting-edge technologies to develop a novel CAR T approach to target CD79b to increase the efficacy and minimize the chance of immune escape and relapse after CAR T-cell therapy. In the long-term, these studies are expected to significantly improve the survival and curability of patients with relapse or refractory DLBCL as well as other B-cell malignancies.