CD19 CAR T-cell therapy has been a major breakthrough and is the last chance of a cure for many relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients. Despite the success, over 50% of patients fail to respond or relapse following an initial response. Identifying patients that are likely to fail such a therapy is an important challenge, and could potentially allow for the consolidation with additional therapy following CAR T infusion to improve its efficacy. In addition, elucidating the mechanisms of primary resistance/relapse will help develop novel combinational strategies targeting the resistance mechanisms to improve its efficacy. We have found that monitoring tumor mutations...

Read More

CD19 CAR T-cell therapy has been a major breakthrough and is the last chance of a cure for many relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients. Despite the success, over 50% of patients fail to respond or relapse following an initial response. Identifying patients that are likely to fail such a therapy is an important challenge, and could potentially allow for the consolidation with additional therapy following CAR T infusion to improve its efficacy. In addition, elucidating the mechanisms of primary resistance/relapse will help develop novel combinational strategies targeting the resistance mechanisms to improve its efficacy. We have found that monitoring tumor mutations in the blood allows for prediction of treatment failure in the first week following therapy. Using parallel analysis of CAR T-cells themselves, we identified a signature of T-cell dysfunction associated with treatment failure and identified LAG3 and TIM3 as important regulators of T cell dysfunction. Both molecules can be targeted by therapeutic antibodies. Based on our preliminary data, we proposed three aims: (Aim 1): Validate day 7 molecular response as a powerful predictor of long-term clinical outcome in a larger cohort of DLBCL patients; (Aim 2): Characterize the features of CD19 CAR T-cells associated with their exhausted activity, examine when T-cell exhaustion occurs and how it alter T-cell functionality following infusion to the patient; (Aim 3): Examine whether LAG3 and/or TIM-3 inhibition can improve T-cell function in DLBCL mouse models. The proposed project, if successful, will have a major impact on cancer. It will lead to the development of a CLIA-certified test for early and dynamic response assessment, a practical signature for response prediction, and novel strategies to improve the efficacy of CAR T-cell therapy. Such knowledge can be broadly applicable to CAR T-cell therapy that is being expanded to a wider spectrum of other malignancies.

Read Less