Prevention of antigen escape by modulation of off-target tumor killing in T cells
Ivan Odak
PhDIcahn School of Medicine at Mount Sinai
Project Term: July 1, 2024 - June 30, 2026
T-cell mediated therapies are all impeded by the same cause- tumoral antigen (Ag) escape: rare Ag– cells in tumors survive the initial attack and lead to relapse. We recently took an innovative approach by enhancing T cells' ability to attack the Ag- cells during the initial treatment. That process is modular by pharmaceutical intervention.
The proposed project will analyze cryopreserved excisional B-NHL biopsies to identify possible pharmaceutical targets potentiating their 'vulnerability’.
B Cell Non-Hodgin's Lymphoma (B-NHL) is a type of cancer originating from the lymphatic system. Generally, B-NHL is considered incurable. However, Newer T cell (mediated) therapies such as bispecific antibodies (bsAbs) and Chimeric Antigen Receptor (CAR) T cells induce complete remission in a big number of B-NHL patients. This suggests that next aim of B-NHL therapies should be either durable remission or cure. However, T-cell mediated therapies are all impeded by the same cause- tumoral antigen (Ag) escape: rare Ag– cells in heterogeneous tumors survive the initial attack and lead to relapse. Indeed, following anti-CD19 CAR-T therapy or CD3xCD20 bsAbs a large proportion of relapsing patients have developed CD19- or CD20- tumors respectively. Retargeting another molecule (e.g.CD22) might be limited by either concurrent loss of candidate target or by lack of tumor-specific homogenously expressed Ag candidates.
Another way of tackling this problem is to prevent it altogether. We recently suggested an innovative approach by enhancing T cells' ability to attack the Ag negative cells during the initial treatment- thus eliminating potential relapse drivers. A large CD19 CART clinical trial already provided evidence that T cells may already utilize this process to prevent Ag escape as we provided evidence that Fas-expression is an even better predictor of survival than CD19 expression itself. Importantly, we demonstrated the modular nature of that process by pharmaceutical intervention.
The proposed project will utilize cryopreserved excisional biopsies from three prior cohorts to answer currently open questions by i) single-cell analysis of excisional B-NHL biopsies to identify possible pharmaceutical targets potentiating their 'vulnerability ' ii) investigation if bs-Ab treatment can further mediate the T cells' ability to kill Ag- negative cells and iii) assessment of possibility to pharmaceutically potentiate the process.