Modulation of both tumor and T cell apoptosis to enhance CART immunotherapy
Sponsor
Chimeric Antigen Receptor T-cell (CART) immunotherapy has led to unprecedented responses in patients with refractory or relapsed B-cell Non-Hodgkin’s Lymphoma (NHL). However, only one-third of patients achieve long-term remission. We hypothesized that enhanced sensitivity to apoptosis in tumor cells would increase the efficacy of CART therapy. We demonstrated that low expression in leukemic blasts of pro-apoptotic factors related to the extrinsic pathway are associated with poor outcomes after treatment with CART19 in both pediatric and adult B-ALL. In another recently published study, we studied the role of the intrinsic pathway and, in particular, BCL-2 in NHL patients treated with CART19. We observed that the response rate in patients harboring BCL-2 translocation and gain was the most inferior overall as compared to that in patients without BCL-2 alterations.
Based on these results, we combined pro-apoptotic small molecules with CART in vitro and in vivo. While observing initial synergy, we noticed toxicity with long-term CART treatment. To combat this, we developed a strategy to endow CART cells with resistance to pro-apoptotic drugs and developed this combination in multiple models. Finally, we studied the role of BCL-2 in CART cells and found that CART cells overexpressing BCL-2 as measured by NanoString® nCounter® gene expression analysis persist longer in vivo and lead to better tumor control compared to wild-type CART. In conclusion, our work highlights the importance of apoptosis in both cancer cells and CART cells in driving response to CART immunotherapy and describes potential strategies to overcome resistance.
- CART cell immunotherapy is leading to outstanding clinical results in lymphoma, but only one-third of patients have long-term responses
- Resistance to apoptosis in cancer cells is a key feature of CART immunotherapy failure, and strategies to enhance tumor apoptosis during CART therapy lead to better tumor control
- Apoptosis also plays a role in the function of CART cells, limiting their role term function; modulation
SPEAKERS
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