Yan X, Chen D, Guo Y, et al. Identification of NOXA as a Pivotal Regulator of Resistance to CAR T-Cell Therapy in B-Cell Malignancies. Signal Transduction and Targeted Therapy. 2022; 7 (98) (doi: 10.1038/s41392-022-00915-1).
Unbiased CRISPR/Cas9 screening implicates loss of NOXA as a contributor to failed chimeric antigen receptor (CAR) T-cell treatment, but pharmacological targeting of the B-cell lymphoma 2 family protein promises to improve immunotherapy for B-cell malignancies. T cells eradicate cancer cells by initiating apoptosis, but investigators suspect NOXA ablation disrupts this process, thereby facilitating resistance to CAR T cells. In a sample of patients undergoing CD19/20 CAR T-cell therapy, they observed that patients with low NOXA expression in tumor samples had a worse response to immunotherapy than those with high NOXA expression. Additional analysis indicated that low NOXA level correlated to poor overall and progression-free survival outcomes in relapsed or refractory B-cell lymphoma. However, using histone deacetylase inhibitors to increase NOXA expression makes tumor cells more vulnerable to CAR T cells. Based on this understanding, investigators propose that NOXA might be leveraged as a prognostic resource for response and survival in patients undergoing CAR T-cell transfusions.