Posted: Tuesday, October 10, 2023
Francesco Maura, MD, of the University of Miami, Sylvester Comprehensive Cancer Center, and colleagues conducted a study to examine the intrinsic mechanisms of antigen escape from B-cell maturation antigen (BCMA)- and G protein–coupled receptor, class C, group 5, member D (GPRC5D)-directed immunotherapies in patients with multiple myeloma. Their findings, which were published in Nature Medicine, identified genomic events in their respective therapeutic targets as drivers of relapse.
“Recognizing these mutations and gaining a clearer understanding of the resistance mechanisms to these potent immunotherapies is pivotal,” commented Dr. Maura in an institutional press release. “This knowledge plays a crucial role in devising tailored strategies and making informed choices regarding the selection of products and targets for individual patients.”
The investigators performed combined bulk and single-cell whole-genome sequencing and a copy number variation analysis of 30 patients who were treated with anti-BCMA and/or anti-GPRC5D chimeric antigen receptor T-cell or bispecific T-cell engager therapy. In two cases, resistance was found to be driven by either BCMA-negative clones harboring focal biallelic deletions at the TNFRSF17 locus at relapse or selective expansion of preexisting subclones with biallelic TNFRSF17 loss. Despite detectable surface BCMA protein expression, in another five cases of relapse, the efficacy of anti-BCMA T-cell engager therapy seemed to be thwarted by newly detected, nontruncating missense mutations or in-frame deletions in the BCMA ectodomain.
“This finding revealed that the proportion of patients with myeloma who experience relapse due to antigen escape is considerably more extensive than initially anticipated,” said study coauthor Ola Landgren, MD, PhD, also of the University of Miami, Sylvester Comprehensive Cancer Center.
The investigators also reported four cases of relapse with biallelic mutations of GPRC5D in patients who received anti-GPRC5D T-cell engager therapy. This included two cases with convergent evolution, in which multiple subclones appeared to have lost GPRC5D via somatic events.
Disclosure: For full disclosures of the study authors, visit nature.com.