Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with multiple myeloma
Menée à partir du séquençage de l'ensemble du génome de cellules de moelle osseuse de patients atteints d'un myélome multiple, cette étude met en évidence, dans le cadre d'un essai clinique évaluant un traitement par lymphocytes CAR-T ciblant l'antigène de maturation des lymphocytes B (BCMA), la présence chez un patient de cellules cancéreuses présentant une délétion homozygote du gène codant pour BCMA puis analyse le mécanisme moléculaire pouvant expliquer ce type de délétion
B cell maturation antigen (BCMA) is a target for various immunotherapies and a biomarker for tumor load in multiple myeloma (MM). We report a case of irreversible BCMA loss in a patient with MM who was enrolled in the KarMMa trial (NCT03361748) and progressed after anti-BCMA CAR T cell therapy. We identified selection of a clone with homozygous deletion of TNFRSF17 (BCMA) as the underlying mechanism of immune escape. Furthermore, we found heterozygous TNFRSF17 loss or monosomy 16 in 37 out of 168 patients with MM, including 28 out of 33 patients with hyperhaploid MM who had not been previously treated with BCMA-targeting therapies, suggesting that heterozygous TNFRSF17 deletion at baseline could theoretically be a risk factor for BCMA loss after immunotherapy.
Nature Medicine 2021