Mechanisms of antigen escape from BCMA- or GPRC5D-targeted immunotherapies in multiple myeloma

  • Nat Med. 2023 Aug 31. doi: 10.1038/s41591-023-02491-5.
Holly Lee  1 ,  Sungwoo Ahn  1 ,  Ranjan Maity  1 ,  Noemie Leblay  1 ,  Bachisio Ziccheddu  2 ,  Marietta Truger  3 ,  Monika Chojnacka  2 ,  Anthony Cirrincione  2 ,  Michael Durante  2 ,  Remi Tilmont  1 ,  Elie Barakat  1 ,  Mansour Poorebrahim  1 ,  Sarthak Sinha  4 ,  John McIntyre  5 ,  Angela M Y Chan  5 ,  Holly Wilson  5 ,  Shari Kyman  6 ,  Amrita Krishnan  7 ,  Ola Landgren  2 ,  Wencke Walter  3 ,  Manja Meggendorfer  3 ,  Claudia Haferlach  3 ,  Torsten Haferlach  3 ,  Hermann Einsele  8 ,  Martin K Kortüm  8 ,  Stefan Knop  8  9 ,  Jean Baptiste Alberge  10 ,  Andreas Rosenwald  11 ,  Jonathan J Keats  #  6  7 ,  Leo Rasche  #  12  13 ,  Francesco Maura  #  14 ,  Paola Neri  #  1 ,  Nizar J Bahlis  #  15
Affiliations
  • 1. Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada.
  • 2. Sylvester Comprehensive Cancer Center, Miami, FL, USA.
  • 3. MLL Munich Leukemia Laboratory, Munich, Germany.
  • 4. Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada.
  • 5. Precision Oncology Hub Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada.
  • 6. Translational Genomics Research Institute, Phoenix, AZ, USA.
  • 7. City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
  • 8. Department of Internal Medicine 2, University Hospital of Würzburg, Würzburg, Germany.
  • 9. Department of Internal Medicine 5, Paracelsus Medical School, Nuremberg General Hospital, Nuremberg, Germany.
  • 10. Harvard Medical School, Boston, MA, USA.
  • 11. Institute of Pathology, University of Würzburg, Würzburg, Germany.
  • 12. Department of Internal Medicine 2, University Hospital of Würzburg, Würzburg, Germany. [email protected].
  • 13. Mildred Scheel Early Career Center, University Hospital of Würzburg, Würzburg, Germany. [email protected].
  • 14. Sylvester Comprehensive Cancer Center, Miami, FL, USA. [email protected].
  • 15. Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada. [email protected].
  • # Contributed equally.
PMID: 37653344 DOI: 10.1038/s41591-023-02491-5
Abstract

B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates multiple myeloma (MM) resistance to anti-BCMA chimeric antigen receptor T cell (CAR T) or bispecific T cell engager (TCE) therapies. Emerging data report that downregulation of G-protein-coupled receptor family C group 5 member D (GPRC5D) protein often occurs at relapse after anti-GPRC5D CAR T therapy. To examine the tumor-intrinsic factors that promote MM antigen escape, we performed combined bulk and single-cell whole-genome Sequencing and copy number variation analysis of 30 patients treated with anti-BCMA and/or anti-GPRC5D CAR T/TCE therapy. In two cases, MM relapse post-TCE/CAR T therapy was driven by BCMA-negative clones harboring focal biallelic deletions at the TNFRSF17 locus at relapse or by selective expansion of pre-existing subclones with biallelic TNFRSF17 loss. In another five cases of relapse, newly detected, nontruncating, missense mutations or in-frame deletions in the extracellular domain of BCMA negated the efficacies of anti-BCMA TCE therapies, despite detectable surface BCMA protein expression. In the present study, we also report four cases of MM relapse with biallelic mutations of GPRC5D after anti-GPRC5D TCE therapy, including two cases with convergent evolution where multiple subclones lost GPRC5D through somatic events. Immunoselection of BCMA- or GPRC5D-negative or mutant clones is an important tumor-intrinsic driver of relapse post-targeted therapies. Mutational events on BCMA confer distinct sensitivities toward different anti-BCMA therapies, underscoring the importance of considering the tumor antigen landscape for optimal design and selection of targeted immunotherapies in MM.

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