Nizar Jacques Bahlis: Thrilled to share our work Nature Medicine, led by the very talented Holly Lee, with Dr Paola Neri, Francesco Maura, Leo Rasche, Jonathan Keats.
Nizar Jacques Bahlis, associate professor at the Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary and member of the Divisions of Hematology and Medical Oncology, shared the following insights on Twitter:
“Thrilled to share our work Nature Medicine, led by the very talented Holly Lee, with Dr Paola Neri, Francesco Maura, Leo Rasche, Jonathan Keats.
We uncovered mechanisms of resistance & differential sensitivity to BCMA- or GPRC5D-targeting T cell engagers TCE / CART. Anti-BCMA and -GPRC5D CAR T and TCE have yielded unprecedented responses in TCR myeloma (MM) with 2 FDA approved anti-BCMA CART and 3 TCEs.
Despite promising initial responses, MM relapse remains inevitable. BCMA antigen escape post anti-BCMA therapies has thus far been considered rare, involving biallelic deletion or monoallelic deletion with truncating mutations in the BCMA encoding gene TNFRSF17.
We set out to examine MM intrinsic mechanisms of escape to targeted immunotherapies by performing WGS and single cell CNV analysis of bone marrow MM samples from 30 patients who received anti-BCMA or -GPRC5D CAR T or TCE. We highlight our key findings:
#1. We identified BCMA antigen escape post anti-BCMA TCE in 42.8% of patients at progression, much more frequent than previously reported post anti-BCMA CAR T. GPRC5D loss was more prevalent with 80% cases showing evidence of antigen escape at relapse post anti-GPRC5D TCE.
#2. Patterns of convergent clonal evolution for BCMA Ag escape include 1) emergence of previously undetected clones with biallelic TNFRSF17 del, 2) expansion of pre-existing minor clones with biallelic TNFRSF17del or expansion of pre-existing clones with monoallellic TNFRSF17 del with de-novo non-truncating BCMA extracellular domain mutations.
#3. Recurrent hotspot mutations in BCMA extracellular domain included p.Arg27Pro (n=1), p.Pro34del (n=3), and p.Ser30del (n=2), with one patient carrying two MM clones with different BCMA mutations.
#4. Acquired resistance to one anti-BCMA TCE does not equate to pan-resistance to other anti-BCMA TCE/ CAR T. Despite retaining surface BCMA expression, these BCMA extracellular domain mutants differentially abrogated binding and cytotoxicity of anti-BCMA TCEs, all the while retaining sensitivity to anti-BCMA CAR T. These findings provide guidance for the selection and sequencing of TCE and CAR T (Main Figure 4 in manuscript).
#5. These BCMA extracellular domain mutants retained APRIL binding and NF-kB signaling, and therefore maintained APRIL-BCMA pro-survival signaling while evading TCE binding (Extended Data Figure 7 in manuscript).
#6. Screening for BCMA extracellular domain mutations requires NGS based methodologies or functional binding assays. These mutants retain surface BCMA expression, rendering polyclonal anti-BCMA flow or IHC antibodies ineffective as a screening method.
#7. Soluble BCMA may not always reflect disease burden in certain BCMA extracellular domain mutations. BCMA p.Arg27Pro failed to shed soluble BCMA (Extended Data Figure 4 in manuscript).
#8. GPRC5D Ag escape demonstrated evidence of convergent evolution. In 4/5 cases of relapse post anti-GPRC5D TCE, we detected presence of clones harboring GPRC5D biallelic or monoallelic del with variable GPRC5D mutations leading to Ag escape (Extended Data Fig 10).
Incorporating serial genomic and/ or functional interrogation of immunotherapy-targeted antigens will be required for optimal selection, sequencing, and development of immunotherapeutic agents in MM.”
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Source: Nizar Jacques Bahlis / Twitter