Antigen escape as a mechanism of resistance to T-cell-engaging therapies in multiple myeloma

T-cell-engaging therapies function to form an immune synapse between immune effectors and multiple myeloma (MM) cells. The transient durability of clinical response associated with T-cell engagers, and the mechanisms underlying these, are not fully understood. However, antigen escape is one of the key mechanisms that has been linked to resistance to T-cell engagers.¹

Here, we summarize a presentation by Paola Neri,¹ presented at the 5th Immune Effector Cell Therapies in Multiple Myeloma Workshop on the mechanisms of antigen escape after T-cell-redirecting therapies.

Key points^1,2

• Two of the most common targets for immunotherapies in MM are B-cell maturation antigen (BCMA) and G-protein-coupled receptor family C group 5 member D (GPRC5D).
  • Amongst both BCMA- and GPRC5D-directed T-cell engagers, clinical effectiveness is often transient, particularly in the relapsed/refractory setting.
• Antigen escape is one of the most prominent mechanisms of acquired resistance to T-cell-engaging therapies.
  • Target antigen loss is commonly observed following BCMA- and GPRC5D-directed CAR T-cell and T-cell-engaging therapies (Figure 1).
• A biallelic loss or mutation in TNFRSF17 has been observed in 42% of patients after treatment with T-cell-engaging therapies and 6% after BCMA-directed chimeric antigen receptor (CAR) T cells.
• Amongst patients treated with GPRC5D-directed CAR T cells, a reduction or loss of GPRC5D protein was observed in all six cases who experienced progression after treatment.
  • The downregulation of GPRC5D is often observed at the point of relapse after directed CAR T-cell therapy.
• Antigen escape can also be attributed to tumor heterogeneity and selection pressure.²
  • Interpatient and intratumor heterogeneity have both been linked to progression and therapy resistance.
• The genomic loss of BCMA is attributed to biallelic TNFRSF17 loss involving pre-existing chromosome 16p loss.
• A monoallelic loss of 16p may be associated with an increased risk of progression after BCMA-directed therapies.
• An epigenetic silencing of GPRC5D has been observed after treatment with talquetamab, associated with:
  • Biallelic genetic inactivation of GPRC5D; or
  • Long-range epigenetic silencing of its promoter and enhancer regions.

CAR, chimeric antigen receptor; MM, multiple myeloma.
Created with BioRender.com.
*Adapted from Golden, et al.³

Key learnings1

Resistance to T-cell-engaging therapies in MM are most commonly attributed to target antigen loss after BCMA- or GPRC5D-directed CAR T-cell and T-cell-engaging therapies. Evaluating patients for plasma cell genomic alterations as well as immune profiling may be used to identify patients with the highest likelihood of response to therapy and to aid in developing individualized treatment strategies.