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.

Figure 1. Antigen escape as a mechanism of resistance to CAR T-cell therapy*

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