Bispecific antibodies in multiple myeloma: understanding therapy resistance through imaging

Summary Bispecific T-cell engager antibodies (BiTEAs) targeting the B cell maturation antigen (BCMA) and G protein coupled receptor class C group 5 member D (GPRC5D) have shown promising efficacy in the treatment of relapsed and refractory multiple myeloma (MM). These treatments redirect the patient’s own T cells to elicit an anti-tumor response. Approximately 35% of patients do not respond to these therapies despite the presence of the target antigen on the tumors and the exact mechanism of this resistance is not well understood. Additionally, almost all patients relapse eventually and patients with extramedullary disease have a much shorter duration of response. We therefore need tools to better understand T cell engagement and trafficking in the context of these therapies and strategies to improve efficacy particularly in patients with extramedullary disease. Unlike invasive biopsies, non-invasive imaging can elucidate the role of BiTEAs in engaging endogenous T-cells towards the tumor cells on the whole-body level. In this study we aim to develop a novel T-cell imaging paradigm that will provide real-time information on the endogenous T-cell trafficking, tumor targeting, and persistence in patients with MM under BiTEA treatment. We hypothesize that T-cell specific anti-CD8 and anti-CD4 PET agents will allow for continuous monitoring and prediction of the efficacy of BiTEA therapies supported by local radiation for medullary and extramedullary disease in MM. Our results, we predict, will provide preclinical support and justification to move toward clinical application in patients with MM and other cancers undergoing immunotherapy with BiTEAs.