Strategies to Mitigate T-Cell Exhaustion Following CAR T-Cell Failure

In an interview on treatments following failure of chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma, Rahul Banerjee, MD outlines the theory behind potential therapeutic strategies that address T-cell exhaustion or dysfunction following CAR T-cell therapy. As these patients often face a depleted immune landscape, the focus shifts to drugs and interventions that can either rejuvenate existing immune cells or provide a fresh cellular foundation for subsequent therapies.

Pharmacological Interventions: CELMoDs and Selinexor

Banerjee highlights the potential of the investigational cereblon E3 ligase modulators (CELMoDs) iberdomide and mezigdomide as agents that may reduce T-cell dysfunction. Beyond these, he identifies selinexor (Xpovio) as a noteworthy option. Selinexor is typically utilized in the relapsed/refractory setting and emerging preclinical data suggest it may play a role in reducing T-cell exhaustion.

Banerjee notes that he has personally utilized selinexor-based regimens such as the combination of selinexor, carfilzomib (Kyprolis), and dexamethasone in patients where T-cell fitness is a concern. He shares an anecdotal success involving a patient who has maintained a response for over 7 months, exceeding typical clinical expectations for this heavily pretreated population.

The Role of Stem Cell Boosts and Bispecific Antibodies

An approach he acknowledges as speculative involves the use of a stem cell boost. This strategy is primarily considered for patients who have pre-collected hematopoietic stem cells from earlier in their treatment journey such as if it was intended for a second transplant that was never performed. Banerjee suggests that this boost can address prolonged hematotoxicity resulting from lymphodepletion and CAR T-cell therapy, and provide a fresh bolus of native T-cells that have not been impacted by recent CAR T-cell therapy or intensive chemotherapy.

This washout technique of using chemotherapy followed by a stem cell boost is proposed as a bridge to bispecific antibody therapy. The goal is to provide a new population of healthy T-cells that the bispecific antibodies can effectively engage to target the myeloma. Banerjee emphasizes that this remains a non-standard, speculative approach for difficult cases, but it offers a potential pathway when conventional options have been exhausted and illustrates the challenge of exhausted T cells in using further T-cell redirection therapy.