Lori A. Leslie, MD, and Andre H. Goy, MD, discuss retreatment with CAR T-cell therapy.
Lori A. Leslie, MD, assistant professor, Hackensack Meridian School of Medicine, director, Indolent Lymphoma and Chronic Lymphocytic Leukemia Research Programs, John Theurer Cancer Center, and Andre H. Goy, MD, physician in chief of the Hackensack Meridian Health Oncology Care Transformation Services, chairman and chief physician officer at John Theurer Cancer Center at Hackensack University Medical Center, and Lymphoma Division Chief at the John Theurer Cancer Center, discuss retreatment with CAR T-cell therapy.
Data regarding retreatment with CAR T-cell therapy is limited, Goy says. Anecdotal evidence has shown that responses are generally shorter with retreatment than with the first infusion, prompting questions about the mechanism of resistance to CAR T-cell therapy. In acute lymphoblastic leukemia, the loss of CD19 has been shown to be a primary mechanism of resistance, whereas its relevance in large B-cell lymphoma (LBCL) is less clear, Goy says. In LBCL, it is more likely that T-cell exhaustion and a suppressive microenvironment have a greater effect on responses. Similarly, in follicular lymphoma, responses with retreatment are high, suggesting loss of CD19 may not be a primary resistance mechanism, Leslie adds.
Early retreatment may be an approach worth exploring because approximately 30% of patients who experience a partial response or stable disease following first infusion can convert to a long-term complete remission, Goy says. However, he adds that retreatment may be futile if there is minimal T-cell amplification following infusion and the underlying resistance mechanism is not addressed. An alternative approach that has been studied to elicit a more durable response is adding a checkpoint inhibitor to CAR T-cell therapy, Goy says. Alternatively, data have shown that the administration of ibrutinib (Imbruvica) prior to CAR T-cell therapy enhances T-cell fitness, Leslie adds.
For patients who cannot be retreated with CAR T-cell therapy, bispecifics such as mosunetuzumab have shown promise as salvage therapy, Goy says.
Another important question is: At what point should retreatment be considered? To that end, research is evaluating longitudinal cell-free DNA persistence to see whether there is an opportunity for early treatment escalation strategies to augment T-cell responses, Goy says. Ultimately, the emergence of allogeneic and bispecific CAR T-cell therapies may affect how retreatment is thought about entirely. As more is understood about the biology of CAR T-cell therapy, the field will be better equipped to answer whether retreatment is a strategy worth pursuing, Leslie concludes.