Dr Neelapu on Addressing CAR T-Cell Resistance in Lymphoma

Sattva S. Neelapu, MD, deputy department chair, professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses mechanisms of resistance to CAR T-cell therapies in lymphoma and how CAR T-cell resistance may be addressed.

One of the main reasons patients with lymphoma experience relapse after receiving CD19-directed CAR T-cell therapy is the loss of CD19 expression in the tumor at the time of progression, Neelapu begins. This issue can be addressed through the development of CAR T-cell therapies targeting other markers in B-cell lymphoma, such as CD22 and CD79, he says. For example, a phase 1/1b clinical trial (NCT04088890) conducted at Stanford University investigated CD22-directed CAR T cells; this research is now progressing to phase 2 trials, Neelapu reports. Other trials targeting different markers are in the early stages of development.

The second major reason for relapse after CAR T-cell therapy is T-cell dysfunction, Neelapu continues. At the time of apheresis, T cells in these patients are often dysfunctional, leading to a poor-quality CAR T product, he explains. Neelapu adds that this dysfunction can arise from the disease itself or, more commonly, from the various therapies the patients have previously received.

To address T-cell dysfunction, several strategies are being explored. One approach is to move CAR T-cell therapy to earlier lines of treatment, potentially before the T cells become too compromised, Neelapu details. Another strategy is to modify the manufacturing process of CAR T cells, he states. Traditionally, production takes 7 to 10 days for currently approved commercial products. However, recent data suggest that reducing the manufacturing time to 2 to 3 days can produce a higher-quality CAR T product with better function and efficacy in patients, without increasing toxicity, Neelapu notes.

A third approach to overcoming T-cell dysfunction is the development of allogeneic CAR T-cell therapies, Neelapu says. These therapies, derived from healthy donors rather than the patients themselves, are currently being evaluated in phase 1 and 2 trials, he adds. Allogeneic CAR T cells may provide a solution by bypassing the issues related to the patient’s own dysfunctional T cells, potentially offering a more robust and effective treatment option, Neelapu concludes.