Dr Michael Green: Neurotoxicity, Poor Molecular Response Are Top Investigative Priorities

Investigating circulating tumor DNA (ctDNA) for predicting response to chimeric antigen receptor T-cell therapy is a top priority for patients with diffuse large B-cell lymphoma, noted Michael R. Green, PhD, associate professor of lymphoma and myeloma and director, Translational and Laboratory Research, Department of Lymphoma/Myeloma, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center.

Transcript

What unanswered questions need to be addressed for patients with diffuse large B-cell lymphoma?

I think there's 3 things that are immediate next steps from the work that we've described in the paper. First of all, I mentioned the association between molecular response and patient outcome. That was in a relatively limited series of patients, in terms of number, so that needs to be validated in a much larger cohort to either validate the existing 3 shots that we've set for predicting response or prospectively determine other informative thresholds moving forward. So, validation of ctDNA for predicting response is number 1.

Number 2: the phenotype that we found to be associated with poor response, and poor molecular response, in particular, was an exhaustion phenotype of CD8 T cells characterized by the co-expression of the LAG-3 [lymphocyte-activation gene 3] and TIM-3 [T-cell immunoglobulin and mucin domain-containing protein 3] co-inhibitory molecules. These are potentially therapeutically targetable, using blocking antibodies that are in early-phase clinical trials. So another immediate next step, which we're pursuing as part of a secret funded study here at MD Anderson, is to see whether LAG-3– and TIM-3–blocking antibodies are able to rescue the function of these exhausted CD8 T cells.

The third would be really validation of not only the association between ICANS [immune effector cell-associated neurotoxicity syndrome] cells and neurotoxicity—we're quite confident about this association, but really, association is not causation—[but] trying to dig in deeper into the causative role that these ICANS-associated cells and monocyte-like cells within the infusion products may have in mechanistically driving neurotoxicity once they're infused into the patient.