Dr Davila on ​the Clinical Implications of Tumor Driver and Immune Escape Research in LBCL

"What can we do today to try to improve responses in patients with combinatorial therapies? Likely, [we will need to] look at drugs that are available on the shelf, things like anti-CD79 antibodies [and] antibody-drug conjugates that might kill those residual lymphoma cells that aren’t killed by CAR T cells." 

Marco Davila, MD, PhD, the senior vice president and associate director for Translational Research in the Department of Medicine, as well as the Rustum Family Endowed Chair in Translational Research at Roswell Park Comprehensive Cancer Center, discusses the future implications for investigating intrinsic tumor drivers and immune escape mechanisms in patients with aggressive large B-cell lymphoma (LBCL) who develop resistance to CD19-directed CAR T-cell therapy.

The presence of the CD19 antigen in LBCL provides a rationale for developing CAR T-cell therapies that target multiple antigens, Davila begins. Current research, including data presented at the 2024 ASH Annual Meeting, is focused on designing CAR T-cell constructs that target CD19 as well as CD20 and/or CD22, which may help mitigate antigen escape, he says. If CD19 is downregulated in a specific LBCL case, these therapies may still recognize and target lymphoma cells that express CD20 or CD22, he explains. Although this approach offers a potential solution forpreventing antigen escape, the development and regulatory approval of such therapies will require time, Davila emphasizes.

Another challenge in managing LBCL arises in the immune synapse, which may necessitate next-generation CAR T-cell therapy designs that rely less on other proteins within the synapse, he notes. These advancements will also take years to develop and implement in clinical practice, according to Davila. 

In the interim, strategies to enhance patient responses to CD19-directed CAR T-cell therapies include combinatorial approaches using currently available therapies, Davila reports. Agents like CD79-directed antibodies and antibody-drug conjugates may help eliminate residual lymphoma cells that CAR T-cell therapies fail to eradicate, he states. These approaches provide a more immediate means of improving treatment outcomes for patients who experience treatment resistance prior to the development of more advanced, multitargeted CAR T-cell therapies, he concludes.