Dr Davila on Efforts to Overcome CD19-Directed CAR T-Cell Therapy Resistance in LBCL

"Part of [the solution] is recognizing that patients can be grouped [based on whether they are] more vs less likely to achieve good responses. If we have patients [who are] likely to have a good clinical outcome, we probably don't want to investigate common combinatorial therapies. We are really trying to identify these poor-risk patients...and we're focusing clinical trials on those patients."

Marco Davila, MD, PhD, senior vice president, associate director, Rustum Family endowed chair, Translational Research, Roswell Park Comprehensive Cancer Center, discusses emerging strategies to overcome resistance to CD19-directed CAR T-cell therapy in aggressive large B-cell lymphoma (LBCL).

Recognizing that patients with aggressive LBCL exhibit varying responses to CD19-directed CAR T-cell therapy is central to overcoming resistance, Davila begins. He adds that prior research supports the use of biomarkers, laboratory tests, and genetic analyses to stratify patients based on their likelihood of achieving favorable outcomes. For patients identified as having a very low risk of poor outcomes—those predicted to respond well to standard therapy—there is limited benefit in exploring combinatorial or investigational therapies, as these patients are already likely to achieve a good clinical outcome, Davila says.

Accordingly, efforts to overcome CAR T-cell therapy resistance in LBCL are primarily focused on identifying high-risk patients who are unlikely to achieve favorable outcomes, and tailoring interventions to this subgroup, he states. Prior research has identified approximately 20% of patients with elevated biomarkers, such as C-reactive protein and ferritin, who are at higher risk for poor responses to therapy, Davila reports.

Approaches under investigation include cytokine modulation and post-infusion interventions such as checkpoint inhibitors or bispecific antibodies to enhance CAR T-cell efficacy, Davila details. These strategies aim to convert partial responses into complete responses or rescue patients with no response into achieving meaningful clinical benefit, he explains. Early trials are evaluating whether these interventions can provide a therapeutic signal in this high-risk patient population, Davila says.

Future research with CAR T-cell therapy in LBCL may include efforts to build upon initial signals of efficacy, refining biomarker-driven patient selection, and developing combination regimens or sequential therapies to address the resistance mechanisms, he states. The challenge remains complex, as understanding the biological underpinnings of resistance often precedes the identification of effective solutions, Davila notes. However, this approach holds promise for optimizing outcomes in a subset of patients who may otherwise have limited therapeutic options, Davila concludes.

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Marco Davila, MD, PhD, discusses emerging strategies to overcome resistance to CD19-directed CAR T-cell therapy in aggressive large B-cell lymphoma.

Marco Davila, MD, PhD, explains the role of intrinsic tumor drivers in CD19 CAR T-cell therapy resistance in aggressive large B-cell lymphoma.

Dr Davila on CD19 CAR T-Cell Therapy Resistance in Large B-Cell Lymphoma

“We’ve done prior work that’s been published showing that the tumor microenvironment has a big role in resistance [to CD19-directed CAR T-cell therapy], but we wanted to look to see what role the tumor itself may be having in [driving] this resistance.”

Marco Davila, MD, PhD, senior vice president, associated director, Rustum Family endowed chair, Translational Research, Roswell Park Comprehensive Cancer Center, explains how intrinsic tumor drivers inform patient stratification and pretreatment decision-making for CD19-directed CAR T-cell therapy in aggressive large B-cell lymphoma (LBCL).

In an expanded cohort study evaluating intrinsic tumor drivers in CD19-directed CAR T-cell therapy resistance, the main focus was determining what may lead to poor responses for patients with LBCL receiving CD19-directed CAR T-cell therapies, Davila says. He notes that previous work has established that the tumor microenvironment plays a key role in resistance to CAR T-cell therapy. However, in this study, Davila explains that he and colleagues wanted to delve into how tumors itself could be associated with resistance.

The cohort included 54 patients with LBCL treated with CD19-directed CAR T-cell therapy; 61 whole-genome sequencing (WGS) and 54 RNA sequencing samples were analyzed by investigators. Of note, 39 samples were collected at baseline, 15 at relapse, and 7 both before and after treatment. A phylogenetic analysis was conducted on the 7 paired samples and somatic driver discovery on baseline samples, which integrated single nucleotide variants, small insertions/deletions, copy number variants, and structural variants.

Davila says looking into potential genetic mutations and genetic abnormalities within tumor cells was one major opportunity. Since the CAR T cells are targeted toward CD19, genetic pathways that could alter or destroy CD19 expression could potentially mediate resistance, according to Davila. He emphasizes that this observation is crucial, as this is a mechanism of antigen escape in acute leukemia, although this notion has been a common area for debate.

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Dr Davila on Efforts to Overcome CD19-Directed CAR T-Cell Therapy Resistance in LBCL

Dr Davila on CD19 CAR T-Cell Therapy Resistance in Large B-Cell Lymphoma

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