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

Dr Davila on the Future Use of Biomarkers to Predict CAR T-Cell Therapy Resistance in LBCL

“The big question is: Can we use other biomarkers that are readily available [when assessed through] lab tests, other flow cytometry assays, and other genetic tests that…we can design [to deliver] quick and easy readout?”

Marco Davila, MD, PhD, senior vice president and associate director for Translational Research in the Department of Medicine and the Rustum Family Endowed Chair in Translational Research at the Roswell Park Comprehensive Cancer Center, discussed the clinical implications of a study investigating intrinsic tumor drivers and immune escape mechanisms associated with CD19-directed CAR T-cell therapy resistance in patients with aggressive relapsed/refractory large B-cell lymphoma (LBCL).

Davila and colleagues conducted a study to identify potential mechanisms through which genomic complexity leads to CD19-directed CAR T-cell therapy resistance in patients with relapsed/refractory LBCL. In total, 61 samples from 54 patients were collected, including 39 from the pre–CAR T-cell therapy setting, 8 from the post–CAR T-cell therapy setting, and 7 from both the pre– and post–CAR T-cell therapy settings. The investigators found that LBCL tumors likely become resistant to CD19-directed therapies because of genomic drivers that are already present at baseline. Additionally, CAR T-cell therapy resistance is driven by genomic complexity that promotes several genomic drivers that influence CD19 cell activity, the immune system, and tumor cell immunogenicity. These drivers include the biallelic inactivation of the HLA class I complex, the inactivation of natural killer cell–mediating killing mechanisms, PD-L1 alterations, and CD19 pathway alterations.

This type of analysis will likely not be generalizable to use in routine clinical practice due to the length of time it takes and the level of expertise it requires to process and analyze the findings, Davila said. However, this research has generated questions regarding the potential clinical utility of other biomarkers—including those detected through flow cytometry assays and other genetic tests—that may become more readily detectable, Davila concluded.

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Marco Davila, MD, PhD, discusses how a study of tumor drivers of CAR T-cell therapy resistance in LBCL may promote future biomarker investigations.

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 

, 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. 

Marco Davila, MD, PhD, discusses research investigating ways to combat immune escape mechanisms in LBCL treated with CD19-directed CAR T-cell therapy.

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.

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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Articles

Dr Davila on the Future Use of Biomarkers to Predict CAR T-Cell Therapy Resistance in LBCL

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

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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Articles

Dr Davila on the Future Use of Biomarkers to Predict CAR T-Cell Therapy Resistance in LBCL

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

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

Gene and Cell Therapy: Shaping the Future of Medicine

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