Molecular, cellular characteristics of CAR T-cell therapy may predict response, toxicity
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Molecular and cellular characteristics of commercial chimeric antigen receptor T-cell therapies appeared associated with treatment response and toxicity among patients with large B-cell lymphoma, according to a study in Nature Medicine.
Early changes in circulating tumor DNA after infusion were predictive of response, a finding that could help clinicians determine which patients might benefit from consolidative therapy to boost the effectiveness of CAR T-cell therapy.
“CAR T cells have been revolutionary for the treatment of relapsed or refractory large B-cell lymphoma, but most patients will not have a durable response to treatment,” Michael R. Green, PhD, associate professor and director of translational and laboratory research in the department of lymphoma/myeloma research at The University of Texas MD Anderson Cancer Center, told Healio. “Approximately 60% of patients will either be refractory to this new therapy or ultimately experience disease relapse.”
One of the main reasons why patients are unable to achieve a durable response to CAR T-cell therapy is because the product is not active enough to eradicate the tumor cells, Green said.
“Activity of CAR T cells can vary based on their functional state,” he said. “The patients in this study have undergone multiple rounds of chemotherapy in most cases, which has a deleterious effect on T-cell function.”
‘Discovery-based analysis’
Green and colleagues designed their study to identify characteristics of CAR T cells associated with treatment response and toxicity.
Rather than predicting which markers may be detected and designing experiments to measure them, the researchers used single-cell RNA sequencing with capture-based cell identification to evaluate the heterogeneity of the cellular population in commercially prepared CAR T-cell therapy samples. This allowed for what Green called agnostic, “discovery-based analysis” of the relationship between cellular populations and treatment outcomes.
The researchers collected leftover cells from infusion bags of 24 patients with large B-cell lymphoma who received the CD19-directed CAR T-cell therapy axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead) at The University of Texas MD Anderson Cancer Center. They evaluated responses to therapy based on PET/CT scans at 3-month follow-up.
The results showed patients who had a complete response to therapy received CAR T cells that had up to three times as many CD8 T cells expressing memory signatures as the CAR T cells administered to patients who had a partial response to therapy or progressive disease after infusion.
Green and colleagues also observed an association between molecular response — as measured by cell-free DNA sequencing 7 days after infusion with CAR T cells — and clinical response to therapy (P = .008).
“A CD8 T-cell exhaustion signature was associated with failure to achieve an early molecular response,” Green told Healio.
Because CAR T cells expand to their peak within the body between 1 and 2 weeks after infusion, having this information about what happens in the first week can allow physicians to “provide a therapy that can enhance CAR T-cell activity,” Green said.
Finally, the researchers found CAR T-cell therapies that contained a rare cell population with monocyte-like transcriptional features were associated with development of high-grade immune effector cell-associated neurotoxicity syndrome after infusion (P = .0002).
“This is an association, which of course does not demonstrate causation, so we have more work to do to elucidate what these monocyte-like cells are doing once they are in the patient,” Green told Healio. “However, using their phenotype, we may be able to predict patients who have a high likelihood of developing neurotoxicity.”
Future clinical impact
Every CAR T-cell product contains exhausted T cells, and this has a quantitative relationship with outcomes, according to Green.
"Every patient has some exhausted T cells, but the more you have, the worse your outcomes,” he said.
Green said his team’s research has the potential to impact clinical practice, although not immediately. Additional preclinical studies are needed to determine effective consolidative therapies once it has been determined that a patient is having a poor response to CAR T cells, he added.
Green said he hopes that one day clinicians will be able to monitor molecular response to CAR T cells and provide poor responders with a consolidative therapy that would promote greater expansion of the CAR T cells.
“We need a good consolidative therapy to turn to in these patients, and without that — even if we can use [circulating tumor] DNA sequencing to accurately predict early response to CAR T cell therapy — we don’t have any way to take action on that information,” Green said. "So, our research could have a very high impact in the future, but not on immediate practice.”
The research continues as part of a study being supported by the Cancer Prevention Institute of Texas, Green said. His group’s next steps are to identify the nature and origin of T-cell exhaustion, validate the circulating tumor DNA findings, and continue preclinical research on potential blocking antibodies that could “rescue” poorly responding CAR T cells and enhance their effectiveness.
“These points are going to be key because if T-cell exhaustion preexists in the apheresis product and is not the result of the manufacturing process, it may suggest that some patients might be better off with an allogeneic product instead of an autologous one,” Green said.
For more information:
Michael R. Green, PhD, can be reached at mgreen5@mdanderson.org.
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