Researchers have identified molecular and cellular characteristics of anti-CD19 chimeric antigen receptor (CAR) T-cell infusion products associated with how patients with large B-cell lymphoma respond to treatment and develop side effects. The research team also found that early changes in circulating tumor DNA 1 week after administration of CAR T-cell therapy may be predictive of treatment response. These findings were published by Deng et al in Nature Medicine.
“CAR T-cell therapy is highly effective against [large B-cell lymphoma],” said corresponding study author Michael Green, PhD, Associate Professor of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center. “However, we experience two main clinical challenges [with the therapy]: achieving long-term remission and managing treatment-associated adverse events.”
Michael Green, PhD
This study suggests that, within the first week of therapy, clinicians may be able to identify a subset of patients who may experience more poor outcomes or adverse treatment reactions, said Dr. Green. This would allow the care team to adjust therapy to improve efficacy or to act to mitigate toxicity.
Analysis of CAR T-cells
For this study, researchers performed single-cell analysis on CAR T-cells to study gene-expression profiles in the infused cells. CAR T-cells were collected from those remaining in infusion bags following treatment of 24 patients with large B-cell lymphoma. These genetic profiles were compared to treatment responses, determined at 3 months postinfusion by positron-emission tomography/computed tomography scan.
“When we look at the characteristics of the infused CAR T-cells, we found that samples from patients who were less responsive to treatment had exhausted T cells, whereas those who experienced complete responses had T cells expressing ‘memory’ signatures,” said co-corresponding author Sattva Neelapu, MD, also Professor of Lymphoma and Myeloma at MD Anderson. “Additionally, one cellular signature of T-cell exhaustion was more commonly found in patients who exhibited a poor molecular response, and poor molecular response is generally associated with less positive long-term outcomes.”
Sattva Neelapu, MD
Further, the researchers analyzed early molecular responses in the patients by monitoring changes in circulating tumor DNA from treatment to 1 week postinfusion. The magnitude of change in tumor-associated DNA corresponded with response, suggesting that patients who displayed an early molecular response were more likely to experience a clinical response to treatment.
Side Effect Prediction
Adverse side effects of CAR T-cell therapy can include cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome. These adverse events can delay patients’ recovery and can lead to increased need for hospitalization and intensive care.
“When we examined the infusion product, we found that a cell population with characteristics similar to myeloid cells, with a monocyte-like transcriptional signature, was associated with development of high-grade neurotoxicity,” said Dr. Green. “Detecting these cells may subsequently lead us to identify patients who would be at higher risk of developing neurotoxicity, allowing us to provide prophylactic treatment with agents that target the specific cellular features.”
Further examination may lead to insights into the types and attributes of the cells present within the CAR T-cell infusion product.
Linghua Wang, MD
“This study also tells us that some rare and unexpected cells identified by single-cell analysis could be biologically important,” said co-corresponding study author Linghua Wang, MD, Assistant Professor of Genomic Medicine at MD Anderson. “Going forward, we plan to functionally characterize these monocyte-like cells to better understand their specific biological mechanisms driving these clinical results.”
These findings will help researchers develop clinical interventions that can block or target these cells. Researchers also plan to validate the capacity of circulating tumor DNA to accurately predict patients’ long-term outcomes.
The authors concluded, “Our results suggest that heterogeneity in the cellular and molecular features of CAR T-cell infusion products contributes to variation in efficacy and toxicity…in [large B-cell lymphoma], and that day 7 molecular response might serve as an early predictor of CAR T-cell efficacy.”
Disclosure: For full disclosures of the study authors, visit nature.com.
