Study Identifies Characteristics of CAR T-Cell Products Associated with Outcomes in LBCL

A study published in Nature Medicine identified molecular and cellular characteristics of anti-CD19 CAR T-cell infusion products associated with how patients with large B-cell lymphoma (LBCL) respond to treatment and experience adverse events (AEs).¹

Additionally, researchers also found that early changes in circulating tumor DNA 1 week after CAR T cell therapy may be predictive of treatment response in a particular patient.

Overall, these findings suggest that, within the first week of therapy, clinicians may be able to identify a subset of patients who could experience worse outcomes or AEs. This would allow a patient’s care team to adjust therapy to improve efficacy or to work to alleviate toxicity.

“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,” corresponding author Michael Green, PhD, associate professor of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, said in a press release.² “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.”

In this study, investigators performed single-cell RNA sequencing with capture-based cell identification on autologous axicabtagene ciloleucel (axi-cel) anti-CD19 CAR T-cell infusion products to establish transcriptomic features associated with efficacy and toxicity in a cohort of 24 patients with LBCL.

Those who achieved a complete response by positron emission tomography/computed tomography at their 3-month follow-up were found to have 3-fold higher frequencies of CD8 T-cells expressing memory signatures than participants with only a partial response or progressive disease. Moreover, molecular response measured by cell-free DNA sequencing on day 7 following infusion was significantly associated with clinical response (P = .008), and a signature of CD8 T-cell exhaustion was associated (q = 2.8 x 10−149) with a poor molecular response.

“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,” co-corresponding author Sattva Neelapu, MD, professor of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, said in the release. “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.”

Even further, a rare cell population with monocyte-like transcriptional features was associated (P = .0002) with high-grade immune effector cell-associated neurotoxicity syndrome (ICANS). According to researchers, these AEs can delay patients’ recovery and can lead to increased need for hospitalization and intensive care. However, the researchers suggested that further research is necessary and may lead to insights into the types and attributes of the cells present within the CAR T infusion product.

“This study also tells us that some rare and unexpected cells identified by single-cell analysis could be biologically important,” co-corresponding author Linghua Wang, MD, assistant professor of Genomic Medicine at The University of Texas MD Anderson Cancer Center, said in the release. “Going forward, we plan to functionally characterize these monocyte-like cells to better understand their specific biological mechanisms driving these clinical results.”

Moving forward, these findings will also aid in the development of 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.

References:

1. Deng Q, Han G, Puebla-Osorio N, et al. Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas. Nature Medicine. doi: 10.1038/s41591-020-1061-7

2. Study identifies characteristics of infused CAR T cells associated with efficacy and toxicity in patients with large B-cell lymphoma [news release]. Published October 5, 2020. Accessed October 6, 2020. https://www.mdanderson.org/newsroom/study-identifies-characteristics-of-infused-car-t-cells-associated-with-efficacy-and-toxicity-in-patients-with-large-b-cell-lymphoma.h00-159385890.html