A group of scientists from The University of Texas MD Anderson Cancer Center has identified cellular and molecular features of anti-CD19 CAR T cell infusion products that are correlated with how patients suffering from large B-cell lymphoma (LBCL) react to treatment and develop side effects.
Michael Green, PhD. Image Credit: The University of Texas MD Anderson Cancer Center.
The researchers also discovered that early changes in the circulating tumor DNA one week following CAR T cell therapy can predict treatment response in a specific patient. The article was recently published in the Nature Medicine journal.
CAR T cell therapy is highly effective against LBCL. However, we experience two main clinical challenges: achieving long-term remission and managing treatment-associated adverse events.”
Michael Green, PhD, Study Corresponding Author and Associate Professor of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
According to Green, the study indicates that, within the first week of CAR T cell therapy, clinicians could identify a subset of patients who may have adverse treatment reactions or experience more poor outcomes. This approach would enable the care team to modify the therapy to enhance its efficacy or to act to reduce toxicity.
CAR T cell signature, early molecular response may predict long-term outcomes
In this research work, the team conducted single-cell analysis on CAR T cells to investigate the profiles of gene expression in the infused cells. They collected CAR T cells from those remaining in infusion bags after treating 24 patients with LBCL. The genetic outlines were then compared to treatment responses, established at three months after infusion by PET/CT 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. 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, Study Co-Corresponding Author and Professor of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
The team also studied early molecular responses in the patients by tracking early changes in the circulating tumor DNA from treatment to one week post-infusion. The extent of these changes in tumor-related DNA matched with the response, indicating that patients who exhibited an early molecular response have greater chance to experience a clinical response to treatment.
CAR T cell features predict likelihood of severe side effects
CAR T cell therapy can cause adverse side effects, such as immune effector cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome. Such adverse events can delay the recovery of patients and can increase the requirement for hospitalization and intensive care.
Green added, “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.”
He continued, “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.”
Additional analysis may lead to better insights into the types and features of cells found inside 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. Going forward, we plan to functionally characterize these monocyte-like cells to better understand their specific biological mechanisms driving these clinical results.”
Linghua Wang, MD, Study Co-Corresponding Author and Assistant Professor of Genomic Medicine, The University of Texas MD Anderson Cancer Center
These latest discoveries will allow the researchers to develop clinical interventions that can target or block these cells. They have also planned to confirm the capacity of the circulating tumor DNA to precisely estimate the long-term outcomes in patients.
Deng, Q., et al. (2020) Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas. Nature Medicine. doi.org/10.1038/s41591-020-1061-7.