How the characteristics of CAR-T cell infusion products impact their effectiveness and toxicity in patients with large B cell lymphomas

The study evaluated how characteristics of CAR-T cell infusion (CTCI) products impact their effectiveness and toxicity in patients with large B cell lymphoma (LBCL). The authors found that diversity in molecular and cellular features of CTCI products caused variations in efficacy and toxicity after axicabtagene-ciloleucel (axi-cel; Yescarta) therapy in such patients. 

T-cells are immune cells capable of destroying pathogens such as bacteria, viruses. Axi-cel is a CAR-T-cell therapy. It uses patients’ own T-cells which are genetically modified to specifically kill leukemic cells. CTCI can effectively treat patients with LBCL. However, it causes frequent toxicities and less than half of such patients achieve remission (disappearance of cancer).

Previous studies showed that cellular and molecular characteristics of the CTCI product may influence treatment responses in leukemia. The impact of these factors is unexplored with respect to LBCL.

The study used CTCI products given to 24 patients with LBCL. CTCI products were analyzed by single-cell-RNA-sequencing (scRNAseq) for determining molecular features. Patients’ blood samples were obtained during infusion, and at 1 week, 2 weeks, and 1 month after infusion. Plasma, which is the liquid component of blood, was isolated from these samples. They were used for analyzing cell-free DNA (cfDNA). Plasma from 24 healthy people was used for comparison.

After a 3-month follow-up, 13 patients (50%) had progressive disease (PD), 1 (4%) had a partial response (PR), and 9 (38%) had a complete response (CR) as measured by PET/CT scans. PR means the partial absence of cancer symptoms while CR refers to a complete lack of them.

scRNAseq revealed that patients with PR/PD received CTCI products enriched in exhausted T-cells, while those with a CR received CTCI products enriched in memory T-cells. T-cells get exhausted after over-utilizing their abilities to kill a particular target. Memory T-cells retain the ability to recognize and kill a particular target for the long-term. Patients who achieved a CR at 3 months had 3 times higher frequencies of memory T-cells compared to those with a PR/PD.

cfDNA analysis showed patients’ response to treatment at the molecular level by revealing a reduction in leukemic genetic changes. A clinical response (CLR) was defined as an improvement in actual symptoms of cancer. A molecular response (MR) at day-7 after infusion led to a measurable CLR. Exhausted T-cells were found in the CTCI products given to patients with poor MR.

Immune effector cell-associated neurotoxicity syndrome (ICANS) often occurs as a side effect of CAR-T-cell therapy. It includes brain damage, drowsiness, tremor, seizures. Patients experiencing severe ICANS were found to receive CTCI-products enriched in T-cells which had similarities with monocytes. Monocytes are blood cells involved in the immune response.

The study concluded that molecular and cellular differences in CTCI products contribute to variations in the safety and effectiveness after axi-cel therapy in patients with LBCL. The authors suggested that the effectiveness of CAR-T cell therapy may be predicted early by assessing MR at day 7.