Novel CAR T-Cell Process Shows Promise in Relapsing/Refractory B-ALL

A new type of chimeric antigen receptor (CAR) T cell may be able to overcome resistance in some patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL).

The findings were published in the Journal of Hematology & Oncology. Corresponding author Ying Wang, PhD, of the Chinese Academy of Medical Sciences and Peking Union Medical College, and colleagues, noted that while 70%-90% of patients with B-ALL who are treated with anti-CD19 CAR T cells achieve complete remission (CR), 40%-50% of patients who respond to the therapy will relapse within a year, and nearly half of those patients will have CD19-positive leukemic cells.

“Recent studies indicate that relapse may be due to mutations in CD19 that destroy the cognate epitope recognized by the anti-CD19 single-chain variable fragment (scFv), such as FMC63 clone, thus rendering the tumor cells invisible to CD19 CAR T cells,” Wang and colleagues noted.

One strategy to get around that problem is to develop CAR T cells with scFvs that can bind to different CD19 epitopes. The team has developed a new type of cell derived from the HI19α clone, dubbing it CNCT19. The hope was that the scFv generated by the HI19α clone would locate different binding epitopes on the CD19 extracellular domain than the ones detected by the FMC63 clone. The results of preclinical model evaluations were positive, prompting Wang and colleagues to conduct the present pilot study to evaluate the safety and efficacy of CNCT19 in both pediatric and adult patients with B-ALL.

They enrolled 20 patients in the study, giving them infusions of CNCT19 cells. Of those, 90% of patients achieved CR or complete remission with incomplete count recovery (CRi) within 28 days. Two relapsed patients saw their extramedullary leukemia disease disappear completely after the infusion.

At a median follow-up of 10.09 months, the median overall survival for the patients was 12.9 months, and the relapse-free survival was 6.93 months.

“Differences with respect to immune profiles associated with a long-term response following CAR T cell therapy were also addressed,” the authors wrote. “Our results revealed that a relatively low percentage of CD8+ naïve T cells was an independent factor associated with a shorter period of relapse-free survival.”

The authors said their results suggest that CD19 CAR T cells derived from the HI19α clone can promote high anti-leukemic efficacy and may help curb the poor prognosis faced by patients with R/R B-ALL.

However, Wang and colleagues also sounded a note of caution, pointing out that a high percentage of their patients, 14 of 20, subsequently underwent hematopoietic stem cell transplantation, which they said may play a significant role in maintaining the long-term response to treatment.

“As such, the duration of the response associated specifically with CNCT19-based T cell therapy requires further investigation,” they said.

And while their new cells may help counteract the shortcomings of anti-CD19 CAR T cells, the investigators said the new cell does not overcome one other problem with CAR T cell therapy—the high rate of toxicities. In their study 45% of patients experienced high-grade cytokine release syndrome (CRS), a rate similar to other studies. Severe CRS seemed to correlate with a high tumor burden, so the authors said the results underscore the importance of decreasing tumor burden prior to CAR T cell infusion.

Still, the authors concluded that their new therapy appears to be highly effective against malignant cells in patients with R/R B-ALL, and may have also identified a notable biomarker.

“Our results also suggest the percentage of circulating CD8+ TN cells may be developed as a biomarker to predict the long-term prognosis of patients undergoing CAR T cell therapy,” they said.

Reference

Gu R, Liu F, Zou D, et al. Efficacy and safety of CD19 CAR T constructed with a new anti-CD19 chimeric antigen receptor in relapsed or refractory acute lymphoblastic leukemia. J Hematol Oncol. Published online September 7, 2020. doi:10.1186/s13045-020-00953-8