Potency of CAR T-Cell Therapy for Myeloma May Vary by Disease Stage

CAR T cells are a more effective therapy if manufactured for patients with multiple myeloma prior to the onset of relapsed or refractory disease, according to study results¹ published in Blood Advances.

“CAR T cells directed against the B-cell maturation antigen (BCMA) have demonstrated impressive initial results, but available data suggest that most patients with initial responses eventually progress,” wrote Alfred L. Garfall, MD, of Abramson Cancer Center, and colleagues. “New strategies are therefore needed to improve CAR T-cell therapy for multiple myeloma.”

Garfall and colleagues reported that in patients with chronic lymphocytic leukemia (CLL) treated with anti-CD19 CAR T cells frequency of a memory T-cell subset, defined by a CD8+ CD45RO- CD27+ immunophenotype, the premanufacturing leukapheresis product was the only parameter that was associated with clinical response. 

“Frequency of this memory subset in the leukapheresis product was associated with transcriptomic and metabolomic features of early memory differentiation and enhanced antigen-responsive cytotoxicity of the manufactured product,” reported Garfall and colleagues. 

They hypothesized that a similar association might exist among patients with multiple myeloma, and that the frequency of the T-cell subset might be higher early in the disease course when disease burden is low. 

The phase I trial evaluated this hypothesis in 38 patients with multiple myeloma who had undergone leukapheresis prior to first line autologous stem cell transplant, after response to induction therapy (postinduction), and expanded with anti-CD3/anti-CD28 agnostic monoclonal antibody-conjugated beads at clinical scale. 

The leukapheresis product was then compared with that of patients with relapsed or refractory disease from a phase 1 trial of anti-BCMA CAR T-cell therapy. 

Similar to the patients with CLL, the researchers found that in these patients with myeloma, a higher frequency of CD8+ CD45RO- CD27+ T cells and higher CD4/CD8 ratio at the time or leukapheresis were both associated with clinical response. 

The postinduction cohort had significantly higher percentage of T cells with the memory phenotype (43.9% vs 29.0%; P = .001) and a significantly higher CD4/CD8 ratio (2.6 vs 0.987; P < .0001) compared with patients with relapsed or refractory disease. 

“Our results suggest that CAR T cells manufactured from leukapheresis samples obtained after response to induction therapy would be, on average, more clinically effective than those obtained from heavily relapsed/refractory multiple myeloma patients,” the researchers wrote. “Our findings are hypothesis generating and provide rationale to evaluate the potency of CAR T cells generated from patients with multiple myeloma at different points in the disease course and from the CD45RO2 CD271 memory subset.”

References:

Garfall, A., Dancy, E., Cohen, A., Hwang, W., Fraietta, J., Davis, M., Levine, B., Siegel, D., Stadtmauer, E., Vogl, D., Waxman, A., Rapoport, A., Milone, M., June, C. and Melenhorst, J. (2019). T-cell phenotypes associated with effective CAR T-cell therapy in postinduction vs relapsed multiple myeloma. [online] Blood Advances. Available at: http://www.bloodadvances.org/content/3/19/2812?sso-checked=true [Accessed 7 Oct. 2019].