Results of an ex vivo study evaluating the phenotypic and growth characteristics of T cells collected by leukapheresis from cohorts of patients with newly diagnosed or relapsed/refractory multiple myeloma support use of chimeric antigen receptor (CAR)-T therapy earlier in course of the disease. The hypothesis-generating findings from this study were published in Blood Advances.
While CAR-T therapy targeted against the B-cell maturation antigen (BCMA) has been associated with promising results in patients with multiple myeloma, nearly all of the patients responding to this approach eventually develop progressive disease. Hence, strategies to optimize patient selection for CAR-T therapy in the setting of multiple myeloma are being actively pursued.
The ratio of CD4 to CD8 T cells and/or the frequency of the CD81 CD45RO2 CD271 T-cell memory phenotype were used in this study as surrogates for the clinical effectiveness of CAR-T therapy since previous studies of CAR-T therapy in patients with chronic lymphocytic leukemia and multiple myeloma showed that of all baseline patient- and disease-related characteristics considered, clinical response to CAR-T therapy was associated only with this T-cell ratio and/or the frequency of this subset of memory T cells in the premanufacturing leukapheresis product.
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Two cohorts of patients where compared in this study: 38 patients with newly diagnosed multiple myeloma who had participated in clinical trials of induction therapy and on whom leukapheresis was performed before consolidation therapy and autologous stem cell transplantation (ASCT); and 25 patients with relapsed/refractory multiple myeloma enrolled in a phase 1 clinical trial of anti-BCMA CAR-T therapy and on whom leukapheresis was performed during a washout period shortly following study enrollment.
In both patient cohorts, leukapheresis samples were exposed ex vivo to anti-CD3 and anti-CD28 monoclonal antibodies covalently linked to magnetic beads to provide stimulatory/costimulatory signals for T-cell proliferation and the expansion of functional T cells.
The 2 patient cohorts were similar with respect to median age (ie, 55 years; 58 years [relapsed/refractory]), although the time from multiple myeloma diagnosis was 222 days for those treated with induction therapy and 4.6 years for those with relapsed/refractory disease.
In addition, differences in the median number of prior lines of therapy (1 vs 7), and bone marrow cellularity occupied by myeloma plasma cells (13% vs 65%) were observed when the former and latter cohorts were compared at the time that leukapheresis was performed.
A key finding from this study was a significantly higher frequency of T cells with the CD81 CD45RO2 CD271 T-cell memory phenotype (43.9% vs 29.0%; P =.001), as well as a significantly higher median CD4/CD8 ratio (2.6 vs 0.87; P <.0001) in the postinduction versus the relapsed/refractory patient cohort.
In addition, the CD4/CD8 ratio was also significantly higher in the postinduction cohort compared with responders to anti-BCMA CAR-T therapy from the relapsed/refractory cohort (2.6 vs 1.3; P= .0009); however, while higher in the postinduction cohort, the difference in the frequency of T cells with the CD81 CD45RO2 CD271 T-cell memory phenotype was not statistically significant when these 2 groups were compared.
Regarding capacity for ex vivo proliferation during manufacturing, significantly higher numbers of population doubling by day 9 (PD9) were observed for the postinduction cohort compared with either the overall relapsed/refractory cohort or the group of responders within the relapsed/refractory cohort.
“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 study authors concluded.
Reference
Garfall AL, Dancy EK, Cohen AD, et al. T-cell phenotypes associated with effective CAR T-cell therapy in postinduction vs relapsed multiple myeloma. Blood Adv. 2019;3:2812-2815.
