CAR-T Therapy May Be More Effective When Administered Earlier in the Multiple Myeloma Treatment Continuum – Cancer Therapy Advisor

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-cellmaturation antigen (BCMA) has been associated with promising results inpatients with multiple myeloma, nearly all of the patients responding to thisapproach eventually develop progressive disease. Hence, strategies to optimizepatient selection for CAR-T therapy in the setting of multiple myeloma arebeing actively pursued.

Theratio of CD4 to CD8 T cells and/or the frequency of the CD81 CD45RO2 CD271 T-cell memory phenotype were usedin this study as surrogates for the clinical effectiveness of CAR-T therapysince previous studies ofCAR-T therapy in patients with chronic lymphocyticleukemia and multiple myeloma showed that of all baseline patient- anddisease-related characteristics considered, clinical response to CAR-T therapywas associated only with this T-cell ratio and/or the frequency of this subsetof memory T cells in the premanufacturing leukapheresis product.

Twocohorts of patients where compared in this study: 38 patients with newly diagnosedmultiple myeloma who had participated in clinical trials of induction therapy andon whom leukapheresis was performed before consolidation therapy and autologousstem cell transplantation (ASCT); and 25 patients with relapsed/refractorymultiple myeloma enrolled in a phase 1 clinical trial of anti-BCMA CAR-Ttherapy and on whom leukapheresis was performed during a washout period shortlyfollowing study enrollment.

Inboth patient cohorts, leukapheresis samples were exposed ex vivo to anti-CD3and anti-CD28 monoclonal antibodies covalently linked to magnetic beads toprovide stimulatory/costimulatory signals for T-cell proliferation and theexpansion 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.

Inaddition, 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%) wereobserved when the former and latter cohorts were compared at the time thatleukapheresis was performed.

Akey finding from this study was a significantly higher frequency of T cellswith the CD81 CD45RO2CD271 T-cell memory phenotype(43.9% vs 29.0%; P =.001), as well asa significantly higher median CD4/CD8 ratio (2.6 vs 0.87; P <.0001) in the postinduction versus the relapsed/refractorypatient cohort.

Inaddition, the CD4/CD8 ratio was also significantly higher in the postinductioncohort compared with responders to anti-BCMA CAR-T therapy from the relapsed/refractorycohort (2.6 vs 1.3; P= .0009); however,while higher in the postinduction cohort, the difference in the frequency of Tcells with the CD81 CD45RO2CD271 T-cell memory phenotypewas not statistically significant when these 2 groups were compared.

Regardingcapacity for ex vivo proliferation during manufacturing, significantly highernumbers of population doubling by day 9 (PD9) were observed for thepostinduction cohort compared with either the overall relapsed/refractorycohort or the group of responders within the relapsed/refractory cohort.

Ourresults suggest that CAR T cells manufactured from leukapheresis samplesobtained after response to induction therapy would be, on average, moreclinically effective than those obtained from heavily relapsed/refractorymultiple 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.

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CAR-T Therapy May Be More Effective When Administered Earlier in the Multiple Myeloma Treatment Continuum - Cancer Therapy Advisor