To that end, Dr Garfall and his colleagues recently investigated the properties of T cells when extracted before the onset of relapsed or refractory myeloma, and compared them to those from patients with advanced disease, in another study in Blood published earlier this month.3 

For the comparison, the researchers examined leukapheresis samples from a recently concluded phase 1 BCMA CAR-T therapy trial in 25 patients who had been administered a median of 7 to 8 prior lines of therapy (ClinicalTrials.gov Identifier: NCT02546167). They compared them to T cells extracted from 38 patients enrolled in other studies prior to a first-line stem cell transplantation with a relatively low burden of disease. Those cells were subjected to a similar expansion process to that typically conducted during the manufacture of CAR-T products.

T cells from the postinduction cohort exhibited not only a higher capacity for proliferation than those from the relapsed or refractory cohort, but importantly, they also had a significantly higher percentage of a particular memory phenotype of T cell, CD8+ CD45RO CD27+, which is associated with early memory differentiation and an enhanced antigen-responsive cytotoxicity, as well as a significantly higher ratio of CD4 to CD8 T cells.

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Previous research in patients with chronic lymphocytic leukemia treated with anti-CD19 CAR-T found that among a range of patient- and disease-specific characteristics, the most important predictive factor associated with sustained remission was the frequency of cells with the CD8+ CD45RO CD27+  immunophenotype.4 Data from Garfall and his colleagues’ phase I study in myeloma patients also found higher frequencies of that particular T-cell immunophenotype and a higher CD4/CD8 ratio to be associated with response to treatment.5

Dr Garfall and his colleagues concluded that T cells extracted from patients before the onset of relapsed or refractory disease may form more efficacious CAR-T products for multiple myeloma treatment. However, more research is necessary to determine whether the changes in T cells are driven by disease burden or prior therapy, Dr Garfall added.

“This is a very interesting study. It definitely lends support to using CAR T cells earlier in the disease course,” Dr Cowan noted, adding that “it would be nice to see this finding replicated in a larger study with more patients.” Dr Landgren agreed: “No one at this point has [proven] that this translates into longer survival or progression-free survival.”

“There’s a long list of good ideas to improve the activity of BCMA-directed CAR T cells,” Dr Garfall added. “We know from patients treated with acute lymphocytic leukemia and diffuse large B-cell lymphoma that a subset of them seem to be cured, and we haven’t seen that as much in myeloma. Our hope is that with various improvements we can get closer to that theoretical … potential of CAR T-cells to be curative.”  

Disclosure: Several investigators involved in the new research disclosed various ties to pharmaceutical companies in this abstract. For a full list of disclosures, please refer to the original papers.

References

  1. Pont MJ, Hill T, Cole GO, et al. γ-secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma. Blood. 2019;134(19):1585-1597.
  2. Laurent SA, Hoffman FS, Kuhn PH et al. γ-secretase directly sheds the survival receptor BCMA from plasma cell. Nat Commun. 2015;6:7333.
  3. 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(19):2812-2815.
  4. Fraietta JA, Lacey SF, Orlando EJ et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia [published online April 30, 2018]. Nat Med. 2018;24(5):563-571.
  5. Cohen AD, Garfall AL, Stadtmauer EA at al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J Clin Invest. 2019;129(6):2210-2221.