The team then used computational methods to project the CLL clusters onto apheresed CD8+ T cells from the other 4 hematological malignancies, to see if the same response-related features of CLL cells would apply to other cancers. Interestingly, the cluster of T cells expressing early memory features also predicted response to CAR-T therapy in NHL and myeloma — but not in adult or pediatric ALL.

“What is significant about this study . . .  is that we validated this phenotype in myeloma, where patients were treated with a BCMA-specific CAR, and NHL, which was treated with the same CAR as in CLL,” Dr Melenhorst explained. “That means that the same principles governing CAR T-cell efficacy in CLL also play a major role in clinical responses in the other 2 diseases.”

The fact that these naive, early-memory clusters did not seem to have the same effect in ALL could be because large numbers of those patients respond to the therapy, Dr Melenhorst said. “Especially in young patients — the pediatric patients with ALL — most of those individuals respond to CAR-T cell therapy anyway, so having that separation between respondent and nonrespondent is very hard to find … I think that’s 1 of the main reasons why we didn’t find this profile to fit onto those ALL cases.”

Andrew J. Cowan, MD, of the University of Washington, Seattle, who was not involved in the study, said the findings suggested a way forward for how clinicians can improve the durability and degree of response in patients with hematological malignancies — by exploring ways to enrich the CAR-T product for early-memory CAR T-cell populations. “We should be trying to make the composition of the T-cell product more like [those in] these patients [who] have good responses.”


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Interestingly, another presentation at the ASGCT conference suggested that results of a phase 1 trial evaluating the safety and efficacy of the BCMA-directed CAR-T therapy idecabtagene vicleucel (ide-cel, bb21217, which has the same CAR construct as bb2121, but a different manufacturing process than the first-generation version) in MM suggested that a CAR-T product that is enriched for early-memory phenotypes is also associated with more robust expansion of T cells and durability of disease response.4

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In addition, ide-cel was deemed effective in heavily pretreated, refractory multiple myeloma during a presentation of the results from the pivotal phase 2 KarMMa trial at the ASCO20 Virtual Scientific Program. Patients in this setting who had prior treatment with immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies (triple-exposed patients) experienced improvements in progression-free survival compared with a similar real-world population of patients.5

Dr Melenhorst added that prescreening patients for the proportion of cells that express the early-memory phenotype could help clinicians rule out whether CAR-T therapy would be appropriate for certain individuals. “[Perhaps] we can avoid giving them a therapy that we have learned will actually not work for them. So we can seek other means of treating these individuals,” he said, and added that allogeneic CAR-T treatments could be an option worth exploring.

Disclosures: Dr Melenhorst has received research funding from Novartis and Incyte, and currently from IASO Biotherapeutics, has served as a speaker for Novartis and Johnson & Johnson, as a consultant for Simcere of America, Shanghai Unicar Therapy, Johnson & Johnson, Poseida, and IASO Biotherapeutics, and is on the medical and scientific advisory board of IASO Biotherapeutics.

References

  1. 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.
  2. Cohen AD, Garfall AL, Stadtmauer EA, et al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myelomaJ Clin Invest. 2019;129(6):2210-2221.
  3. Wang M, Pruteanu I, Cohen AD, et al. Identification and validation of predictive biomarkers to CD-19- and BCMA-specific CAR-T-cell responses in apheresed T-cells. Presentation scheduled for: the 2020 American Society of Gene & Cell Therapy. 2020 ASGCT Annual Meeting Abstracts. Mol Ther. 2020;28(4S1): Abstract 1342.
  4. Finney OC, Yeri A, Pandya C, et al. Correlative analysis from CRB-402: An ongoing phase 1 clinical study of bb21217 anti-BCMA CAR T cell therapy. Presentation scheduled for: the 2020 American Society of Gene & Cell Therapy. 2020 ASGCT Annual Meeting Abstracts. Mol Ther. 2020;28(4S1): Abstract 1343.
  5. Jagannath S, Lin Y, Goldschmidt H, et al. KarMMa-RW: A study of real-world treatment patterns in heavily pretreated patients with relapsed and refractory multiple myeloma (RRMM) and comparison of outcomes to KarMMa. Poster presented at: ASCO20 Virtual Scientific Program. J Clin Oncol. 2020;38(suppl):abstr 8525.