“It’s thought that these cells could have this self-renewal potential [and] a higher degree of proliferative capacity,” making them more equipped to expand in the patient and differentiate rapidly at the tumor site, Dr Fraietta explained.

That said, although the study authors posited that ibrutinib has this enhancing effect by inhibiting interleukin-2-inducible T-cell kinase, which plays a role in T-cell differentiation, “I still don’t think we have a firm handle on what the mechanism is,” Dr Fraietta said. “I would have liked to have seen . . . more mechanistic insight into what ibrutinib is doing.”

Though the clinical benefits of these drug-enhanced CAR-T products are yet to be tested, “the current study provides, to our knowledge, the first proof of concept that ibrutinib-based CAR-T production may be beneficial for efficient CAR-T cell products in CLL patients,” the authors concluded. However, they noted that the proportions of CLL-derived T cells with the less-differentiated phenotypes are relatively small in the CAR-T product — in the one-digit percentage range — and could be improved.

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The approach is in line with other strategies explored by other groups to optimize CAR-T production. One ongoing study, for instance, is investigating the efficacy of bb21216, a B-cell maturation antigen (BCMA)-targeted CAR-T, while manufactured in the presence of a phosphoinositide 3-kinase inhibitor that is thought to enrich the CAR-T product for memory-like T cells.3

Previous research in 2016 by Dr Fraietta and his colleagues found that in patients with CLL pretreated with more than 5 cycles of ibrutinib therapy who then received CD19-directed CAR-T therapy, the CAR T cells had an improved expansion, which positively correlated with patients’ clinical response.4 Later studies suggested that ibrutinib improves T-cell number and function in patients with CLL, and the cells showed signs of a less-differentiated T-cell phenotype, Dr Fraietta said.5

Culturing T cells directly with ibrutinib during the manufacturing process may have benefits, Dr Fraietta said. However, curiously, in his 2016 research, exposing T cells in culture to ibrutinib did not alter T-cell proliferation nor transduction efficiency. While the reasons for this discrepancy are a mystery, it could possibly have something to do with the starting quality of T cells, Dr Fraietta acknowledged, noting that his group worked with T cells from patients which were likely battered due to multiple prior lines of therapy.

Dr Fraietta would like to have seen a thorough characterization of the German team’s cells prior to CAR-T manufacturing, Dr Fraietta said. “Were you starting with sort of a bonafide, pseudo-exhausted population of T cells, and is ibrutinib reversing that exhaustion state, or are you starting with T cells from CLL patients that are higher quality?”

It would also be good to see a more detailed characterization of their final CAR-T product, he added. “One of the big problems in the field is that we all define these populations differently. Of course, there are some conserved markers, but everybody’s using . . . different ways to define a naive-like population or a central memory population. So whether or not they’re truly the same [cells] is a big unanswered question . . .The only way we’ll get at that is with single-cell sequencing technologies.”

Disclosure: Some of the investigators of the primary study discussed here disclosed various financial ties to the pharmaceutical industry. For a full list of disclosures, please refer to the original paper.


  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. Nat Med. 2018;24(5):563-571. doi:10.1038%2Fs41591-018-0010-1
  2. Fan F, Yoo HJ Stock S et al. Ibrutinib for improved chimeric antigen receptor T-cell production for chronic lymphocytic leukemia patients. Int J Cancer. doi:10.1002/ijc.33212
  3. Berdeja JG, Alsina M, Shah ND et al. Updated results from an ongoing phase 1 clinical study of bb21217 anti-Bcma CAR-T cell therapy. Published online November 13, 2019. Blood. doi:10.1182/blood-2019-126660
  4. Fraietta JA, Patel PR, Ruella M et al. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood. 2016;127(9):1117–1127.
  5. Long M, Beckwith K, Do P et al. Ibrutinib treatment improves T cell number and function in CLL patients [published online July 17, 2017]. J Clin Invest. doi:10.1172/JCI89756