New Manufacturing Process Could Improve CAR T Cell Efficacy Against Aggressive Form of Leukemia

LaQuisa C. Hill, MD, an assistant professor at Baylor College of Medicine, Center for Cell and Gene Therapy in Houston, Texas, talks with Pharmacy Times about the significance of manufacturing CD5 chimeric antigen receptor (CAR) T cells with a tyrosine kinase inhibitor (TKI) to possibly prevent the T cells from killing themselves off before reaching patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL).

Hill will give a presentation titled “Enhanced anti-tumor activity of CD5 CAR T cells manufactured with tyrosine kinase inhibitors in patients with relapsed/refractory T-ALL” at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois from June 2 to 6.

PT Staff: What are current limitations of CD5 CAR-T cells as a monotherapy for relapsed/refractory disease? Limitations of TKIs?

LaQuisa C. Hill, MD: Primarily, I think some of the biggest challenges or limitations of using not just CD5-directed CAR T cells, but any CAR T cell that's targeting T cell malignancies, is that when we're trying to use autologous T cells, these are many times expressed the same markers as the malignant T cells. So that makes it challenging in terms of trying to prevent fratricide when we're selecting target antigens.

But the other major thing is that, at least right now, most of the trials are for patients that have relapsed or refractory (r/r) disease. And so many of these patients have been very heavily pretreated, which ultimately impacts the quality and the function of the T cells that we're collecting from these patients to try to make the CAR T cells. And I think that that's something that is very relevant and important as we continue to try to improve upon the products that we're developing for these patients.

PT Staff: What is the impact of manufacturing CD5 CAR T cells with a TKI?

LaQuisa C. Hill, MD: So again, one of the big challenges with creating a CAR T cell product for T cell malignancies is the fratricide, or self-targeting, of the CAR T cells against normal healthy T cells in addition to the CARs themselves, because they all express the same antigens. And so, our group, which all this work was led by Maksim Mamonkin and my laboratory co-primary investigator; he was able to develop a manufacturing process that incorporated the use of TKIs, particularly ibrutinib (Imbruvica; Janssen) and dasatinib (Sprycel; Bristol Myers Squibb). Essentially what this does is it inhibits or mutes the CAR T cell signaling during the manufacturing process, which prevents activation of the CAR T cells. So therefore, they don't kill themselves off during manufacturing, and they're able to expand exponentially in comparison to normal T cell, so it overcomes that issue of fratricide. But in addition to that, it also helps prevent exhaustion and terminal differentiation of the CAR T cells so we end up with the naiver CAR-T cell population in the final product, which ultimately impacts the potency of the product.

PT Staff: What toxicities are associated with manufactured CD5 CAR T cell/TKI therapy for relapsed/refractory T-ALL?

LaQuisa C. Hill, MD: In terms of the common toxicities that we think of such as cytokine release syndrome (CRS), neurotoxicity, Immune effector cell-associated neurotoxicity syndrome (ICANS), prolong cytopenia, we actually have not seen significant rate of severe events in terms of CRS or neurotoxicity. For both of those side effects, the maximum grade that we've observed has been great 2 for both CRS and for ICANS, and all of those events either self-resolve if they were grade 1, or resolved with tocilizumab (Actemra; Genentech) if it was persistent grade 1 or you know, reached a grade 2.

And then in terms of the neurotoxicity, which was observed in 1 patient, it also resolved subsequently with steroid therapy. And so we haven't really seen any severe events in those terms, but what we have observed is that for 2 patients that were treated with the products manufactured using the TKIs, that they developed significant Epstein-Barr virus (EBV) reactivation that ultimately led to the development of Post-Transplant Lymphoproliferative Disorder (PTLD) or post-transplant for 1 patient that had actually relapsed following allogeneic stem cell transplant. The other patient had not undergone transplant. So it was a more of a immunodeficient lymphoproliferative disorder.

But ultimately both of those patients, while they were in remission from their T-ALL require treatment; multi-agent chemotherapy for the EBV-related lymphoproliferative disease. And so that is something that we are now monitoring very aggressively. And we have since instituted a mitigation plan and hopefully we won't see any more of these events. We have treated to patients, 3 now since then. But those were also Peripheral T-cell lymphoma (PTCL) patients, so maybe a different patient population, and none of the PTCL patients have developed EBV related issues.

PT Staff: What are the clinical applications of CD5 CAR T cells manufactured with TKIs for patients with relapsed/refractory disease?

LaQuisa C. Hill, MD: The implications are that hopefully we will have a CAR T cell product that we're able to use to get patients with very refractory disease into deep-enough remissions that they're able to ultimately proceed to allogeneic stem cell transplant, which, currently, is the only the best chance for long term cure. But ultimately, as we treat more and more patients and we have a better idea of the more long-term data, the adverse event profile, the persistence about [how] this might alleviate the need for stem cell transplant. We are looking into other things in terms of trying to improve upon the safety while maintaining a low toxicity profile, including looking at the use of other immune effector cells.

We also are considering developing our opening donor-derived arm, where patients who have relapsed after allogenic transplant, we can use their donors healthy normal T cells to make the CAR T cell product. And while this may improve upon the ability to make products, it is still obviously only an option for a certain set of patients— those who have a donor that is available after transplant, but there are many things that we're looking into, as well as ultimately developing possibly dual targeting CARs. So going after CD5, potentially targeting other antigens such as CD7, CD70, and things of that nature.

PT Staff: Final thoughts?

LaQuisa C. Hill, MD: I'm just I, you know, I'm just very honored and humbled to be able to be a part of, you know, this trial, and it's very exciting and encouraging. And, you know, I'm hoping that we will be able to continue to push this therapy forward and be able to expand access to a larger number of patients because this really is an area of unmet need for patients who have T-ALL that is refractory. My hope is that if people do see this video and see our data that they would be encouraged and if they have potential patients [to] consider sending them to us, even after the first line of therapy is failed. Again, the earlier we get the patients, the less beat up their T cells are, the healthier the patients are, the more likely they are to survive while we make the CAR T cells to get the treatment, which is often a challenge in these patients. Their disease can be very aggressive and so they can end up progressing very rapidly or died from complications of prior therapy. But I'm excited and hopefully, not just for this, but for other CAR T cell products that are being investigated for this group of patients who really need something better for them.