Investigating Donor-Derived CAR T Cells in R/R Large B-Cell Lymphoma

Michael T. Tees, MD

In patients with relapsed or refractory (r/r) large B-cell lymphoma (LBCL), treatment with the donor-derived chimeric antigen receptor (CAR) T-cell products ALLO-501A and ALLO-647 demonstrated preliminary efficacy with an acceptable safety profile.¹

“ALLO-501A reduces the likelihood of an argument between the donor and the recipient. One of the initial concerns was using someone else's T cells to fight the malignancy as it is a potential risk of graft-versus-host disease [GVHD], and that's what we see in patients with allogeneic stem cell transplant where donor hematopoietic stem cells grow into an immune system that can potentially argue with the recipient, said Michael T. Tees, MD, in an interview with Targeted Oncology™.

In the 11 patients evaluated in the ALPHA1 study (NCT03939026), there were no dose modifications or dose-limiting toxicities observed with either agent. In terms of safety, the most common adverse events (AEs) were anemia, leukopenia, neutropenia, and thrombocytopenia (73%), and lymphopenia (64%). A second study, ALPHA2, (NCT04416984) will investigate the safety and efficacy of ALLO-501A in patients with r/r LBCL.

In an interview with Targeted Oncology™, Tees, an associate member physician at the Colorado Blood Cancer Institute and part of the Lymphoid and Autoimmune Disease Groups, discussed the donor-derived CAR T-cell product, ALLO-501A, and research supporting the agent.

Targeted Oncology: Can you talk about ALLO-501A and what sets it apart from other CAR T-cell products?

Tees: CAR T-cell therapy has been around for quite some time. It's been about 5 years since the first CAR T product was approved by the FDA, which was an autologous product. It’s patient's own cells that are genetically re-engineered to recognize that the cancer is foreign. Typically, it's CD19. ALLO-501A is a clinical trial evaluating not autologous CAR T cells, but allogeneic CAR T cells using cells from a donor population to achieve the same effect as using your own cells. There are multiple reasons why this is important to investigators. Primarily, there is a lag time between when we need to collect those donor cells and send them away for the re-engineering until we can do the treatment for the patient. That lag time can be dangerous and potentially deadly for those patients who have refractory diseases. Having an off-the-shelf product ready to go, if it's safe, is key. We would not have the potential 3-to-4-week lag time of the processing and collection, which is extremely important.

What we're also seeing now is a backlog for the products that are commercially available because they can't keep up with that demand. With this agent, the product is ready to go from a different donor with comparable benefit. Ideally, an even better safety profile would make this the ideal situation.

ALLO-501A reduces the likelihood of an argument between the donor and the recipient. One of the initial concerns was using someone else's T cells to fight the malignancy as it is a potential risk of graft-versus-host disease [GVHD], and that's what we see in patients with allogeneic stem cell transplant where donor hematopoietic stem cells grow into an immune system that can potentially argue with the recipient. In early ALLO-501A, there was 1 patient with low-level, cutaneous GVHD, and its question on whether that was a true [adverse event]. That risk has really been demonstrated to not be an issue. We can safely infuse these T-cell products from a different donor into a recipient.

The next phase of this is efficacy and safety. There are other safety signals that we need to be looking at for CAR T-cell therapies such as cytokine release syndrome [CRS] and neurotoxicity. The current products that are available for patients commercially do have a high incidence of CRS and neurotoxicity. I am hopeful that perhaps having a donor-derived product can reduce the severity of CRS.

What is important to note about the ALPHA-2 study?

Importantly for an allogeneic product that is donor-derived, 1 of the things that we need to be considering is the potential for rejection of a cell. With that, the lymphodepleting therapy is a little bit different from what we would say is standard of care right now, which typically is clear meaning cyclophosphamide.

With the ALPHA-2 study, we are doing fludarabine/cyclophosphamide, and ALLO-647, which is a an anti-CD52 antibody. This agent is comparable with alemtuzumab [Campath], which is a historic product for treating certain lymphoid malignancies. With this additional suppression, the idea is that these T cells from the donor are able to persist longer and do the job of fighting the malignancy. That’s the biggest difference with this clinical trial, other than the fact that we're just using donor-derived product.

Preliminary data from this study were presented at ASCO this year. Can you discuss those findings?

The preliminary data is exciting. It's showing comparable efficacy with many products that are currently available for patients. I think that's promising and allows many of us to be comfortable with thinking of using this on our patients in the future. Assuming efficacy is as we would want it to be and safety signals are even better, which are already safe, this may lead to an FDA approval at some point. There might also be a different patient population that we would need to use this product. For example, it may be better for a patient that has highly refractory disease and cannot wait to consider an autologous product using their own cells.

The safety signals are what's exciting to me. We saw low-grade neurotoxicity and I think that's a promising outcome right there. CRS is another big risk factor with CAR T cells, but those signals are also much lower than what would be expected from an autologous product, so that's exciting as well. Another thing that we’ve been watching closely is infection. Now, there is an added theoretical risk of viral reactivation such as cytomegalovirus and Epstein-Barr virus.

_REFERENCES:

_{1. Locke FL, Malik S, Tees MT, et al. First-in-human data of ALLO-501A, an allogeneic chimeric antigen receptor (CAR) T-cell therapy and ALLO-647 in relapsed/refractory large B-cell lymphoma (R/R LBCL): ALPHA2 study. J Clin Oncol. 2021;39(5): 2529-2529. doi:10.1200/JCO.2021.39.15_suppl.2529}

_{2. Safety and efficacy of ALLO-501A anti-CD19 allogeneic CAR T Cells in adults with relapsed/refractory large b cell lymphoma (ALPHA2) (ALPHA2). ClinicalTrials.gov. Updated April 8, 2022. Accessed November 21, 2022. https://clinicaltrials.gov/ct2/show/NCT04416984?term=ALLO-501A&draw=2&rank=1}