CAR T-Cell Immunotherapy in Acute Lymphoblastic Leukemia
Insights From:Stefan Faderl, MD, John Theurer Cancer Center; Raoul Tibes, MD, PhD, Mayo Clinic; Bijal D. Shah, MD, Moffitt Cancer Center
Raoul Tibes, MD, PhD: One improvement has been in antibody-based therapies targeting ALL-specific antigens. We’ve heard about CD20 incorporated in rituximab in PH-negative treatment for ALL patients. We talked about CD19 antibodies or bispecific CD19 antibodies, blinatumomab. Another approach is antibody drug conjugates. So, essentially, you have a C-19 antibody and you link a cytotoxic to this antibody. There are several of those constructs in development. We were involved in one trial of such antibodies, and yet you can see responses with antibody drug conjugates in patients with ALL, but also aggressive B-cell lymphomas. I think this is a proof-of-concept; that with different strategies, you can target lymphoid cells and achieve remissions that we were not able to achieve with chemotherapy or in the relapsed and refractory setting.
So another approach is CAR T-cell, or chimeric antigen receptor T-cell, therapy. This is essentially taking a patient’s own T-cells, transfecting them with a construct that brings the T-cells close to the CD19-positive lymphoid or leukemia cells again, and then activates the T-cells to fire and destroy the leukemia cells. I think it’s a very normal, very elegant approach. It takes some time to construct for each patient individually, in an autologous fashion, their own CAR T-cells. So the patient needs to be put on an apheresis machine; the cells need to be isolated. They need to be expanded. They need to be transfected with a lentiviral or some other constructs, and then, after some time, they’re given back to the patient. Often, in addition to just giving back the CAR T-cell product, the patients do receive an immunosuppressive or a chemotherapy/immunosuppressive conditioning regimen prior to re-infusing the CAR T-cells.
This has first been tested now over the last several years in pediatric patients with ALL, and the responses were quite remarkable. Now, we bring it to adult patients with ALL and the trials. There are some reports out there, but the trials are just really starting to be conducted. So, I do think it’s a very promising strategy. The remissions that we have seen can be very deep and long-lasting. But I think we need to await the results in adult patients before we can draw any conclusions. We don’t have enough data at this point, but it’s another new therapy in the treatment of adult ALL.
Bijal D. Shah, MD: I’m very, very excited about CAR T-cell therapy for ALLs . I think this is where we have the most data. Whether we’re talking about Carl June’s experience at the University of Pennsylvania, whether we’re talking about the experience at the NIH, or whether we’re talking about the experience at Sloan Kettering Cancer Center—we can see now, both in adults and kids, a very high response rate that is extraordinarily encouraging. The challenges, as they relate to CAR T-cells, relate more to the toxicity. That is not a question, but more of an expectation. We will see cytokine release phenomena. We will see the hypotension and the fevers, and we’re very likely to see neurologic sequalae, as well. Not necessarily severe, but we are very likely to see some confusion, very likely to see some aphasia that develops.
Remember, in the context of CAR T-cell therapies, we don’t want to give steroids; we don’t want to give anything to suppress or otherwise minimize that T-cell activity. We want that expansion to really take place. We want a memory T-cell response to take place. And even though the CAR T-cells may fade depending on the vector that’s used, CD28 versus the 41-BB, we want to know that whether it is a consequence of epitopes spreading or just T-cell memory responses in general, that we’re generating a long-lived response in the context of ALL. Ultimately, my hope is that as this technology gets better, we’ll even be talking about doing CAR T-cell therapies in lieu of allogeneic transplant, and that would be a phenomenal accomplishment.
I think that as it relates to the durability, I’m also very excited about experimental approaches. I had mentioned blinatumomab as a way of rescuing those CAR T-cells, perhaps if the disease is relapsing. Or perhaps even just saying, okay, we want to administer blinatumomab at these sequential intervals to do our best to nonspecifically engage those CAR T-cells before they go away to keep them around for longer. Another opportunity is the PD-1 or PD-L1–based therapies. Can we exploit that so that we don’t see these regulatory T cells ultimately impede the response to our CAR T-cells?
One thing that’s really very interesting about CAR T-cell therapies is the difference in the treatment that each individual patient receives. While on the one hand, we’re trying to ask very important scientific questions as they relate to the type of CAR T-cell we use, one of the harder questions to answer is: what is the actual T-cell infusion that a patient receives? What is the ratio of the CD4 to the CD8 to the CD4 effectors to the CD8 effectors to the memory T-cells? And how is that ultimately going to influence outcome in the long run? And very, very interestingly, it may surprise you that each patient is receiving a different ratio of these different types of T-cells. I know that there are a lot of very, very smart people who are actively trying to better understand this.