CAR T Cell, Bispecific Therapies: Enhancing Treatment for Patients With Hematological Malignancies

Zahra Mahmoudjafari, PharmD, MBA, BCOP, FHOPA, a clinical pharmacy manager with the division of hematological malignancies and cellular therapies at the University of Kansas Cancer Center, offers insights into CAR T cell and bispecific therapies for patients with hematological malignancies. She shares the potential for these treatments to offer patients improved responses and renewed quality-of-life.

Pharmacy Times:What are the primary challenges in the development and implementation of CAR T-cell therapies and bispecific antibodies?

Zahra Mahmoudjafari, PharmD, MBA, BCOP, FHOPA: The biggest constraints related to cellular therapies at this point are more for the CAR T cell therapies, and a lot of it relates to the patient's own cells, which are being collected and shipped to a manufacturer for expansion. The manufacturing process at this point takes anywhere from 4 to 6 weeks. So oftentimes, our patients don't have that sort of time in the hematologic malignancies space. That does not seem to be a concern for bispecifics, as those are readily available off the shelf, they follow a traditional pathways—you could just pick one from the shelf and are able to utilize it. So, for bispecifics, the challenges really relate to sequencing more than anything. Whether you use CAR T or bispecifics, now, most recently, we've had a lot of approvals moving up the CAR T cell therapies in the [multiple myeloma (MM)] space to earlier lines of care. And so that argument is “no,” at this point, no longer valid. If you have a patient who's eligible for CAR T, you would utilize car T cell therapy. If your center has access to those therapies, then you would want to utilize CAR T and then save the bispecifics for later on. But the challenges right now primarily include the manufacturing capacity constraints, and just the fact that not all centers have access to the CAR T-cell therapy. So that continues to be a major challenge.

Pharmacy Times: Are there potential benefits or challenges in combining CAR T-cell therapies with bispecific antibodies for cancer treatment?

Mahmoudjafari: At this point, there is no readily available literature supporting using them in combination. They're typically used either sequentially, or one after the other. However, there is emerging evidence that even though you've had exposure to CAR T, for example, in [MM] that's a BCMA [b-sell maturation antigen], CAR T patients are still responding with bispecifics. And so that is definitely very encouraging, as oftentimes you're not looking to utilize a product that has perhaps the same target. So that's definitely a very promising development and one we're continuing to monitor. But at this point, they're used individually.

Pharmacy Times: What innovative approaches or emerging technologies hold the most promise for overcoming the current limitations of CAR T-cell therapies and bispecific antibodies?

Mahmoudjafari: Instead of doing emerging technologies, I really want to give a a major kudos and shout out to organizations and institutions that are looking at providing these therapies in innovative ways in terms of being able to administer these therapies on the outpatient side, looking into the toxicities of each of these therapies, and individualizing our toxicity management as it relates to cytokine release syndrome [CRS] and neurotoxicity. So, there are several articles highlighting the importance of site of care what types of things you need to do in order to ensure your site is prepared for outpatient management and monitoring of these patients. Then we're also getting exceptionally good at the toxicity management and learning how to best care for these patients and prevent perhaps [CRS] from occurring in the first place.

Pharmacy Times: Can you speak to the toxicity of CAR T-cell and bispecific antibodies and how that is overcome to improve patient outcomes?

Mahmoudjafari: With CAR T cell therapies, the two biggest side effects that we are cognizant of acutely includes [CRS] and neurotoxicities. For those, we often will utilize either tocilizumab [Actemra; Genentech] as an IL-6 agonist [interleukin-6 receptor antagonist] for the treatment of CRS, and then for neurotoxicities we’re utilizing steroids. Now, for the bispecifics, it also has the ICANS [immune effector cell-associated neurotoxicity syndrome] and CRS, but it also leads itself to patients having risk of infection. So, we're learning a lot about infections related to bispecifics and how to best manage those because CAR T is just a 1 and done treatment versus bipecifics is, in some cases, a continual treatment until a patient has progression of disease. And so those infections can be very difficult to manage and to prevent. The other challenge that we have found with bispecifics, the GPRC5D [G protein–coupled receptor, class C, group 5, member D] bispecifics in particular is nail changes and kind of just toxicities of the mouth and so that those are newer toxicities. For us, again, that's something we can't manage. But just something we have to be a lot more aware and cognizant of trying to think if there's anything else related to the question long term with CAR T. These are some of the toxicities that we appreciate and have worked on conditions like hypogammaglobulinemia. So that ensures patients often have to get IVIG [intravenous immunoglobulin] replacement monthly. That can be a burden on the healthcare system as to the patient. And then patients often experience long term B-cell aplasia. So that is also something that we have to ensure patients are properly supported and managed. And so, those have long term ramifications because often our patients are getting CAR T cell therapy and then transitioning to bispecifics. And so, you put those together, the patients tend to have additional toxicities.

Pharmacy Times: How does real-world data compare to clinical trial data in terms of the efficacy and safety of CAR T-cell therapies and bispecific antibodies?

Mahmoudjafari: I have certainly seen a lot of more recent literature even in the last several months demonstrating that the real-world patients who often are not maybe your ideal clinical trial patients, are exhibiting good responses and sustained responses. And so, oftentimes those patients in the real-world are the higher risk patients who have maybe extramedullary disease, or maybe a renal dysfunction of some sort. And those patients are responding and doing very, very well with great outcomes. So, we've definitely know that the real world patients are, are showing sustained responses to both CAR T and bispecifics.

Pharmacy Times: Can you share any compelling patient stories that highlight the transformative impact of these therapies?

Mahmoudjafari: Oftentimes with CAR T and bispecifics, these patients are not newly diagnosed. They've been through several rounds of therapy, and oftentimes, they are deconditioned or they're having to take treatment every single day. And what this can allow for patients is a little bit of freedom, or the opportunity to live their life by their terms, and to be able to get to some sort of normal to them. And so, it has definitely been a cure for the lymphoma patient populations, for those that do respond to ultimately giving them back a very important quality of life. Now for [MM], it does not still serve as a cure, but it does give them time away from therapy. Again, just an emphasis on the quality of life that they ultimately have, and there are so many stories that we don't have time to get into them, but it's really nice to be able to give patients know kind of a new lease on life. And there's so much hope related to CAR T cells and bispecifics. These patients who oftentimes are second or third line of care, who traditionally haven't had very many good options, their response rates were in the lower 20s now have 80%, 90%, 100% chance of response and so that's pretty incredible results in patients who are relapsed and refractory.