Pharmacists' Role in Addressing CAR T-Cell Therapy Resistance and Tumor Microenvironment Factors

Kelsea Seago, PharmD, BCOP, clinical pharmacy specialist, hematological malignancies and cellular therapies at West Virginia University, shares her insights into the multifaceted, complex underlying mechanisms of chimeric antigen receptor (CAR) T-cell resistance, effective treatment administration, and how pharmacists can improve health outcomes for their patients.

Pharmacy Times^®: What is the role of immunosuppressive cells within the tumor microenvironment in contributing to CAR T-cell therapy resistance?

Kelsea Seago, PharmD, BCOP: There is literature discussing the role of immunosuppressive cells and CAR T-cell therapy resistance, we know. B cell lymphomas, for example, there's some evidence that tumor associated macrophages can inhibit cytotoxic T lymphocyte responses and a few other mechanisms, as well. And the myeloid derived suppressor cells can also suppress the activation and proliferation of T cells, which can be associated with insufficient product expansion, and that can affect resistance.

We also know that prior publications discuss impact of the tumor microenvironment on the success of CAR T-cell therapy in solid tumors, such as the decreased ability to infiltrate the physical barrier of the target tumor with a dysregulated tumor vasculature and the dense extracellular matrix.

Pharmacy Times: Can you discuss the impact of T-cell exhaustion on CAR T-cell therapy resistance?

Seago: T-cell exhaustion can be a real problem. As we've used CAR T-cell therapy and more patients in the real-world setting, we've definitely seen that T-cell exhaustion can drive resistance and ultimately relapse. And this can be a real barrier to remission or the longevity of remission, in some situations. T-cell exhaustion in general, is caused by persistent antigen stimulation, and this in turn leads the T cells to differentiate into more of a dysfunctional state, and therefore they have reduced proliferation and effect or function of the CAR T cells. This phenomenon is associated with poor responses and oftentimes resistance and therefore relapse

Pharmacy Times: How do patient-specific factors, such as prior treatments and overall health, impact the likelihood of CAR T-cell resistance?

Seago: If you think about prior treatments, we have learned so much over the years, and we know that prior treatments can really impact our ability to adequately collect T cells for manufacturing, and likewise, impact the confidence that we have in expecting a robust manufacturing of the CAR T cell therapy product. I think the story of bendamustine [Bedeka; Teva Pharmaceuticals] is a good example of how we've learned more about prior therapies negatively impacting our collections and even post infusion cytopenia. If we're able to collect and manufacture, these all play into resistance and the robustness of our CAR T-cell product.

Additionally, we have to think about prior therapy as it relates to the tumor associated antigen that we are targeting. If a patient has already seen a therapy with the same antigenic target—so BCMA currently, in terms of commercial products available for myeloma—that could lead to antigen loss or a lower chance of response, which we've seen also in CD19 therapies.

Other factors for prior therapies: it can be more difficult if you have a patient with a very heavy disease burden. Those patients can sometimes just not clinically allow for much of a washout period before we need to collect the T cells, and that can really impact the T-cell function prior to collection. Additionally, patients that go into CAR T-cell infusion with a higher disease burden are likely at higher risk for that T-cell exhaustion that we just talked about after infusion overall. I would say that patients with multiply relapse or refractory disease can sometimes have lower T-cell fitness in general, and this increases the chance of resistance as well.

Pharmacy Times: What have been the key findings from recent clinical trials focused on CAR T-cell therapy resistance?

Seago: Clinical trials are so important, and I think especially in CAR T-cell therapy and cellular therapy, where we still have so much to learn. We've continued to learn through our trials about how some prior therapies can potentially decrease resistance and have a positive effect on our CAR T-cell manufacturing and efficacy. I think we've also learned a lot about predictive models for poor response and early treatment failure. So, really learning more about our patient selection, the best approach to treating these patients after relapse from CAR T-cell therapy, when it does happen, are things we've also learned from trials, which is obviously helpful when knowing the next steps.

Additionally, I think we've learned more about whether and when we need a consolidated approach with an allogeneic stem cell transplant, depending on the situation. I think results of many ongoing trials are going to be critical and understanding the best approach to increase our efficacy, get rid of some of that toxicity that can be a little bit of a deterrent for patients, and how we can avoid resistance mechanisms that we still need to overcome.

Pharmacy Times: Can you describe your experience in translating CAR T-cell therapy from clinical trials to routine clinical practice?

Seago: Clinical trials typically include patients that are relatively healthy, and check all the boxes to be included, but many of the patients that I have seen and treated in real world practice would certainly not qualify for a clinical trial. And those patients, based on their disease, they need CAR T-cell therapy. And so, utilizing the knowledge from the trials that we have with prior experience and the surfacing real world data that we have is interesting to see play out and apply to patient specific scenarios.

Pharmacy Times: What advancements show promise in helping to improve CAR T-cell therapy efficacy and overcome resistance?

Seago: There are many advancements and strategies continually being researched for CAR T-cell improvements. I'm really excited about advancements in targets and how these can help us overcome resistance. Not only new targets to expand indications and disease impact, but also multi-antigen targeting CAR T-cell products that are being studied. These can potentially help us mitigate the antigen escape that we see.

Some examples of these are varying types of bispecific CARs, like the bisystronic approach, where the CAR expresses 2 different receptors on the surface; old CARs, where there are a few mono-specific CARs mixed together that target different antigens; or tandem CARs, where a single receptor is utilized, but the 2 antigen targeting domains are fused together and outside of advancements and targets.

I'm also excited to see how the allogeneic or off the shelf CAR T cells can transform the field, especially in patients that are unlikely to collect well or manufacture well for the autologous products, or in patients that can't clinically tolerate extensive washouts or longer manufacturing times.

Pharmacy Times: What integrated strategies or innovations do you believe will most significantly enhance patient care and improve treatment outcomes in the coming years? What role do pharmacists play?

Seago: I'm really hopeful that there will be many impactful advancements as it relates to CAR T-cell therapy, cellular therapy in general. I think we're going to see many more disease states impacted, including additional hematologic malignancies, solid tumors, autoimmune disorders and more. I think we're also going to see increasingly effective and less toxic products. And from a clinical application perspective, I'm really excited to continue learning more about how to best treat our patients with the available products, either commercially or through trials.

We continue to learn more about the best strategies for product selection, patient selection therapy, sequencing, how early to use CAR T-cell therapy, and are there combinations that we need to utilize with augmenting our CAR T-cell approach or utilizing a consolidated or maintenance approach after infusion. All of these things, I think are going to be really exciting in the future in terms of the role of the pharmacist in CAR T-cell therapy. I think it's really crucial, right? It's been really crucial. And I think as we continue to see the field expanding, our role is going to grow.

A lot of centers—I think current state—probably don't have a cellular therapy specific pharmacist in some capacity outside of utilizing the BMT [bone marrow transplant] [pharmacist] or the heating pharmacist, but I think that more centers will look to have a cellular therapy specific pharmacist. There's just so much to be done from a formulary management and financial perspective.

Clinically, we have to understand how to safely and effectively treat these patients, and that includes a lot of proactive management of treatments before CAR T is needed. [These include] critical thinking surrounding the washout periods and what's best for the patient in manufacturing, bridging therapies, how to approach that [and] trying to get that good response before we go to CAR T-cell therapy so we don't have T-cell exhaustion, concurrent therapies, toxicity management, [and] infection prevention. You have to think about long-term survivorship and management of these patients. All of these things, a pharmacist is really uniquely positioned to help manage and will have a huge impact on the cellular therapy field in the future.