The Tumor Microenvironment and CAR T-Cell Therapy Resistance: Insights For Pharmacists

In a Pharmacy Times interview, Mary McGann, PharmD, BCOP, clinical pharmacy specialist of blood and marrow transplantation and cellular therapy at the Hollings Cancer Center in the Medical University of South Carolina (MUSC), discussed the complex nature of the tumor microenvironment and CAR T-cell resistance. Her insights provide clarity around the multifaceted impact of immunosuppressive cells, factors influencing resistance to CAR T-cell therapy, and the crucial role of pharmacists as members of interdisciplinary care teams.

Pharmacists are crucial members of interdisciplinary care teams treating patients with hematological malignancies, such as multiple myeloma. Image Credit: © Drazen - stock.adobe.com

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

Mary McGann, PharmD, BCOP: This is a huge topic as CAR T-cell therapy is explored in solid tumors. We haven't had any solid tumor CAR T trials at my center yet, so I have limited experience in this area.

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

McGann: We know that T-cell exhaustion is an issue with CAR T-cells likely due to prolonged antigen stimulation, previous therapies, and/or immunodeficiencies. Relapse within 1 year of CAR T-cell therapy still occurs in roughly half of patients. Early relapse is typically associated with relapse of antigen-positive disease then later relapse is associated with antigen loss. Antigen-positive relapse is associated with limited CAR T-cell persistence or T-cell exhaustion, which may be due to the inherent T-cell quality, as those T-cells may be lower quality if they've had numerous previous therapies; the co-stimulatory domain, we know CD28 products do not persist as long as 4-1BB products; or T-cell phenotype such as the proportion of CD4 and CD8 cells, although we don't yet know the optimal proportion of those cells.

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

McGann: We know for DLBCL [diffuse large B-cell lymphoma], risk factors for disease relapse include poor performance status, higher stage disease, extra-nodal sites, elevated LDH and CRP [levels]. Since these are autologous T-cells directly from the patient with a hematologic disease, they've had previous lines of cytotoxic therapy, and those T-cells utilized are already exhausted and terminally differentiated.

Pharmacy Times: What have been the key findings from recent clinical trials focused on CAR T-cell therapy resistance? Can you speak to your experience working in clinical trials?

McGann: CAR T research is such an exciting area because there are so many trials down the pipeline and many of them are trying to figure out how to make CAR T-cells persist longer and/or prevent resistance but also considering consolidative therapy after CAR T-cell-induced remission. Some specific exciting areas with ongoing clinical trials include exploring immune checkpoint blockade, combination with tyrosine kinase inhibitors, and allogeneic T-cells. It’s been helpful to see studies showing that continuing ibrutinib [Imbruvica; Janssen Biotech] during CAR T-cell therapy is not only safe but was shown to improve CAR T expansion and is a strategy that we sometimes will use in patients with aggressive lymphoma on a BTK inhibitor.

We have a few CAR T trials at MUSC aimed at improving CAR T efficacy and safety, which has been exciting to be a part of and see first-hand, we have a phase 2 trial looking at consolidation therapy post CAR T and a phase 1 trial with metabolically fit CAR T-cells with a CD34 selection marker. There are patients that have a partial response at day 30 that convert to a complete response at subsequent time points, at MUSC we have a trial looking at consolidation therapy for those that have stable disease or partial response at day 30 to determine if therapies like polatuzumab [Polivy; Genentech], mosunetuzumab [Lunsumio; Genentech], or the combination of both can induce improved CAR T responses versus no consolidative therapy. An active area of research to combat relapse is to improve CAR T-cell fitness and reduce T-cell exhaustion. The function of each product may also be improved by increasing the number of CAR T-cells infused and/or reinvigorating the CAR's cytotoxic function and persistence within the manufacturing process. At MUSC, we have a trial utilizing a CD34 tagged CD19 CAR T-cell product to allow for a more purified product via CD34 selection with the goal of improving antigen reactivity and persistence of the cellular product as well as limiting toxicity. Secondly to improve CAR T-cell fitness, these products are exposed to priming conditions that enhance a TH1/TH17 hybrid leading to a metabolically enhanced CAR T-cell product.

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

McGann: As there is so much research surrounding CAR T-cell therapy for all healthcare providers caring for these patients, staying up to date is vital. With the vast amount of new information constantly coming out it can be overwhelming, but I've found attending conferences, or just following along virtually, that highlight updates in the field has been helpful. There are also many up-to-date webinars discussing new data with experienced and well-respected providers in this field that can help breakdown all of this data, quickly summarize, discuss future directions, and take-away points.

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

McGann: There are lots of advancements that hopefully will translate from initial trials to promising results in patients that I've mentioned previously like PD1 blockade, combination with small molecule inhibitors, and optimizing the T-cells to combat T-cell exhaustion after leukapheresis. Allogeneic CAR T-cells is also an exciting area of research which should allow for more fit and healthy T-cells from a donor without a hematologic malignancy to be utilized, although at this time they haven't shown the same level of efficacy as autologous products and also come with their own challenges of finding ways to overcome and lessen the risk of graft versus host disease that we see with allogeneic hematopoietic stem cell transplants.

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?

McGann: I think in the coming years, there will continue to be new advancements surrounding CAR T-cell therapy including optimizing patient selection to determine who best responds, optimizing the lymphodepletion regimen, consolidative therapy to induce deeper CAR T remissions, and many others. Another big area that continues to improve is patient access to CAR T. As we gain more experience, we should be able to safely move this therapy to the community setting to reach more patients.

Pharmacists can play a great role within the interdisciplinary team to keep up with current and emerging literature as well as optimizing how CAR T is given, appropriate supportive care and management of toxicities. Especially as future directions may involve combining CAR T with therapies or considering therapies shortly after cell infusion to help prevent relapse and resistance, pharmacists will be crucial in ensuring that is done safely considering potentially overlapping toxicities.