Insights into CAR T Cell Therapy Resistance: The Impact of the Tumor Microenvironment and T Cell Exhaustion

Dan Schrum, PharmD, BCOP, inpatient lead for the cellular therapies group at Duke University Hospital, presents valuable insights about the tumor microenvironment and its association with CAR T cell therapy resistance in patients with hematological malignancies. His perspectives provide a deeper understanding of the dynamic mechanisms underlying CAR T cell therapy resistance, and how to best navigate them to reduce toxicity and increase response rates for patients receiving treatment.

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Pharmacy Times: What is the role of immunosuppressive cells within the tumor microenvironment in contributing to CAR (chimeric antigen receptor) T cell therapy resistance?

Dan Schrum, PharmD, BCOP: It certainly plays a big role and I think it's a piece of the puzzle as to why lymphodepletion is so important for the success of CAR T. There have been a lot of findings supporting the fact that there's increased tumor regression with the absence of host lymphocytes, kind of underscoring the lymphodepletion point that I just made. The biggest areas that are affected by lymphodepletion are (1) endogenous T cells, and (2) something called cytokine sinks. For typical lymphodepletion with CAR T, fludarabine/cyclophosphamide or bendamustine [Bendeka; Teva Pharmaceuticals] are used. These are T cell toxic agents [that] specifically have an impairment effect on regulatory T cells, which unlike CD4 and CD8 positive T cell, are immunosuppressive in nature. In the case of Tregs [regulatory T cells], for someone with cancer, sometimes these regulatory T cells are suppressing tumor-reactive T cells, whether that be downstream CAR T cells, or endogenous tumor-reactive T cells. In that case, that's not a good thing. The removal or the inactivation of regulatory T cells via lymphodepletion plays a big role in altering the tumor microenvironment.

The other point that I had mentioned is the modulation of homeostatic cytokines, which is colloquially known as cytokine sinks. The premise here is that there are these endogenous immune cells, including T cells and B cells that are soaking up homeostatic cytokines. And by removing those with lymphodepletion, and allowing those homeostatic cytokines to sit there, they can be used by CAR T cells, as opposed to endogenously found immune cells that normally would be using those. Things like IL-7 or IL-15 are floating around in higher quantities comparatively, for the CAR T cells to be able to use. So those are probably the 2 biggest components of the tumor microenvironment that can play a role in resistance. And like I said, why lymphodepletion is so important I think is nicely underscored with a little bit of data that came out from the JULIET trial [NCT02445248] from [tisagenlecleucel] [Kymriah; Novartis Pharmaceuticals Corporation] where they allowed for omission of lymphodepletion if a patient's white blood cell count was less than or equal to 1.

Just white blood cell count as a marker for whether or not a patient has an adequate level of lymphodepletion is probably not appropriate because of the tumor microenvironment’s role. This was shown both in this [JULIET] study and Ramos [Carlos Almeida Ramos, MD, PhD, professor of medicine at the center for cell and gene therapy at Baylor College of Medicine in Houston] and colleagues showed later that the patients who had white blood cells level lower than 1 and did not receive lymphodepletion did substantially worse at lower peak CAR T exposure. In summary, tumor microenvironment is playing a role here. It's not just the white blood cell level that matters.

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

Schrum: In CAR T cell therapy, the persistence of CAR T cells is very important. For them to stick around in the body for a long period of time and still be able to act is of the utmost importance not only for tumor regression, but for ideally preventing the tumor from coming back or repopulating. There are a variety of different ways that these T cells could in theory become dysfunctional, which leads to exhaustion as it's known; but probably the biggest 2 are prolonged antigen stimulation and previous exposure to lymphotoxic therapies.

The first of these, prolonged antigen stimulation, has a lot of different ways that it can happen. The most prominent antigens that we think of that might play a role here that a lot of folks watching this and reading this probably will have heard of, are PD1 and CTLA4. And the reason that so many people know of these is that these are both targetable antigens. So, there are a lot of studies that have been done and are ongoing using, for example, PD1 and PD-L1 inhibitors to see if that can actually help play a role in terms of long term CAR T cell persistence.

The other portion that I mentioned is increased number of previous lines of lymphotoxic therapy. And the data for this is pretty good. The number of lines or the amount of lymphotoxic therapy that a patient has seen in the past can substantially affect memory T cells, which, when CAR T is being made, a portion of those cells are memory T cells. And so, if there's a lower quantity or more dysfunctional memory T cells that are being used to manufacture CAR T cells, the actual CAR T product can be affected and have lower persistence.

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?

Schrum: I think the most important paper that's been published recently, that has not gotten enough press, is a paper that was published in Nature Medicine in January of this year by Fred Locke [Frederick Locke, MD, medical oncologist and translational researcher in the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center] and his group that does a fantastic job of demonstrating the effect of the tumor microenvironment and its effect on CAR T cell response. So, while it's not necessarily a clinical trial for a new agent or augmentation of agents, I think they did a nice job of showing ways that we might be able to better structure how we're approaching these patients, whether it's on workup, diagnostics, or even when we're thinking about line of therapy.

What they looked at was the tumor microenvironment characteristics of the patients from ZUMA-7, which was the use of [axicabtagene ciloleucel] [Yescarta; Gilead Sciences, Inc] in the second line setting, and the association of these characteristics with response to CAR T versus standard of care. I thought they were able to do a very nice job of demonstrating the important tumor microenvironment factors that played a role in a response to standard of care versus [axicabtagene ciloleucel] in that second line setting. But what they were also able to demonstrate is they didn't just reinforce the findings in ZUMA-7 that [axicabtagene ciloleucel] can be used in the second line setting like it's now approved, but really that it should be used instead of standard of care. And this is all based on the fact that the tumor microenvironment, as you have more exposure to lymphotoxic therapies, actually changes and becomes less responsive to CAR T. So, use of CAR T up-front in that second line setting or even earlier, as we'll see maybe in future studies, has a higher benefit than if it's used later in lines.

References

1. ClinicalTrials.gov. A study of a new drug in patients with non-hodgkin's lymphoma. ClinicalTrials.gov identifier NCT02445248. Updated August 7, 2024. Accessed August 7, 2024. https://clinicaltrials.gov/ct2/show/NCT02445248

2. ClinicalTrials.gov. ZUMA-7: a study of kte-x19 in patients with relapsed/refractory large b-cell lymphoma. ClinicalTrials.gov identifier NCT03391466. Updated August 7, 2024. Accessed August 7, 2024. https://clinicaltrials.gov/ct2/show/NCT03391466