The Ins and Outs of CAR-T Therapy and Combined Treatment Approaches

Chimeric antigen receptor (CAR) T-cell therapy, which involves patients’ own immune cells being collected, reprogrammed, and used to treat their cancer, has demonstrated great outcomes in the treatment of certain patients with some blood cancers who have not responded to other therapies. Although there have been approvals of CAR-T therapies by the US Food and Drug Administration (FDA), the authorization to use next-generation CAR T-cells or combination treatments involving CAR T-cell therapy remains to be seen. Researchers, however, have already begun to examine the benefits of using next-generation CAR T-cells or combined therapeutic approaches involving CAR T-cell therapies in this patient population.

In a recent issue of Gene Therapy, Mauro Castellarin, PhD, Postdoctoral Researcher, Center for Cellular Immunotherapies, Abramson Cancer Center, University of Pennsylvania, Philadelphia, and colleagues provided a review of CARs that delved into the structural intricacies of CAR molecules and provided an overview of cell-intrinsic (ie, modifications to the T-cell that improve the cell’s cytotoxicity or safety) and cell-extrinsic (ie, modifications to the tumor microenvironment that can lead to improved tumor control) combination CAR T-cell therapies (Gene Ther. 2018;25[3]:165-175).

Oncology Learning Network had the opportunity to speak with Dr Castellarin, who shared his expert insight on next generation CARs, the barriers to and benefits of CAR-T therapy, and the future outlook of this treatment.

What is CAR T-cell therapy?

CAR T-cell therapy is a type of cancer immunotherapy where the patient’s own T cells are genetically reprogrammed to become highly specific and robust cancer-cell killers. The components of a CAR include an antigen-binding domain on the outside of the T cell that is attached to stimulatory signaling domains inside the cell. Hundreds of millions of these CAR T-cells are expanded in culture and then reinfused back into the patient.

Recently, this type of therapy received FDA approval to treat B-cell malignancies.

What are next-generation CARs, and what types of cancers are they being developed for?

Each type of cancer has a different antigen profile, so CAR targeting needs to match the type of cancer being treated. For example, the FDA has approved CAR T-cell therapies that target CD19 on B-cells. However, there are dozens of clinical trials currently being conducted that target different tumor antigens, such as HER2 [human epidermal growth factor receptor 2] to treat breast cancer, or PSMA [prostate-specific membrane antigen] to treat prostate cancers.

What are the biggest barriers to treating solid tumors with single-agent CAR T-cell therapy?

Treating solid tumors has proven to be more challenging than liquid tumors for many different reasons.

First, solid tumors are almost always heterogeneous, meaning they are made up of different tumor cells within the same patient—and even within the same tumor itself. To be completely effective, CAR T-cells need to target and kill every variant of the tumor to prevent relapse of refractory disease.

Second, many tumor antigens are expressed on normal cells, so extreme care needs to be taken to not target the healthy cells along with the cancerous ones. We and others are developing ways to improve the specificity of CAR T-cells to reduce this type of “on-target, off-tumor” toxicity.

Other barriers include physical ones, because the solid tumor microenvironment can be physiologically too harsh for T cells. Tumors can be poorly perfused, leading to a hypoxic and nutrient-deficient environment that would prevent CAR T-cells from properly infiltrating and killing the tumor.

Another major barrier is overcoming the immunosuppressive environment of tumors. Many tumors have chronic inflammation, which causes immunosuppressive molecules to be present in high concentrations within the tumor and can promote recruitment of immunosuppressive immune cells (eg, regulatory T cells or myeloid-derived suppressor cells). Furthermore, these immune cells and tumor cells highly express immune checkpoint inhibitor ligands (eg, PD-L1, CD200, Gal-9, PVR, or B7-H4) to induce strong immunosuppression within the tumor microenvironment.

Of all the potential CAR T-cell therapy combinations discussed in your review, which ones are you most excited about, and why?

The combination therapies that I believe will benefit CAR T-cells the most are those that can boost an anti-tumor immune response by enhancing the CAR T-cells themselves and by recruiting other immune cells to the tumors. Strategies to do this include using proinflammatory cytokines such as interleukin (IL)-12 and IL-18 or administering antibodies that can block immune checkpoints. An added benefit to treating patients with CAR T-cells is that the cells can be engineered to deliver these molecules directly to the tumor, making these compounds more effective and safer than systemic delivery.

Another promising therapeutic combination is using oncolytic viruses with CAR T-cell therapy. Oncolytic virus therapy has already received FDA approval to treat melanoma, and it acts by directly lysing or inducing apoptosis of tumor cells and by stimulating an immune response. Preclinical studies have shown that using CAR T-cells with viruses can enhance the cytolytic activity of the CAR T-cells.

During your research, did you come across anything particularly surprising about CAR T-cell therapy that most healthcare professionals would be unaware of?

CAR T-cells are a living drug, so one-time treatment can have life-long benefits and therefore the cost-effectiveness is good in the long-term.

Also, it has been recently reported that the quality of a patient’s T cells can affect the outcome of the therapy. This suggests that we will see even better results when this therapy is used to treat healthier patients rather than those with advanced cancers—as has been the case so far.

Are there any other modifications or reconfigurations of CAR T-cells that you find promising as potential therapy options for patients with cancer?

The field is moving very quickly with new technological advancements for CAR T-cell therapies.

One promising development is the creation of a universal donor CAR T-cell. This would allow every patient to receive high quality and highly functional CAR T-cells, and would also simplify the manufacturing process so that CAR T-cell therapy could eventually become an “off-the-shelf” treatment. Our group has designed a universal donor CAR T-cell by using CRISPR gene editing to knock out the endogenous T-cell receptor and HLA genes.

Another intriguing development is the generation of CAR T-cells with multiple receptors that work together to improve the targeting specificity. Good examples of this are the synNotch CAR T-cells, which only kill cancer cells that have both of the targeted antigens. This allows us to consider targeting many more antigens that would otherwise cause off-tumor toxicity if targeted on their own.

Another important innovation for CAR T-cells will be to make them capable of switching targets. This is important because many solid tumors are heterogeneous and contain tumor cells with different antigen profiles that cannot be killed using a single type of CAR. This has already been seen in some CAR T-cell–treated patients with relapsed/refractory disease. “Switchable” CAR T-cells have been designed where the CAR does not directly recognize the tumor antigen, but instead binds to a specially designed antibody, and it is this antibody that attaches to the tumor antigen. It is then possible to retarget the CAR T-cells by simply adding another antibody that recognizes a different antigen.

According to the review article, you and your co-investigators are currently investigating the use of ibrutinib in combination with CD19-redirected CAR T-cell therapy. Can you briefly describe the objective of this trial, and why you chose this particular combination?

Ibrutinib is frequently used to treat chronic lymphocytic leukemia, and our group found that ibrutinib can act synergistically to enhance the effectiveness of CAR T-cells. I am not involved in this study, but other members of our group are conducting a pilot clinical trial testing the combination of ibrutinib with CD19-redirected CAR T-cells.

As this study is still ongoing I cannot comment on any results at this time.

In your opinion, what is the future outlook of CAR T-cell therapy?

CAR-T therapy has already proven itself to be a potent and effective therapy for blood cancers, but this is only the beginning.

The technologic leaps that have been made recently in the field of cellular engineering will lead to even more innovations and improved CAR T-cell therapies.

The sky is the limit and I am certain that CAR-T cell therapies will be further developed so that they can successfully treat a variety of cancers, and even diseases other than cancer.