Chimeric antigen receptor (CAR) cell therapy offers hope where other cancer therapies have failed. However, CAR-T therapy still faces limitations. How can combination therapy enhance its success in treating cancer?
Combination therapy involves pairing two cancer treatments with each other to enhance the benefits of both. CAR-T cell therapy, which uses white blood cells called T cells to target cancer, is a particularly promising candidate for combination therapy.
“In CAR-T cell therapy, T cells are taken from the patient. They are then engineered ex vivo with a CAR on the cell membrane,” explained Matthieu Pesant, Senior Market Strategy Manager at Takara Bio Europe.
“The CAR is designed to recognize specific molecules presented at the surface of cancer cells. Upon recognizing the tumoral molecules, the CAR-T cell jumps into action against the cancer cell.”
CAR-T cell therapies that use the patient’s own cells are known as autologous therapies. All five CAR-T cell therapies on the market today are autologous and are used to treat blood cancers, such as leukemia and lymphoma.
These therapies have shown astonishing results in patients who did not initially respond to treatment. For example, Kymriah, the first CAR-T therapy to enter the market in 2017, has led to cancer remission rates of 83% in patients who did not respond to standard treatments.
However, as it is a personalized approach, autologous CAR-T cell therapy takes a while to develop and remains costly.
Allogeneic or “off-the-shelf” CAR-T cell therapy is currently in preclinical and clinical development and uses T cells obtained from a healthy donor. The donor T cells are genetically modified so they can be used for different patients, rather than just one.
Allogeneic CAR-T cell therapy comes with a number of advantages, including the immediate availability of the therapy, lower manufacturing and therapy costs, and the possibility to use combinations of CAR-T cells for different targets.
Testing the limits of CAR-T therapy
Despite its effectiveness, CAR-T cell therapy can be associated with severe adverse reactions, such as neurotoxicity and cytokine storms.
“As with many therapies, when you manipulate the immune system, the impact can potentially be important for the whole body,” Pesant elaborated.
“Side effects and symptoms can be mild, let’s say, fever or allergic reactions to the CAR-T therapy. But they can be more severe in some cases and can even be life-threatening to the patient. So it’s not a black and white situation.”
A key limitation of CAR-T therapy is the development of tumor resistance to a single CAR antigen. Tumors can evade the immune system’s watchful eye in a process known as antigen escape, where the surface of tumor cells becomes unrecognizable to CAR-T cells. Antigen escape is being addressed by designing CAR-T cells that target multiple antigens.
“Targeting multiple antigens is what we call dual or tandem CARs,” Pesant explained. “In a preclinical model of breast cancer, for instance, dual-targeting has shown superior anti-tumor response compared to a single targeted therapy.”
Another challenge in improving CAR-T treatments is targeting solid tumors. The immunosuppressive tumor microenvironment makes it difficult for CAR-T cells to access and infiltrate tumors, and the tumor itself can act as a solid barrier.
Local delivery, meaning injecting CAR-T cells directly into the tumor, could help CAR-T cells access and attack the cancer.
Solid tumors can also be targeted by enhancing CAR-T cells’ trafficking thanks to specialized molecules. Engineering CAR-T cells to express such cell surface proteins, called chemokine receptors, has been shown to improve CAR-T cell trafficking and antitumor response.
Combination therapies: giving cancer a one-two punch
Combination therapies with CAR-T therapy are one of the most promising therapeutic avenues in cancer cell treatment. These approaches couple CAR-T cell therapy with another therapeutic agent, such as a checkpoint inhibitor, an oncolytic virus, or an RNA vaccine.
Checkpoint inhibitors block proteins used by cancer cells to evade the immune system. For example, the PD-1 receptor is a checkpoint that tells T cells not to attack cells expressing the PD-L1 protein. Some tumor cells, however, express PD-L1, a prime example of antigen escape. Hence, if PD-1 is blocked, CAR-T cells can target tumor cells expressing PD-L1.
Combination therapy with a checkpoint inhibitor might be one way to make CAR-T treatments more effective in solid tumors.
“The idea is to try to revert the immunosuppressive tumor microenvironment to enhance the efficacy and persistence of the CAR-T therapy,” Pesant explained.
Alternatively, oncolytic viruses tear tumor cells open, release their antigens, and make them more recognizable to the patient’s immune system, including T cells. This form of combination therapy could also make CAR-T cell therapy more effective in solid tumors as shown in a mouse model of melanoma.
Another form of combination therapy, which uses RNA vaccines has been shown to facilitate the controlled growth of CAR-T cells once administered to the patient. Last year, preclinical findings reported that CAR-T in combination with RNA vaccines can achieve regression in a human tumor transplanted into mice, with clinical studies in planning.
RNA can benefit CAR-T in more ways. For example, a new study shows that CAR-T cells expressing a naturally occurring RNA molecule can recruit the body’s own T cells in addition to improving the function of CAR-T cells to fight cancer.
Engineering T-cell therapies with Takara Bio
Takara Bio leverages decades of expertise in the cell and gene therapy space to help researchers accelerate scientific discovery in the lab and the clinic. In particular, the company has developed ways to improve the so-called transduction efficiency ‒ the success rate of introducing CAR genes into T cells ‒ and their growth and expansion in cell culture.
Takara Bio’s RetroNectin® helps gene-modifying viruses to enter cultured cells, such as those from which CAR-T therapies are made. RetroNectin is a synthetic protein that binds to the virus on one end and to the target cell with another end. This brings the virus and target cell closer together, thereby enhancing the transduction efficiency.
As of today, RectroNectin has been used in over 68 transduction protocols in clinical trials.
Combination therapy in the future
The future of CAR-T cell therapy is likely to go hand-in-hand with its further development as a combination therapy.
Along with continued engineering to reduce toxicities associated with CAR-T and improved CAR-T cell therapy efficiency, combination therapies promise to bring out the best of each treatment, respectively.
Hence, combination therapies may provide a path forward for safer and more efficient therapies and bring hope to cancer patients who do not respond to conventional therapeutic approaches.
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This article was originally published in November 2021.
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