Side-Effect-Free CAR-T Therapy via Transient Stat5 mRNA Activation

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Side-Effect-Free CAR-T Therapy via Transient Stat5 mRNA Activation

Developing Side-Effect-Free CAR-T Cell Therapy through Transient Activation of Stat5 Signaling with mRNA

CAR-T cell therapy, short for Chimeric Antigen Receptor T-cell immunotherapy, involves genetically engineering a patient’s immune T cells outside the body to recognize antigens on the surface of tumor cells. These modified cells are then reintroduced into the patient’s body to identify and kill cancer cells. Since 2017, the FDA has approved six CAR-T cell therapies for various blood cancers, all of which come with a hefty price tag.

While some cancer patients have experienced remarkable recoveries with CAR-T cell therapy, they may also endure severe and frightening side effects. Part of the reason lies in the need for patients to undergo lymphodepletion, or the removal of lymphocytes, through chemotherapy before receiving CAR-T cell infusions. This step is taken to clear existing T cells in the body, creating space for the CAR-T cells to thrive and enhance the therapy’s effectiveness.

Two years ago, Dr. Richard O’Neil, upon joining the Medical University of South Carolina (MUSC), embarked on a mission to find a more patient-friendly approach to CAR-T cell therapy. Little did he know that within just two years, his team would achieve a groundbreaking breakthrough.

Recently, the team led by Dr. Richard O’Neil published a research paper titled “Efficient T cell adoptive transfer in lymphoreplete hosts mediated by transient activation of Stat5 signaling” in the Molecular Therapy journal.

This study demonstrates that transient overexpression of STAT5 protein through mRNA can facilitate CAR-T cell engraftment and proliferation without the need for pre-infusion lymphodepletion, while also reducing cytokine storms. This lays the foundation for mitigating the side effects of CAR-T cell therapy and extending its application beyond cancer treatment.

Side-Effect-Free CAR-T Therapy via Transient Stat5 mRNA Activation

Professor Richard O’Neil, the corresponding author of the paper, stated that this study provides substantial evidence supporting the concept that effective CAR-T cell engraftment is an autonomous cellular process independent of the host immune status depleted of lymphocytes. Essentially, this process is driven by activated STAT5. Therefore, by briefly activating STAT5 during CAR-T cell infusion, it is possible to “trick” CAR-T cells into believing they are entering a lymphocyte-depleted environment.

The research team initially focused on STAT5 because of its significant role in cytokine signaling pathways. Cytokines such as IL2, IL7, and IL15 are known to play a role in CAR-T cell engraftment, and there have been attempts to inject IL2 or IL15 into patients as an alternative to lymphodepletion. Each of these cytokine pathways requires STAT5.

As directly injecting cytokines like IL2, IL7, and IL15 into patients could pose new risks, the research team experimented with regulating the entire signaling cascade through STAT5. They introduced mRNA encoding STAT5 protein into CAR-T cells to achieve transient STAT5 overexpression.

In preclinical mouse models, they found that this approach reduced the most common and severe side effect of CAR-T cell therapy – cytokine release syndrome (CRS). STAT5-overexpressing CAR-T cells also controlled cancer progression effectively and appeared to generate memory cells targeting cancer.

Side-Effect-Free CAR-T Therapy via Transient Stat5 mRNA Activation

Previous clinical studies have shown significant effectiveness of CAR-T cell therapy in lupus erythematosus, but for this chronic condition, weighing the potential side effects of CAR-T cell therapy was a concern.

For many lupus patients with less severe symptoms, the trade-off of undergoing lymphodepletion before CAR-T cell therapy was not favorable.

However, the emergence of CAR-T cell therapy that does not require pre-infusion lymphodepletion brings hope for extending CAR-T cell therapy to diseases beyond cancer, including lupus.

Furthermore, this research holds the promise of changing existing CAR-T cell therapy protocols by enabling multiple and repeated CAR-T cell infusions without the need for patient lymphodepletion.

The research team is currently collaborating with the lupus research team at the Medical University of South Carolina (MUSC) to advance this novel CAR-T cell therapy into clinical trials for lupus. Additionally, they are in discussions with biotechnology companies in the field of CAR-T cell therapy for technology transfer.

Paper Link:
https://doi.org/10.1016/j.ymthe.2023.07.015