July 16, 2022
Chimeric antigen receptor (CAR)-T cell therapy is emerging as a promising option for patients with certain types of cancer. The advent of this immunotherapy has advanced the field of cancer care, but there are still many ways in which the therapy is being optimized.
"The field is exciting and it's still in its infancy," said Saad J. Kenderian, M.B., Ch.B., a hematologist and oncologist at Mayo Clinic in Rochester, Minnesota. "We have so much potential, and we see cures in some patients."
Dr. Kenderian and other Mayo Clinic researchers continue to study this emerging therapy, new indications for its use, and methods to reduce side effects and improve efficacy.
CAR-T cell therapy
The FDA has approved several CAR-T cell therapy options, and yet wider adoption is slow. While clinical trials have shown CAR-T to be effective in certain indications, it has minimal activity in solid tumors and can cause life-threatening toxicities including cytokine release syndrome (CRS).
It is thought that the lack of success in CAR-T cell therapy for solid tumors is due to poor T-cell expansion, T-cell exhaustion, poor trafficking to the tumor site and inhibition by the tumor microenvironment. CAR-T cells also undergo massive proliferation in the body after administration, which is associated with the development of toxicities.
Currently, CAR-T cell therapy is approved for:
- Relapsed-refractory B-cell acute lymphoblastic leukemia (ALL)
- B-cell non-Hodgkin lymphoma
- Multiple myeloma
Historically, there has been a lack of robust clinical imaging to monitor CAR-T cells in these indications after they have been administered to the patient.
Developing a clinically relevant reporter
Dr. Kenderian and his Mayo Clinic colleagues have developed a reporter to do just that. The results of their research were published in the September 2021 issue of Cancer Immunology Research. The reporter can detect expansion, trafficking and toxicity in vivo.
The research team used the sodium iodide symporter (NIS) as a platform to image and follow CAR-T cells. NIS provides a sensitive clinically applicable platform for CAR-T cell imaging using PET scan.
"When it comes to toxicities, we can catch them early and treat them early," said Dr. Kenderian. "We can also see when CAR-T cells are not working properly and can understand for each patient what the problem is."
This imaging platform, which is in preclinical models, is designed to be used for CAR-T cell therapy regardless of the indication. It is the first such method developed at Mayo Clinic. Researchers believe it to be the most sensitive reporter yet, and further studies are underway comparing it with existing imaging options.
Durable remissions for CAR-T cell therapy in multiple myeloma
Dr. Kenderian was also involved in research that used elements of this imaging method to maximize the impact of CAR-T cell therapy in patients with multiple myeloma. This study was published in the January 2022 edition of the American Society of Hematology's journal Blood.
Although B-cell maturation antigen (BCMA)-targeted CAR-T cell therapy has been approved for patients with relapsed-refractory multiple myeloma, durable remissions have remained low. This is likely due to loss of CAR-T cells and inhibition of their efficacy by the tumor microenvironment. In multiple myeloma, the tumor microenvironment is especially immunosuppressive due to an abundance of cancer-associated fibroblasts (CAFs).
"CAR-T cells are living cells, so they start right away to kill cancer cells," explains Dr. Kenderian of the low rate of durable remissions in multiple myeloma. "The fibroblasts then shut down the CAR-T cells. So they can't continue to fight and fully kill the tumor."
In this preclinical study, researchers targeted CAR-T cells not only to the tumor, but to the CAFs in the tumor microenvironment. The researchers demonstrated that targeting the fibroblasts in this way reverses CAR-T cell dysfunction and enhances anti-tumor activity.
Awards and further research
Dr. Kenderian continues to research CAR-T cell therapy to advance its use and safety. Along with clinical trials testing further indications, Dr. Kenderian was awarded a Method to Extend Research in Time (MERIT) award by the National Cancer Institute (NCI) to continue this work.
"CAR-T is an exciting new line of therapy," said Dr. Kenderian. "Every patient with any cancer regardless of whether CAR-T is currently approved should have a discussion with their care team and be evaluated for this therapy."
The CAR-T Cell Therapy Program at Mayo Clinic provides access to this emerging therapy at all three Mayo Clinic sites and is one of very few such programs with experts trained and certified to manage CAR-T cell therapy.
For more information
Sakemura, et al. Development of a clinically relevant reporter for chimeric antigen receptor T-cell expansion, trafficking, and toxicity. Immunology Research. 2021;9:1035
Sakemura, et al. Targeting cancer-associated fibroblasts in the bone marrow prevents resistance to CAR-T cell therapy in multiple myeloma. Blood. 2022; doi.org/10.1182/blood.2021012811
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