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Medical student Rosalie Sterner receives Outstanding Abstract Achievement Award from American Society of Hematology

Rosalie Sterner (MDPHD ’21, IMM ’21), an M.D.-Ph.D. student at Mayo Clinic, was the only medical student to receive the 2018 Outstanding Abstract Achievement Award from the American Society of Hematology (ASH). She presented her work on development of safer and more effective strategies for chimeric antigen receptor (CAR)-T cell therapies at the ASH annual meeting in December in San Diego.

The award recognizes meritorious science and supports early-career investigators by honoring the trainee with the highest-scoring abstract in five categories: undergraduate student, medical student, graduate student, resident physician, and postdoctoral fellow. Through Mayo’s Medical Scientist Training Program, Sterner completed her doctoral thesis in immunology at Mayo Clinic Graduate School of Biomedical Sciences in 2018 and is now in her third year at Mayo Clinic Alix School of Medicine.

“Getting to present was a great opportunity to share our work with a broader audience,”  Sterner said of speaking before a few hundred people at the largest national meeting in hematology. “While CAR-T cell therapy has proven successful in treating certain cancers, severe toxicities have limited its widespread application.”

Sterner is part of a team of Mayo Clinic researchers from the Department of Immunology, Division of Hematology, T-Cell Engineering Laboratory, and Department of Molecular Pharmacology & Experimental Therapeutics who have developed a strategy to reduce toxicity in CAR-T cell therapy. Animmune-system reaction associated with CAR-T cell therapy can produce two potentially deadly complications:

  1. Cytokine release syndrome (CRS), marked by fever, nausea, headache, rash, rapid heartbeat, low blood pressure, and difficulty breathing
  2. Neurotoxicity, which disrupts the nervous system, causing a variety of symptoms, including headache; cognitive and behavioral problems; limb weakness or numbness; and loss of memory, vision, and/or intellect

About half of the patients who receive CAR-T cell therapy need to be hospitalized for side effects, and some deaths have been reported.

However, the team found that using a clinical-grade antibody (lenzilumab) blocked CAR-T and other cells from producing a protein linked to the development of both CRS and neurotoxicity.

“When we blocked the protein, we found that we could reduce toxicities in preclinical models,” Sterner says. “We also were able to demonstrate that CAR-T cells worked better after the protein was blocked.”

The team is led by Saad Kenderian, M.B. Ch.B., a Mayo Clinic hematologist whose T Cell Engineering Lab focuses on the development, optimization and translation of CAR-T cell therapy for patients with relapsed and refractory hematological malignancies.

CAR-T cell therapy is a type of immunotherapy that involves extracting immune-system T cells from a patient’s blood. The T cells are genetically engineered to attach the gene for a special receptor that binds to a specific protein. Large numbers of CAR-T cells then are grown in the lab and infused into the patient, where they activate the immune system to recognize and destroy cancer cells that produce the target protein.

CRS and neurotoxicity are associated with elevated levels of cytokines (small proteins important to cell signaling in the immune system), especially granulocyte macrophage colony-stimulating factor (GM-CSF).

To evaluate GM-CSF neutralization as a potential strategy to manage toxicity, the team tested lenzilumab with CAR-T cell therapy. In mouse models with acute lymphoblastic leukemia, blocking production of GM-CSF prevented CRS and significantly reduced neurotoxicity. Lenzilumab also enhanced CAR-T cell proliferation, anti-tumor activity and overall survival, the team reported in Blood.

 The team then engineered CAR-T cells, using gene-editing technology, to produce lower levels of GM-CSF. These engineered CAR-T cells demonstrated enhanced anti-tumor activity, suggesting they represent a potential next-generation CAR-T cell therapy.

“We’re very excited by the results. This strategy definitely has a lot of potential and could help a lot of people,” Sterner says.

The research team is designing a phase II clinical trial for the use of lenzilumab to prevent CAR-T toxicities in patients with diffuse large B cell lymphoma. If the trial results are consistent with earlier findings, the therapy could become a standard of care during CAR-T cell therapy at Mayo Clinic.

Sterner was drawn to immunology by the mix of basic science and translational science. “Immunology allows you to bridge that gap,” she says. “You can have a lot of impact on developing better clinical treatments.”

She became involved in the toxicity project while completing her thesis in the cell-signaling lab of Karen E. Hedin, Ph.D., who collaborated on the project with Dr. Kenderian.

 

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