Boosting the effectiveness of CAR T-cell therapies against AML

As a physician-scientist, Erik Kimble, MD, works on understanding how immunotherapy can be trained to attack hematologic malignancies, especially acute myeloid leukemia (AML), his area of focus.

Kimble delves into the mechanisms of resistance that leukemia cells employ to dodge annihilation. His goal: to improve the effectiveness of CAR T-cell therapies against AML, a cancer of the blood and bone marrow in which the bone marrow takes a wrong turn and churns out abnormal white blood cells called myeloblasts. These myeloblasts impede the production of normal white blood cells that fight infection as well as red blood cells that transport oxygen and platelets that produce clots and prevent bleeding.

Kimble recently received the Underrepresented Minority Fellowship in Gene and Cell Therapy for Oncology, a $100,000 award from the American Society of Gene & Cell Therapy for early-career oncology researchers from a racial or ethnic minority group underrepresented in the scientific workforce. The one-year award is intended to address disparities related to representation of minorities within the oncology scientific community.

Robert Bradley, PhD, director of the Translational Data Science Integrated Research Center at Fred Hutch, serves as one of Kimble’s mentors.

“What’s so interesting about Erik is that he is studying something that’s not well understood, a recently described phenomenon that he played a role in articulating,” said Bradley, who holds the McIlwain Family Endowed Chair in Data Science.

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Investigating how CAR T cells interact with antigens

The phenomenon has to do with CAR T cells, which are engineered T cells designed to recognize antigens — unique protein markers — displayed on the surface of tumor cells. CAR T cells can selectively bind to their target-antigen and then destroy the cell.

“This process works when every tumor cell has an antigen. But what if every cell doesn’t have an antigen?” said Bradley. “Erik has shown that tumor cells that don’t have an antigen targeted by CAR T cells can nonetheless still be killed by the CAR T cells.”

Kimble’s work is proof of concept. One reason CAR T-cell therapy can fail is that not all tumor cells within an individual patient contain the antigen targeted by a given CAR T-cell product, so there is a need to develop strategies that allow CAR T cells to kill those antigen-negative tumor cells while minimizing injury of healthy tissue.

Kimble’s alternative approach hinges on a cytokine called TNF alpha, a protein produced by activated CAR T cells. There are various drugs that are in clinical development that modulate proteins in the cells that make them susceptible to TNF alpha. Kimble has proposed combining CAR T cells with these drugs to enhance CAR T cells’ effectiveness against tumor cells with low target antigen expression. His project involves validating this strategy in cell cultures and other models, with an eye toward one day bringing this to patients in the clinic.

Kimble, an acting instructor and research associate at Fred Hutch who is not yet tenured, came to Fred Hutch as a fellow in 2018.

Half Mexican and half Black, Kimble attended medical school in Mexico at Universidad de Guadalajara. The award is critical to Kimble’s research.

“I'm at a pivotal time in my career,” he said. “This is really big for me.”

Bradley notes that the award is validation that others in the scientific community are excited about Kimble’s ideas. “The easiest research to do is to pursue something that everyone is already thinking about,” Bradley said. “This award lets him pursue his research in a way that lets him go after what’s most important even if it’s not the easiest research. What’s important is having the intellectual freedom to surprise people, and that’s what Erik is doing.”

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