Hollings researcher challenges the current CAR-T-cell design to improve immunotherapy options

MUSC Hollings Cancer Center researcher Leonardo Ferreira, Ph.D., is driven by the passion to make chimeric antigen receptor (CAR)-T-cell therapies safer and more widely available for cancer patients. His recent opinion article in Frontiers in Immunology, published as part of the “Emerging Engineering Approaches in Cancer Immunotherapy” research topic, highlights a weakness in the current CAR-T-cell design.

Initial excitement over the introduction of cancer immunotherapy treatment options has been reduced by high levels of adverse side effects. “There’s no rose without a thorn. For CD19 CAR-T-cell therapy, the biggest thorn seems to be the risk for neurotoxicity,” said Ferreira, who is an assistant professor in the Department of Microbiology and Immunology at the Medical University of South Carolina.

The Ferreira Lab uses CARs and other engineered immune receptors to detect the intricate intracellular workings that affect the function of different T-cell subsets in anti-cancer and immune tolerance applications. The ultimate purpose is to inform the design and development of new immune cell-based therapies.

“CAR-T-cell therapy is an advanced form of adoptive cell transfer, which uses engineered receptors in either donor or a patient’s own immune system to fight their cancer,” said Ferreira. This therapy has been most successful with blood cancers that express CD19 on the cell surface. Unfortunately, some CAR-T-cell clinical trials have been halted due to patients dying from brain edema.

Both authors on the opinion article, Ferreira and Yannick Muller, M.D. Ph.D., at the University Hospital of Lausanne, Switzerland, have a strong background in researching adoptive cell transfer for cancer treatment. They previously worked together and discovered that the CD28 molecule component of the CAR and endogenous, or natural, CD28 molecule can join together and strengthen the T-cell activation level.

CARs are artificial molecules that combine the two signals that are required for T-cell activation. With antigen specific CAR-T-cells, ‘signal one’ comes from the cancer antigen. ‘Signal two’ comes from a co-stimulatory molecule, often a molecule called CD28, that is built into the CAR. The large CAR molecules have four parts: the intracellular region, the extracellular region, and the hinge domain and transmembrane domain, which connect the intracellular and extracellular domains.

Ferreira previously found a trend in CAR-T-cell trials where the CAR-T-cells with a CD28 transmembrane domain caused neurotoxicity more often. This led to the team’s discovery that the T-cell activation signal can zigzag between endogenous CD28 and the CAR.

“Researchers often focus on the intracellular and extracellular region like they are two separate things. However, the hinge and transmembrane regions are also important. Our studies with the hinge and transmembrane regions showed us that the endogenous CD28 and CAR CD28 signals could interact and amplify these T-cell activation signals,” said Ferreira.

Overactivated CAR-T-cells are problematic in the clinic. In the case of the CD19 CAR-T-cells, overactivation may lead to neurotoxicity, since some brain cells express low levels of CD19. While the superactivated CD19 CAR-T-cells are very effective at killing the CD19 cancer cells, they can also cross the blood-brain barrier and cause dangerous brain inflammation.

“A key question in CAR-T-cell research is how can we make CAR-T-cells safer for patients?” said Ferreira. “My goal is to help make CAR T-cells more of a first-line therapy, versus a last resort option. However, this is only going to be possible if CAR-T-cells can be made less expensive and safer.”

The Ferreira lab’s goal of improving CAR-T-cell therapy aligns with MUSC’s overall mission, as the Center for Cellular Therapy is the only center in South Carolina administering CAR-T-cell treatments. Additionally, last year MUSC announced a new project, which is precisely aimed at making CAR-T-cell therapy safer.

The hope is that more patients could benefit from CAR-T-cell therapy, which can be an extremely effective cancer therapy, if it were safer. “The good news is that since CARs are artificial, they can be improved. CARs should not be designed with a ‘one-size-fits-all’ approach. They can, and should be, customized to the cancer or even the patient. For example, in some cases, there may be a need for the high level of CD28 activation that we identified to supercharge the CAR-T-cells against particularly tough cancers,” said Ferreira.
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Funding for this project was provided by American Cancer Society Institutional Research Grant #IRG-19-137-20 and Human Islet Research Network Emerging Leader in Type 1 Diabetes Grant U24DK104162-07

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