UCLA Researchers Develop Method to Fix Fuel Shortages in Cancer Immunotherapy

Many immunotherapies developed to combat cancer fail because the CAR-T cells become exhausted after being starved of oxygen in the tumor environment. A new preclinical study conducted by a team at UCLA has uncovered a method to deliver needed glucose to immune cells in a way that tumor cells cannot hijack. This offers hope of keeping anti-cancer fighter cells active and deadly to both solid and non-solid tumors. 

The study, whose findings appeared in Cell journal, documents how the researchers found a way to keep the oxygen supply of CAR-T cells intact in a way that cancer cells cannot steal and starve the immune cells. They explain that cancer often disarms and evades the immune system by consuming all the available oxygen within the tumor environment. This leaves immune cells exhausted and unable to produce the needed cytokines to attack cancer cells. The researchers came up with a method to ensure continuous glucose supply that is inaccessible to tumor cells. 

The method they developed entailed leveraging cellobiose, a form of glucose that occurs naturally in fiber and cannot be metabolized by cancer cells or the human body. The team engineered T cells to be able to utilize this form of glucose using genes taken from fungi, and lab tests showed that when the microenvironment was deficient in oxygen, the modified cells continued to multiply and function by using cellobiose as a glucose source. 

These tests showed that the immune system’s fight against cancer loses steam and eventually fails due to an energy shortage in the environment where the immune cells have been mobilized. 

To further test their findings, the team conducted tests on mice that were grouped into those treated with the genes giving them the capability to utilize cellobiose and those unable to use this glucose source. The tumors in the mice with the modified genes shrunk or exhibited slower growth rates and the immune cells remained active unlike in the unmodified mice that saw the immune system gradually lose its potency due to fuel shortages. 

The researchers say their findings are exciting because they had positive results in not just solid tumors but also blood cancers like lymphoma. This opens the door to using their approach in the immunotherapies under development that have shown limited efficacy after a period of use. Revamping energy sources for these CAR-T therapies could revive their potency and make those approximately 500 treatments available to patients. 

This method of tweaking the metabolic pathways delivering energy to fighter immune cells could provide valuable insights to enterprises like Calidi Biotherapeutics Inc. (NYSE American: CLDI) that are currently developing immunotherapies indicated for solid tumors. The results of clinical trials testing this way of providing a constant supply of energy to CAR-T cells in ways that cancer cannot hijack will provide further validation. 

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