Illustration of CAR-T cell therapy in B-cell lymphoma.

A Keck Medicine of USC cell therapist explains how design innovations could expand the use of CAR-T cell therapy beyond blood cancers.

Chimeric antigen receptor (CAR)-T cell therapy has been a lifesaving option for many patients with advanced blood cancers. This personalized immunotherapy involves genetically engineering the patient’s white blood cells to fight the cancer.

It’s meant for hard-to-treat cases, particularly for patients who have either stopped responding to treatments or relapsed quickly after remission. Success rates vary based on the type of blood cancer and how aggressive it is, but overall about 50% of patients achieve long-term remissions with CAR-T cell therapy.

But physician-scientists have not seen the same success against solid tumors, including prostate, breast, brain, gastrointestinal, skin and lung cancers.

Preet M. Chaudhary, MD, PhD, director of the USC Norris Blood and Marrow Transplant and Cell Therapy Program, part of Keck Medicine of USC and the USC Norris Comprehensive Cancer Center, says the solution lies in looking at CAR-T cell therapy from a different angle. (Dr. Chaudhary is also chief of the Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases at the Keck School of Medicine of USC.)

“CAR-T cell therapy has been transformative,” Dr. Chaudhary says. “However, the lack of efficacy in solid tumors has to do with the design of the CARs themselves.”

Where CAR-T cell therapy falls short in fighting solid tumors

There are some widely believed theories about why CAR-T cell therapy hasn’t been effective against solid tumors. The first is that solid tumors create an immunosuppressive environment that weakens CAR-T cells before they can attack.

“The most prominent theory is that solid tumors secrete certain proteins, creating a hostile environment that prevents the CAR-T from functioning properly,” Dr. Chaudhary says.

The dense structure of solid tumors is another issue.

As Dr. Chaudhary explains, CAR-T cells can more easily kill blood cancer cells because those cells, situated in the bloodstream or bone marrow, are easier for the CAR-T cells to find and reach.

Solid tumors, on the other hand, are located within tissue. In addition, solid tumors are present as dense masses. The CAR-T cells “have to eat through several layers to reach the core and eliminate the tumor,” he says. “The CAR-Ts have to persist a lot longer, and the current generation isn’t designed for that.”

A third challenge involves antigens, which are markers that the immune system uses to determine whether a substance is harmful. Blood cancers contain large amounts of antigens, such as CD19 or BCMA antigens, which are somewhat selectively expressed on blood cells but not on vital organs such as the heart, lung or kidney. Due to the antigens’ high-level and selective expression on blood cells, CAR-T cells are easily engineered to target them. During the therapy, the CAR-T cells will also damage healthy blood cells, but as Dr. Chaudhary emphasizes, patients can recover from this.

Solid tumors, however, contain antigens that are expressed on both cancer cells and on vital organs. Targeting those antigens is trickier because of the risk of life-threatening collateral damage.

After CAR-T cell therapy for blood cancers, “patients can get antibody infusions until their own B cells recover,” Dr. Chaudhary says. “There’s no such equivalent for replacing your heart or lungs or kidneys.”

How the design impacts CAR-T cell efficacy against solid tumors

The widespread theories listed above are based on the idea that solid tumors are inherently different than blood cancers, and that’s why CAR-T cell therapy works for one and not the other.

However, Dr. Chaudhary argues that the underlying issue is the CAR-T itself. While effective against blood cancers, his stance is that the current design of the CAR-T isn’t adequate against solid tumors.

“We’ve been looking at this wrong,” Dr. Chaudhary says. “There’s a fundamental design flaw in the design of the CARs.”

In CAR-T cell therapy, the “receptor” is the lab-engineered protein that is added to the patient’s T cells. (T cells are the white blood cells that power the immune system.) The receptor is what allows those cells to find and destroy cancer.

Natural T-cell receptors are composed of two protein chains. Current CARs, however, have one protein chain. Dr. Chaudhary identifies this design as the problem.

“If you look at the structure of the CAR, it has almost no resemblance with the natural T-cell receptor,” he says, explaining that the single-chain design means the T cells are exhausted too quickly.

“It works in blood cancer because when you infuse the cells, they see the cancer right away and can do a lot of damage to the cancer in a shorter amount of time,” Dr. Chaudhary continues.

“For solid tumors, the CAR-Ts need to persist long-term without exhaustion, and that’s where the design issue comes in.”

To address this, Dr. Chaudhary is leading the development of another option called synthetic immu ne receptor (SIR-T) therapy, which uses different receptors that he says more closely resemble the body’s natural T-cell receptor. He expects that clinical trials with SIR-T will begin in 2027. (Angeles Therapeutics Inc., a University of Southern California startup company, holds rights to the SIR-T platform. Dr. Chaudhary is the founder of Angeles Therapeutics and holds equity interest in the company.)

Ultimately, Dr. Chaudhary is optimistic about the possibilities that cell therapies represent for cancers such as prostate, colon, lung, skin, brain, ovarian and bone cancers. “If we can go after solid tumors with a few injections or combine cell therapies with other modalities, we could potentially cure patients with terminal or relapsed disease. It’s a revolutionary thing.”

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Why CAR-T Cell Therapy Struggles Against Solid Tumors