CAR-T cell therapy, a form of immunotherapy that trains a patient's own immune cells to attack cancer, has shown remarkable promise since the first approval in 2017, but researchers are now tackling the fundamental barriers that prevent it from helping more patients. With seven CAR-T therapies now approved by the FDA, the field is shifting focus from proving the concept works to solving why it fails in more than half of patients whose cancers initially respond to treatment.

Why Does CAR-T Cell Therapy Stop Working?

CAR-T cell therapy works by engineering a patient's T cells (immune cells) to recognize and destroy cancer cells. However, the treatment faces two major obstacles that cause it to lose effectiveness. The first is antigen escape, which occurs when cancer cells stop expressing the target protein that CAR-T cells are designed to recognize. Once the antigen disappears, the engineered immune cells can no longer identify their targets.

The second challenge is T-cell exhaustion, a state where the immune cells become overactivated and essentially "tire out" before completing their cancer-fighting job. Additionally, the current manufacturing process is time-consuming and expensive, requiring several weeks to create personalized therapies. This delay can be critical for patients with rapidly progressing cancers, and the specialized equipment and expertise required limits access to treatment.

What New Strategies Are Scientists Using to Keep CAR-T Cells Active?

Researchers are employing multiple innovative approaches to prevent T-cell exhaustion and extend the life of CAR-T therapies. One strategy involves gene editing to delete specific genes that promote exhaustion. Using CRISPR/Cas9 technology, scientists have successfully deleted three genes in CAR-T cells, including the gene that produces PD-1, an immune checkpoint protein that can suppress immune function.

Beyond gene deletion, researchers are designing CAR-T cells that regulate their own activation levels. The KIR-CAR approach mimics the natural regulatory system found in killer immune cells, ensuring that T cells remain inactive until they encounter their target antigen. This prevents the continuous, exhausting activation that leads to burnout. In a phase I clinical trial, nine patients with advanced, treatment-resistant solid tumors received the mesothelin-targeted SynKIR-110 therapy. Five patients experienced disease control, and one patient's partial response continued for more than three months.

Another innovative approach involves CAR-T cells that shed their CAR (chimeric antigen receptor) shortly after activation. Researchers at Stanford University developed these self-regulating cells by leveraging a natural process in which the enzyme ADAM17 turns off chronic immune signaling. When a 15-amino-acid sequence was inserted into the CAR, it allowed rapid cleavage of the CAR after activation, reducing exhaustion and improving effectiveness in mice.

How Are Researchers Addressing Antigen Escape?

To overcome antigen escape, scientists are equipping CAR-T cells with the ability to target multiple antigens simultaneously. One promising approach uses an engineered protein called GA1 as the antigen-binding portion of the CAR. The actual antigen-binding domain is administered separately and binds to GA1 inside the body, allowing researchers to switch targets if the original antigen is lost. This flexibility could help CAR-T cells remain effective even as cancer cells evolve to evade treatment.

Researchers are also exploring drug-controlled CAR shedding, where the CAR can be turned on and off using medications. In one study, scientists designed a CAR that released its antigen-targeting domain when exposed to venetoclax, a drug already used in cancer treatment. This approach proved reversible in mice; withdrawing the drug reactivated CAR-T cell activity.

Steps Researchers Are Taking to Expand CAR-T Therapy Access

• Gene Editing Advances: Using multiplex CRISPR/Cas9 editing to delete multiple genes simultaneously, enabling CAR-T cells to function longer and resist exhaustion more effectively than previous generations.
• Novel CAR Designs: Developing KIR-CAR and self-regulating CAR architectures that prevent overactivation, reducing the exhaustion that causes treatment failure in more than half of initial responders.
• Multi-Target Strategies: Engineering CAR-T cells to recognize and attack multiple cancer antigens, reducing the likelihood that cancer cells can escape by losing a single target protein.
• Off-the-Shelf Therapies: Creating standardized CAR-T cells that don't require weeks of personalized manufacturing, potentially reducing costs and expanding access to patients without specialized treatment centers nearby.

The field remains optimistic about overcoming current limitations. Carl H. June, MD, a CAR-T pioneer at the University of Pennsylvania, noted that recent innovations in gene editing, the use of different immune cell types, and the development of off-the-shelf CAR therapies could help break down existing roadblocks.

"There are a number of genes that you can delete that then allow the cells to continue to function. I'm excited now that we have the ability to do multiplex CAR editing so we can edit many genes at one time. I never thought that would be possible," said Carl H. June.

Carl H. June, MD, FAACR, University of Pennsylvania

While CAR-T therapy has proven highly effective for blood cancers, solid tumors like melanoma and lung cancer present additional challenges. The tumor microenvironment surrounding solid cancers is difficult for CAR-T cells to penetrate, and solid tumors often express different antigens on different cells, making single-target approaches less effective. However, the innovations described above, combined with ongoing research, suggest that CAR-T therapy may eventually expand beyond blood cancers to help patients with skin cancer, lung cancer, and other solid tumors.