Nagoya University scientists have designed immune cells that successfully eliminated solid tumors in laboratory mice by targeting EVA1, a small protein rich in cancer cells but largely lacking healthy tissue.
Modified CAR-T cells represent a potential new treatment for lung, pancreatic and liver cancer that may be difficult to treat existing therapies.
The study, published in the journal Cancer Immunotherapy, demonstrates how the smaller size of EVA1 (only 128 amino acids) actually makes it an ideal target for immunotherapy. Unlike the larger proteins targeted by previous CAR-T methods, the compact structure of EVA1 enables immune cells to form a closer connection with cancer cells, which may improve therapeutic effects.
Very small size, great influence
CAR-T treatment works by genetically modifying the patient’s T cells to identify specific markers of cancer cells. Despite its great success in hematologic cancer, the method has been struggling with solid tumors, partly because of finding the right target protein.
The small footprint of EVA1 on the cell surface can solve this problem. The researchers found that when Car-T cells are connected to EVA1, they form what scientists call “immune synapses,” the contact areas, which can enable better signaling and more efficient tumor killing.
The team tested 16 different versions of humanized antibodies to find the most effective design. Their best version uses a short connector between immune cells and cancer cells, combining specific protein components that enhance T-cell responses.
Promising laboratory results
In mouse studies, CAR-T cells targeting EVA1 completely eliminated tumors using smaller doses, while CAR-T treatments in other solid tumors usually require only 10-2 million cells. This method targets lung and pancreatic cancer models.
What is particularly attractive about EVA1 is its expression pattern. This protein appears on lung, pancreatic, and liver malignant tumors, but shows much lower levels in most normal cells. This selectivity can reduce the side effects that plague current cancer treatments.
Studies have shown that EVA1 requires a minimum threshold of about 15,000-20,000 copies of protein per cell to trigger an immune response. Only 7,500 copies of normal esophageal cells were unable to activate modified T cells, suggesting that the treatment might avoid healthy tissue.
Solve security issues
A potential complication occurred during the test: EVA1 appeared in small quantities on monocytes (a type of white blood cell). However, the modified immune cells are activated only when cells with high EVA1 levels are encountered, largely ignoring the lower amount of leukocytes.
“These findings are an important step in taking new therapeutic options for difficult-to-treat cancers. This approach may help patients with various types of tumors expressing the EVA1 protein.”
The researchers addressed potential immune rejection by starting from mice-derived antibodies and modifying them to resemble human antibodies. This humanized process should prevent the patient’s immune system from attacking the treatment itself.
Key Design Discovery
The study reveals important technical insights that could improve future CAR-T therapies. Contrary to expectations, despite showing weaker responses in laboratory dishes, the junction domain between immune and cancer cells was shorter in real-time animal tests.
The team found that EVA1 did not shed the cell surface like some other cancer proteins, which could prevent this interference from hindering other targeted therapies. When proteins detach from cancer cells, they can intercept treatments before reaching the intended target.
In addition, EVA1 lacks protease recognition sequences – molecular scissors cut off proteins in cell membranes. This stability can improve treatment durability.
Key advantages include:
- Small protein size enables tighter immune cell junctions
- High expression on cancer cells and low expression on normal cells
- Smaller CAR-T cell doses are effective
- Protein does not fall off the surface of cancer cells
- Successfully targeted multiple cancer types
Going toward human experiments
The next critical step involves confirming safety before conducting other models before performing human testing. The research team plans to develop a treatment version of the mouse version to thoroughly evaluate potential side effects.
“Now, our team will focus on confirming the safety of treatment before the clinical trial,” Terakura noted. “To determine whether EVA1 CAR-T can safely manage people, we are currently generating mouse CAR-Ts that recognize mouse EVA1.”
The researchers must demonstrate that its mouse version does not cause severe toxicity when targeting EVA1 expressed in normal mouse tissues. This security data is crucial for regulatory approval of human trials.
“After accumulating such data, we hope to work with companies and other companies to move towards clinical applications,” Terakura added.
A broader meaning
The insights provided by the EVA1 study can enable CAR-T development to benefit this specific goal. The finding that protein size affects immune synaptic formation suggests that researchers should consider molecular dimensions when selecting future targets.
This work also demonstrates how humanized mouse antibodies can maintain effectiveness while reducing immune rejection, a key consideration for treating patients with the complete immune system, unlike individuals with severe immunity usually receiving current CAR-T treatment.
For patients facing lung, pancreatic or liver cancer, EVA1 CAR-T therapy can ultimately provide new hope. These cancer types have historically proven challenging treatments and often carry adverse prognosis, making novel approaches particularly valuable.
This study represents a step towards significant success in extending CAR-T therapy from hematologic cancer.
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