Scientists at Nagoya University have engineered immune cells that successfully eliminated solid tumors in laboratory mice by targeting Eva1, a small protein abundant on cancer cells but largely absent from healthy tissue.
The modified CAR-T cells represent a potential new treatment approach for lung, pancreatic, and liver cancers that have proven difficult to treat with existing therapies.
Published in the Journal for ImmunoTherapy of Cancer, the research demonstrates how Eva1’s diminutive size—just 128 amino acids—may actually make it an ideal target for immunotherapy. Unlike larger proteins targeted by previous CAR-T approaches, Eva1’s compact structure allows immune cells to form tighter connections with cancer cells, potentially improving treatment effectiveness.
Small Size, Big Impact
CAR-T therapy works by genetically modifying a patient’s T cells to recognize specific markers on cancer cells. While highly successful against blood cancers, the approach has struggled with solid tumors partly due to the challenge of finding suitable target proteins.
Eva1’s small footprint on cell surfaces could solve this problem. The researchers discovered that when CAR-T cells connect to Eva1, they form what scientists call “immune synapses”—contact zones that enable better signaling and more effective tumor killing.
The team tested 16 different versions of humanized antibodies to find the most effective design. Their optimal version used a short connector piece between the immune cell and cancer cell, combined with specific protein components that enhanced the T cells’ response.
Promising Laboratory Results
In mouse studies, the Eva1-targeting CAR-T cells completely eliminated tumors using relatively small doses—just 1-2 million cells compared to the 3-10 million typically required for other solid tumor CAR-T treatments. The approach worked against both lung cancer and pancreatic cancer models.
What makes Eva1 particularly attractive is its expression pattern. The protein appears in high concentrations on lung, pancreatic, and liver malignant tumors but shows much lower levels in most normal cells. This selectivity could reduce side effects that plague current cancer treatments.
The research revealed that Eva1 requires a minimum threshold of about 15,000-20,000 protein copies per cell to trigger an immune response. Normal esophageal cells, which had only 7,500 copies, failed to activate the modified T cells, suggesting the treatment might spare healthy tissue.
Addressing Safety Concerns
One potential complication emerged during testing: Eva1 appears in small amounts on monocytes, a type of white blood cell. However, the modified immune cells only activated when encountering cells with high Eva1 levels, largely ignoring the white blood cells with low amounts.
“These findings are an important step toward a new treatment option for cancers that have been difficult to treat. Patients with various types of tumors that express the Eva1 protein may be helped with this approach,” explained Dr. Seitaro Terakura from Nagoya University Graduate School of Medicine.
The researchers addressed potential immune rejection by starting with mouse-derived antibodies and modifying them to resemble human antibodies. This humanization process should prevent patients’ immune systems from attacking the treatment itself.
Critical Design Discoveries
The study revealed important technical insights that could improve future CAR-T therapies. Contrary to expectations, shorter connecting domains between immune and cancer cells proved more effective than longer ones in live animal tests, despite showing weaker responses in laboratory dishes.
The research team discovered that Eva1 doesn’t shed from cell surfaces like some other cancer proteins, which could prevent the kind of interference that hampers other targeted therapies. When proteins break away from cancer cells, they can intercept treatments before they reach their intended targets.
Additionally, Eva1 lacks protease recognition sequences—molecular scissors that would cut the protein loose from cell membranes. This stability could enhance treatment durability.
Key Advantages Include:
- Small protein size enables tighter immune cell connections
- High expression on cancer cells, low on normal cells
- Effective with smaller CAR-T cell doses
- Protein doesn’t shed from cancer cell surfaces
- Successfully targets multiple cancer types
Moving Toward Human Trials
The next crucial step involves confirming safety in additional models before advancing to human testing. The research team plans to develop mouse versions of the treatment to thoroughly evaluate potential side effects.
“Our team will now focus on confirming the treatment’s safety in humans before moving toward clinical trials,” Terakura noted. “To determine if Eva1 CAR-T is safe to administer to humans, we are currently generating a mouse CAR-T that recognizes mouse Eva1.”
The researchers must demonstrate that their mouse version doesn’t cause severe toxicity when targeting Eva1 expressed in normal mouse tissues. This safety data will be essential for regulatory approval of human trials.
“Following the accumulation of such data, we would like to collaborate with companies and others to advance toward clinical application,” Terakura added.
Broader Implications
The Eva1 research offers insights that could benefit CAR-T development beyond this specific target. The finding that protein size affects immune synapse formation suggests researchers should consider molecular dimensions when selecting future targets.
The work also demonstrates how humanizing mouse antibodies can preserve effectiveness while reducing immune rejection—a critical consideration for treating patients with intact immune systems, unlike the severely immunocompromised individuals who typically receive current CAR-T therapies.
For patients facing lung, pancreatic, or liver cancers, Eva1 CAR-T therapy could eventually offer new hope. These cancer types have historically proven challenging to treat and often carry poor prognoses, making novel approaches particularly valuable.
The research represents a step toward expanding CAR-T therapy’s reach from blood cancers, where it has achieved remarkable success, to the solid tumors that account for the majority of cancer deaths worldwide.
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