New HIT Receptor Technology Enables CAR-T Cells to Detect Low-Antigen Tumor Cells in Solid Cancers

March 03, 2026 –

Researchers at the Columbia Initiative in Cell Engineering and Therapy (CICET) have reported a major advance in engineered cell therapy that could help overcome one of the biggest barriers to treating solid tumors with CAR-T cells. In a study published in Science, investigators demonstrated that a new receptor design known as HLA-independent T-cell (HIT) receptors can detect extremely low levels of the tumor antigen CD70, allowing engineered T cells to eliminate heterogeneous solid tumors in preclinical models.

The work addresses a central challenge in the development of CAR-T therapies for solid tumors. While CAR-T treatments have transformed the care of several blood cancers, including leukemias and lymphomas, their success has been far more limited in solid malignancies. A key reason is antigen heterogeneity—solid tumors often contain a mixture of cells that express varying levels of target molecules. Even when most tumor cells are eliminated, residual cells with low or undetectable antigen expression can survive and drive disease relapse.

“Curing solid tumors is not easy, but this work solves one piece of the puzzle,” said Michel Sadelain, MD, PhD, senior author of the study, director of CICET, and a pioneer in the development of CAR-T cell therapies.

The research team focused on CD70, an immune signaling molecule that has been explored as a potential cancer target. CD70 has attractive therapeutic features because it is expressed in many tumor types while remaining relatively restricted in normal tissues. However, previous studies suggested that CD70 expression in solid tumors is highly heterogeneous, with some tumor cells appearing completely negative for the antigen. This variability has limited the effectiveness of conventional CD70-targeted CAR-T therapies.

Lead author Sophie Hanina, PhD, a research associate scientist at CICET, hypothesized that many tumor cells classified as CD70-negative may actually express the antigen at extremely low levels—below the detection threshold of most laboratory methods and insufficient for activation of standard CAR-T receptors. To investigate this possibility, the research team developed improved detection methods and tested their hypothesis in patient-derived xenograft mouse models of kidney, pancreatic, and ovarian cancers.In these models, traditional CD70-targeted CAR-T cells effectively eliminated tumor cells with high antigen expression but failed to eradicate those with low or undetectable CD70 levels, closely mirroring resistance patterns observed in clinical settings. Further analysis confirmed that tumor cells previously considered CD70-negative indeed expressed very small quantities of the molecule, supporting the hypothesis that low-level antigen expression contributes to therapeutic escape.

To overcome this limitation, the researchers engineered a new receptor system known as HLA-independent T-cell (HIT) receptors. HIT receptors combine the programmability of CAR-T technology with the high sensitivity of natural T-cell receptors, allowing engineered cells to recognize and respond to extremely small numbers of target molecules on tumor cells. “HIT cells are the next generation of CAR-T cells,” Hanina explained. “They can be programmed like a CAR-T cell, but they have the sensitivity of a natural T cell and can detect cancer cells that have only a vanishingly small number of target molecules.”

When tested in xenograft models, CD70-targeted HIT T cells achieved complete tumor eradication in kidney, pancreatic, and ovarian cancer models, whereas conventional CD70-CAR-T cells produced only partial responses due to their inability to eliminate low-antigen tumor cells. Further analysis revealed that many tumor cells previously considered CD70-negative actually retain very low levels of CD70 expression, caused by epigenetic silencing through EZH2-mediated H3K27me3 modification. While this suppresses CD70 below the activation threshold of conventional CAR-T cells, the highly sensitive HIT receptors can still detect these minimal signals. Single-cell profiling confirmed low-level CD70 expression signatures in tumor samples, and safety studies showed no increased toxicity for CD70-HIT T cells compared with conventional CAR-T therapies. These findings suggest that HIT receptors may help overcome tumor escape by enabling engineered T cells to detect and eliminate cancer cells with extremely low antigen expression.

Based on these promising preclinical results, the Columbia research team is now planning early-phase clinical testing of CD70-targeted HIT cells, initially focusing on patients with ovarian cancer and other solid tumors at Columbia University Irving Medical Center. The implications of the technology may extend well beyond a single cancer type. CD70 is expressed to varying degrees in nearly 20 tumor types, including glioblastoma and pancreatic adenocarcinoma. If validated in human trials, HIT receptor technology could potentially broaden the reach of adoptive cell therapies by enabling engineered T cells to detect tumors that express extremely low levels of target antigens, a long-standing obstacle in solid tumor immunotherapy.

The study highlights how advances in receptor engineering and tumor biology are converging to create more sensitive and precise cell therapies. By enabling engineered T cells to detect even the faintest molecular signals from cancer cells, HIT receptors could represent an important step toward achieving complete tumor eradication in solid cancers, one of the field’s most ambitious goals.