HIT Cell Therapy Wipes Out Solid Tumors in Mice Where Standard CAR T Cells Fall Short

CAR T cell therapy transformed blood cancer treatment. By engineering a patient's own immune cells to recognize and destroy cancer cells carrying a specific surface marker - CD19 in the case of many blood cancers - the approach has produced durable remissions in patients for whom conventional chemotherapy had failed. But in solid tumors, which account for more than 85% of all cancers, the same approach has delivered disappointing results.

The problem is partly one of targeting. Blood cancers present a convenient marker that appears on essentially every cancer cell. In solid tumors, no single molecule reliably coats every malignant cell in sufficient quantities to serve as a uniform beacon. Cells within the same tumor vary in what molecules they express and at what density. CAR T cells, which require a threshold number of target molecules to activate, miss cancer cells that fall below that threshold.

Research from Columbia University's Initiative in Cell Engineering and Therapy (CICET), published February 26 in Science, addresses both parts of this problem: finding a target that appears on all cells within certain solid tumors, and deploying an engineered immune cell sensitive enough to detect it even when present in very small amounts.

CD70: A Homing Beacon That Was Being Missed

The molecule at the center of the new work is CD70, a protein previously identified as present on some solid tumor cells but considered highly variable in its expression - some cancer cells displaying it prominently, others appearing to have none at all.

Sophie Hanina, a research associate scientist at CICET and lead author of the paper, suspected that the apparent absence on many cells was a detection problem rather than a biological reality. Standard detection methods might simply be missing CD70 molecules present in very low concentrations.

Hanina developed more sensitive detection methods and re-examined tumor cells. The result: CD70 levels vary widely across cancer cells in a given tumor, but all cells have at least a small number of CD70 molecules on their surfaces. For cell therapies targeting CD70, this means the target is present - but detecting it requires a more sensitive immune cell.

HIT Cells: Natural T Cell Sensitivity in an Engineered Package

Standard CAR T cells are effective when their target is abundant. They can be thought of as broadly calibrated sensors - powerful but requiring a clear signal to act. Natural T cells, by contrast, can detect and respond to even a single molecule of their target antigen on a cell surface. They achieve this through a different receptor architecture and signaling pathway.

HIT (High-sensitivity Immune T) cells, under development in Michel Sadelain's lab at CICET, combine the programmability of CAR T cells - the ability to be directed toward any chosen target - with the extreme sensitivity of natural T cells. They can be engineered to seek a specific molecule, but will activate and kill a target cell even when that molecule is present in vanishingly small amounts.

"HIT cells are the next generation of CAR T cells. 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," Hanina said.

Complete Tumor Eradication in Three Solid Cancer Types

When Hanina tested CD70-targeted HIT cells against mouse models of pancreatic, kidney, and ovarian cancers, the results were complete elimination of tumors in all three models. Standard CD70-targeted CAR T cells, tested under the same conditions, eliminated only a portion of tumor cells - consistent with the observation that they activate against high-CD70 cells but miss those with low expression.

In the mice treated with HIT cells, healthy cells - which generally do not express CD70 - were spared. This selectivity is essential: a therapy that destroys cancer cells while attacking normal tissue would cause unacceptable side effects.

Sadelain, who directs CICET and pioneered the CAR T therapies in clinical use today, described the result as solving "one piece of the puzzle" of curing solid tumors.

Limitations and Next Steps

These are mouse model results. The immune systems of mice differ from human immune systems in important ways, and solid tumors present additional obstacles to cell therapy beyond the targeting problem that HIT cells address - including physical barriers in the tumor microenvironment and mechanisms tumors use to suppress T cell activity. Complete tumor eradication in mice does not guarantee comparable results in human patients.

Hanina and Sadelain are planning clinical trials of CD70-targeted HIT cells in ovarian cancer patients at Columbia University Irving Medical Center. The potential application extends to nearly 20 other cancer types that have been shown to express CD70 at some level, including glioblastoma and pancreatic adenocarcinoma.

"Studies suggest that the escape of undetected cancer cells is the key impediment to therapeutic success with conventional CAR T therapy," Hanina said. "We hope our CD70-directed HIT cells help us find a way to eradicate the entire tumor."