More sensitive cell therapy may be a HIT against solid cancers

Columbia researchers have now found that a new type of cell therapy—HIT cells, a cousin to CAR T with enhanced sensitivity—overcomes a major obstacle to treating solid tumors with cell therapy and can completely eliminate kidney, pancreatic, and ovarian cancers in mice.

The research, conducted by investigators at the Columbia Initiative in Cell Engineering and Therapy (CICET), was published Feb. 26 in the journal Science.

Michel Sadelain, director of CICET, pioneered today’s CAR T therapies, which reprogram a patient’s own immune cells to become trained assassins that seek and destroy the patient’s cancer. For the past few years, his lab has also led the development of HIT cell therapy.

“Curing solid tumors is not easy, but this work solves one piece of the puzzle,” Sadelain says.

The challenge of solid cancers

Though several obstacles are known to thwart CAR T cell activity in solid cancers, the first challenge for any cell therapy is to locate every cancer cell. Blood cancer cells are usually easy for CAR T to spot, as each is covered with numerous CD19 molecules that act as a homing beacon for the CAR T cells.

But in solid tumors, cancer cells are more diverse, and there is no single molecule that can serve as the sole target for cell therapy.

“Some molecules have been identified that are found in 25%, 50%, or 75% of tumor cells, says Sadelain, who is also the Herbert and Florence Irving Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons.

“Though a therapy directed at those targets might be successful in eliminating some tumor cells, you can't cure somebody if you just eliminate a small fraction or even 90% of their tumor. You have to get down to the very last cell.”

CD70 marks many solid cancers

The new study makes the surprising discovery that, for at least a few types of solid cancers, there is a molecule, CD70, that can act as a homing beacon for cell therapy.

Though previous studies had suggested CD70 levels vary from cell to cell in a tumor, the study’s lead author, Sophie Hanina, a research associate scientist at CICET, had a hunch those studies were missing cells that contained CD70 molecules, but at very low levels.

She created new methods to detect the molecule, finding that CD70 levels vary widely on cancer cells, but that all cells have at least a few on their surfaces.

Solid cancers need a harder HIT

To translate that finding into a cell therapy, Hanina had to turn to a new type of cell therapy—HIT—under development in Sadelain’s lab at CICET.

Conventional CAR T cells can only detect cancer cells that possess a high level of the target molecule. Hanina saw that when she tested CD70 CAR T cells against solid tumors in the laboratory, explaining why CAR T therapies programmed to target CD70 have not performed well in patients with solid cancers.

“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 says.

Hanina found that HIT cells programmed to target CD70 completely eradicated the tumors in mice with pancreatic, kidney, and ovarian cancers, while traditional conventional CAR T cells only eliminated a portion of cells.

HIT cells also stayed clear of healthy cells in the mice, since most other cells in the body do not express CD70 molecules.

Next step—clinical trials

Hanina and Sadelain are now planning to test the CD70 HIT cells in patients with ovarian and other cancers at Columbia University Irving Medical Center.

CD70 HIT cells may also have potential in nearly 20 other types of cancers, including glioblastoma and pancreaticadenocarcinoma, which are known to express CD70 to some degree.

Though solid cancers present other obstacles to cell therapies, for cancers expressing CD70, the hunt for every cancer cell may be a critical obstacle to overcome.

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

More information

The paper, “Sensitive CAR T cells redefine targetable CD70 expression in solid tumors,” was published in Science Feb. 26.

All authors: Sophie A Hanina (Columbia University), Tyler Park (Memorial Sloan-Kettering Cancer Center), Michael Lopez (Columbia), Vinagolu K Rajasekhar (MSKCC), Jorge Mansilla-Soto (MSKCC), Sascha Haubner (Columbia), Huiyong Zhao (MSKCC), Friederike Kogel (MSKCC), Sarah Nataraj (Columbia), Priyam Banerjee (Rockefeller University), Richard Koche (MSKCC), Pierre Jacques-Hamard (MSKCC), Zeynep C Tarcan (MSKCC), Dennis S Chi (MSKCC and Weill Cornell Medical College), Dmitriy Zamarin (Mount Sinai Icahn School of Medicine), John H Healey (MSKCC), Elisa de Stanchina (MSKCC), Robert J Motzer (MSKCC), Ritesh R Kotecha (MSKCC), A Ari Hakimi (MSKCC), Christina S Leslie (MSKCC), and Michel Sadelain (Columbia).

The study was funded by the Mazumdar-Shaw Translational Research Initiative in Kidney Cancer, the Kidney Cancer Research Program, Pershing Square Sohn Cancer Research Alliance, Department of Defense Early Career Investigator Award.

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Columbia University Irving Medical Center (CUIMC) is a clinical, research, and educational campus located in New York City. Founded in 1928, CUIMC was one of the first academic medical centers established in the United States of America. CUIMC is home to four professional colleges and schools that provide global leadership in scientific research, health and medical education, and patient care including the Vagelos College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing. For more information, please visit cuimc.columbia.edu. 

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