A New Immunotherapy Ten Times More Sensitive Has Been Discovered

A living cancer drug is a name used for an approach in which a patient's own immune cells are collected, genetically engineered and returned to the patient: Chimeric Antigen Receptor (CAR) T-cell therapy. It has earned acclaim for treating certain aggressive leukemias and lymphomas with striking success in people affected by these diseases.

A newer approach pioneered by Memorial Sloan Kettering Cancer Center (MSKCC) involves taking a person's immune T cells and genetically editing them, equipping them with special receptors that can find cancer in the body. T cells target a protein, or antigen, on the surface of cancer cells.

However, CAR T-cell therapy still does not work in everyone who receives it. Some people do not respond, or their cancer returns despite treatment. One reason is that T cells often cannot eliminate cancer cells with very low levels of the antigen they were engineered to target and destroy—a phenomenon known as antigen escape . This is the name given to that phenomenon.

Michel Sadelian, a physician-scientist at the Sloan Kettering Institute, developed a new way for engineered T cells to target cancer cells better. In this approach, T cells are engineered to be highly sensitive and capable of targeting and destroying cells with very low levels of cancer antigens.

HLA-independent T-cell receptor (HIT) T cells are the name given to these redesigned cells, which offer hope of working where conventional CAR T therapy fails.

The research was published on 13 January 2022 in Nature Medicine. Dr. Sedelain said: “We learned that conventional CAR T-cell therapy needs a certain minimum antigen density on the cancer cell surface to work. This new design increases T-cell sensitivity by at least tenfold. This treatment option may allow us to prevent the disease recurrence that we often see with conventional CARs.”

Precision in Gene-Editing Treatments With Nobel Prize-Winning CRISPR

When designing currently approved CAR T-cell treatments, researchers use viruses to deliver the CAR gene into immune cells. This technique inserts genes randomly into the genome, a somewhat haphazard approach that can produce unwanted side effects.

In 2017, Dr. Sadelain's team adopted a new tactic using a powerful genetic technology that inserts a gene precisely where they want—in a genetic region called TRAC—known as CRISPR. Using TRAC as an "address" enabled them to make better CAR T cells. Nature published this advance, which made a major impact in the field.

After rapid progress over a few years, Dr. Saedelain's team has now found a new way to use this approach to insert a gene for HIT.

“We simply cut out the gene for the T-cell receptor and insert the genetic code for the HIT receptor, this new structure we have designed.”

Researchers showed that cells with HIT were effective against two human cancers in mice—B-cell leukemia and acute myeloid leukemia.

Hitting the Target With Fewer Clues

Experiments suggested that these HIT cells may be more effective because they act faster than conventional CAR T cells. When antigen levels on cancer cells are low, CAR T cells may not remain attached long enough to perform their function. HIT cells kill cancer cells quickly and do not need to remain attached for long.

“This expands the range of potential targets on cancer cells,” says Dr. Sadelain. “We are no longer limited by the need to target large amounts of antigen for CAR T cells to work. With HIT cells, we can go after many other molecules that we otherwise could not. This could really open the way for this field.”

Dr. Sadelain says the next step is clinical trials testing HIT cells in patients.

MSKCC's Cell Therapy and Cell Engineering Branch, led by Isabelle Rivière, has established a process for CRISPR-based editing of CAR T cells, and the first trial is planned for 2022 with medical oncologist Jae Park, testing slightly different TRAC-engineered CAR T cells.