Lab study shows promise of aiming genetically engineered T-cell therapy at a gene fusion.

Precision immunotherapies that aim the power of the body’s soldier cells at cancer have revolutionized the care of certain types of leukemia.

But not all types — yet.

New research by a team from Fred Hutchinson Cancer Research Center is helping to build momentum toward targeted new immunotherapies in acute myeloid leukemia, or AML. This aggressive cancer of white blood cells can’t yet be treated by therapies that harness these disease-fighting cells, called T cells, like those now approved for use in the clinic with other types of leukemia.

The team hopes the first-of-its-kind, precision medicine strategy they developed in the lab becomes part of a “toolbox” of immune-based therapies for this difficult cancer, said Dr. Melinda Biernacki, the lead scientist on the study, published in the Journal of Clinical Investigation on Monday. Biernacki is part of the team of Fred Hutch faculty member Dr. Marie Bleakley, which has been developing other T-cell therapies for AML and other leukemias for several years in lab and clinical research.

“T-cell immunotherapy for AML is coming,” Biernacki said. “It won’t be a one-size-fits-all, but between our work and that of other investigators at the Hutch and at other institutions, we are getting closer and closer.”

Focusing on one genetic reshuffling in AML

AML can be caused by many different changes in the body’s genetic code. Research led by scientists at Fred Hutch has shown that different types of genetic mutations are associated with AML in different age groups. For the youngest AML patients, these changes frequently involve the reshuffling of large chunks of genetic material.

Biernacki, her colleagues in the Bleakley Lab and other Hutch collaborators focused their efforts on one of these reshufflings, which results in two genes called CBFB and MYH11 becoming inappropriately conjoined and predisposes the mutated cells to cancer. A CBFB-MYH11 gene fusion is found in about one of 10 AML patients, most of whom are children, teenagers and young adults.

Genes code for proteins, and immune cells like T cells can read these proteins to tell the difference between friend and foe. The aberrant CBFB-MYH11 fusion gene found in these AML patients’ cancer cells codes for a similarly abnormal fusion protein.

This fusion protein caught the attention of the research team. If T cells could recognize AML cells that had the fusion protein, could the immune system selectively kill the cancer?

The team searched through blood samples from healthy people who had donated their blood to research and found that some of them naturally had T cells that recognized the CBFB-MYH11 fusion protein. These people’s T cells could kill AML with the fusion protein in Petri dishes, and they could greatly reduce the number of cancer cells in mice with leukemias taken from human AML patients.

Then, the researchers copied those T cells’ genetic codes for their CBFB-MYH11-specific weaponry and engineered those snippets of DNA into human T cells in Petri dishes. In lab tests, the newly armed reengineered T cells did what the researchers hoped and killed AML cells with the CBFB-MYH11 mutation. The researchers didn’t find any evidence that the special T cells recognized similar healthy proteins.

New precision treatments needed for AML patients

New, more-targeted treatment strategies are desperately needed in AML, especially for people who are failed by standard first-line chemotherapies. At least one-third of AML patients with the CBFB-MYH11 fusion will have their cancers come back after intensive chemotherapy.

This study is the first time anyone has definitively shown that T cells can target gene fusions in AML, the researchers reported. And they are hopeful that harnessing this ability could be as useful in treating people with advanced, treatment-resistant AML as other T-cell therapies have been for people with other types of advanced leukemias, Biernacki said — though she cautioned it will take several years of work to translate their strategy into a human treatment.

Fusion proteins like CBFB-MYH11 are “particularly good immunotherapy targets,” Biernacki explained, because of two special characteristics.

First, they are specific to cancer cells. Some forms of experimental T-cell therapy that are being studied for AML home in on targets that are also found in some healthy cells, meaning such therapies can lead to collateral damage that AML patients may not be able to handle. A T-cell therapy that targets fusion proteins should be able to avoid these side effects.

Second, the cancer cells can’t mutate to lose the targeted protein — an escape method doctors have seen in cancer patients treated with other kinds of T-cell therapies — because the fusion protein is essential to the cell’s “cancer-ness”.

The research team is now optimizing their methods in the lab for targeting this fusion protein safely and effectively with engineered T cells, and they are searching for other good T-cell targets in other subtypes of AML. They’ve found several promising candidates so far, Biernacki said.

“Our big goal is to build a toolbox of T-cell immunotherapies for many different T-cell targets so that we can treat most patients with AML,” she said.

AML’s resistance to many treatments makes it formidable. But it, like all cancers, has weak points in its armor. And, step by step, science is identifying them thanks to advances in genetic engineering and other new tools.

“We and other scientists are working hard to find these weaknesses to make new treatments that are highly specific and effective,” Biernacki said.

The study was funded by Hyundai Hope on Wheels, Stand Up To Cancer, the National Cancer Institute, the Rally Foundation for Childhood Cancer Research and Alex’s Lemonade Stand Foundation for Childhood Cancer.

Note: Scientists at Fred Hutch played a role in developing these discoveries, and Fred Hutch and certain of its scientists may benefit financially from this work in the future.

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Source: Fred Hutch

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