New System Hunts Down Cancer Cells that Hide from Immunotherapies

Cancer Cells

Cancer cells are particularly good at hide-and-seek, using a number of different strategies to hide from the immune system. The first generation of immuno-oncology therapies do a pretty good job of finding those cancer cells, but aren’t able to find all of them, particularly in solid tumors.

Yale University researchers have developed a new system dubbed Multiplexed Activation of Endogenous Genes as Immunotherapy (MAEGI) that hunts down those cancer cells. They published their research in the journal Nature Immunology.

“This is an entirely new form of immunotherapy,” said Sidi Chen, assistant professor of genetics and senior author of the research.

MAEGI merges viral gene therapy and CRISPR gene-editing. MAEGI tags the tumor cells for immune cell attack, similar to painting a target on them. This allows the immune system to more quickly find and kill the cells.

“And once those cells are identified, the immune system immediately recognizes them if they show up in the future,” Chen says.

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The researchers used CRISPR activation (CRISPRa) to target specific cancer genes, which allows for the presentation of specific tumor antigens. This results in dramatic antitumor immune responses. They tested this in both prophylactic and therapeutic settings, with significant success.

Using an intratumoral adeno-associated virus, the most common vector used in gene therapies, to deliver CRISPRa libraries, resulted in strong antitumor immunity for a range of cancer types. What this means is the system hunted down tens of thousands of genes associated with cancer, and when it found them, it marked them so the immune system would more easily identify the cancer cells.

The researchers wrote, “Precision targeting of mutated gene sets eradicated a large fraction of established tumors at both local and distant sites. This treatment modality led to alterations in the tumor microenvironment, marked by enhanced T-cell infiltration and antitumor immune signatures.”

The researchers believe MAEGI is both versatile and scalable. They plan to continue working to optimize MAEGI for simpler manufacturing and clinical trials in cancer patients.

Checkpoint inhibitors, such as Merck’s Keytruda (pembrolizumab), block specific proteins that cancer cells use to hide from the immune system. But cancer cells have other ways of hiding, hence MAEGI.

In their research, Chen’s MAEGI was successful in decreasing triple-negative breast cancer, pancreatic tumors and melanoma in mice.

In February, researchers at Cedars-Sinai Medical Center used a Bristol-Myers Squibb blood cancer drug, Sprycel, to boost checkpoint inhibitors. Sprycel was given to mice with an anti-PD-1 checkpoint inhibitor, and the combination improved the effectiveness of the immunotherapy across several tumor types.

The authors wrote, “Combining therapies that enhance antitumor immunity has therefore been an area of great interest to the entire cancer community. This is reflected by the number of clinical trials investigating inhibition of PD-1 in combination with a second treatment to enhance response to this relatively new class of anticancer drugs, which has soared from a single new trial in 2009 to over 1,100 trials in 2017. While this growth indicates the excitement surrounding immune-focused treatment modalities, it has also markedly outpaced the gathering of preclinical evidence supporting them.”

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