Inmunologically active proteins on a T-cell: T-cell receptor, CD-4, CD-28, PD-1 and CTLA-4 and a calcium channel. Cancer Immunotherapy
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Researchers from Northwestern University and the University of California, San Francisco (UCSF), reporting Wednesday in the journal Nature, say they have developed a new technique to encode human T cells with a mutation found in malignant T cells that cause lymphoma. The investigators say this new immunotherapy approach is 100 times more potent at killing cancer cells than current treatments. Further, the investigators note that while current immunotherapies have shown very limited success against solid tumors, their engineered T cells were able to kill tumors derived from skin, lung, and stomach in mouse models, without any signs of toxicity.

“We used nature’s roadmap to make better T cell therapies,” Jaehyuk Choi, MD, PhD, associate professor of dermatology and of biochemistry and molecular genetics at Northwestern University Feinberg School of Medicine tells Inside Precision Medicine. “This approach had two advantages. First, all of our mutations have been shown to have large effects in people. Others have to trial in tissue culture dishes then move to mice and then hope it works in people.

“Second, our approach uses any nature’s roadmap. Unlike CRISPR which only modulates gene expression higher or lower. IT uses any mutation available to nature, including point mutations and gene-gene fusions.”

According to the team, the new research was borne from the understanding that in human T cell cancers such as lymphoma, the evolution of the disease positively selects for mutations that make the diseased T cells stronger in challenging situations, similar to those faced by therapeutic T cells.

Navigating the tumor microenvironment remains a major challenge to creating effective immunotherapies against the majority of cancer types, where they encounter harsh metabolites, immunosuppressive cytokines, and T cell exhaustion. In many cases, tumors effectively hijack the immune system causing it to sustain the cancer instead of attacking it.

“Mutations underlying the resilience and adaptability of cancer cells can super-charge T cells to survive and thrive in the harsh conditions that tumors create,” said Kole Roybal, associate professor of microbiology and immunology at UCSF, center director for the Parker Institute for Cancer Immunotherapy Center at UCSF, and a member of the Gladstone Institute of Genomic Immunology.

For this new immunotherapy approach, the researchers hypothesized that perhaps the mutations providing this protective environment for tumors could be discovered and engineered into human T cells. This could improve the efficacy of immunotherapies by conferring the same fitness to T cells that makes some cancers so hard to treat.

“Leveraging mutations from T cell cancers has many potential benefits over current approaches,” the investigators write. “First, evolution employs any mutation available in nature. Like existing approaches, these mutations can modify gene expression by gene locus duplication or deletion. However, unlike current approaches, gain-of-function point mutations or translocations can be introduced that have unique, outsized effects unachievable by modulation of wild-type gene expression. Additionally, an evolution-based approach pre-selects mutations that are more likely to have effects, improving the signal-to-noise as compared to existing approaches.”

The Northwest and UCSF researchers identified and screened 71 mutations found in the T cells of patients with lymphoma and then identified which ones might enhance T cell therapies in mouse models. This process identified a gene fusion CARD11-PIK3R3, which the team demonstrated improves CAR- and T cell receptor-T antitumor activity, reduces T cell dose requirements, as well as eliminates the need to subject T-cell therapies to harsh preconditioning.

Tot test the potency of their candidate, the investigators mixed CARD11-PIK3R3 cells with normal cells an put them in mice. If the CARD11-PIK3R3 conferred a fitness advantage the team hypothesized those cells would be enriched in solid tumors implanted in mouse models. They found that withing days, the CARD11-PIK3R3-expressing cells were enriched 145 fold compared with controls.

More significantly, the team found that they could cure preclinical mouse models using only 20,000 CARD11-PIK3R3 cells—as compared with more than 2 million control cells that had no effect—suggesting they are more than 100 fold more potent.

“This was despite the fact that we used what we called a lymphoreplete mouse. Normally, before receiving CAR-T, human patients receive chemotherapy to ‘lymphodeplete’ and create space for the T cell therapies to take hold,” Choi explains. “If you don’t do this, cells can just disappear. Our cells didn’t need this lymphodepletion, but were still able to clear tumors with such low doses.”

Future studies of this new approach will look for methods to ensure maximum safety of any new T cell therapies combined with CARD11-PIK3R3 or other naturally occurring mutations. Research will also be needed to better understand how to grow these cells safely and at scale for the scale up of any potential therapies. The team also acknowledged the possibility that this approach may lead to the possibility of malignant transformation of these cells, though they did note that none was evident 418 days after adoptive T cell transfer, even at the high cell doses used in this study.

Armed with these highly promising early results, Choi and Roybal have founded a new company called Moonlight Bio, in collaboration with the Parker Institute for Cancer Immunotherapy and venture capital firm Venrock. The goal is to begin in-human testing within a few years.

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