Emmanuelle Charpentier, PhD, and Jennifer Doudna, PhD, who pioneered the site-specific CRISPR gene-editing technology that has revolutionized cancer research and treatment, were awarded the 2020 Nobel Prize in Chemistry. Many CRISPR-based therapies are already in human testing, with gene-edited T cells for blood cancers and solid tumors leading the way.

Two scientists who pioneered the site-specific genome-editing technology that is contributing to innovative and breathtaking cancer therapies were awarded this year's Nobel Prize in Chemistry.

Emmanuelle Charpentier, PhD, of the Max Planck Unit for the Science of Pathogens in Berlin, Germany, and Jennifer Doudna, PhD, of the University of California, Berkeley, led the team that in 2012 first showed how a bacterial immune mechanism known as CRISPR could be repurposed to edit DNA (Science 2012;337:816–21). They are the first two women to share a science Nobel without a male collaborator.

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Emmanuelle Charpentier, PhD (left), and Jennifer Doudna, PhD, were awarded the 2020 Nobel Prize in Chemistry for pioneering CRISPR-based genome-editing technology, a molecular tool that can precisely cut DNA. The system has myriad uses: It could, for example, be used to treat inherited diseases and develop immunotherapies for cancer.

In the years since Charpentier's and Doudna's landmark discovery, CRISPR technologies have become staples of basic research laboratories in all fields, with countless scientists adopting the simple and inexpensive tool to manipulate DNA in unprecedented ways. Cancer researchers have used the tool to precisely disrupt tumor suppressor genes or activate oncogenes to build more accurate disease models, discover drug targets, reveal basic mechanisms of tumor development, and much more.

“CRISPR really made genetic engineering methods a lot more convenient, easier, faster, and cheaper,” says Jerry Li, MD, PhD, of the NCI's Division of Cancer Biology.

“For now, the most impactful outcome of this CRISPR technology is in the cancer biology world,” he says, “but it's trickling into the therapeutic world,” with several CRISPR-based interventions already in human testing. Some take aim at rare blood disorders, others at an inherited form of blindness. Leading the way, however, are trials of gene-edited T cells for cancer.

The first such U.S.-based trial launched in 2018 at the University of Pennsylvania in Philadelphia, where Edward Stadtmauer, MD, and his colleagues treated three patients—two with myeloma and one with liposarcoma—with an autologous NY-ESO-1–directed T-cell product in which they had disabled genes encoding T-cell receptors (TCR) and PD-1 receptors. “CRISPR was essential for the performance of our first-in-human attempt to enhance the function and activity of engineered T cells,” says Stadtmauer, who reported earlier this year that the cells were well tolerated and showed durable engraftment (Science 2020;367:eaba7365).

CRISPR Therapeutics, a company cofounded by Charpentier, is also testing three allogeneic chimeric antigen receptor T-cell therapies that use the gene-editing technique to eliminate the TCR and MHC I molecules from donor cells and to precisely insert the genetic construct equipped with antigens for either CD19, BCMA, or CD70, depending on the therapy. Meanwhile, Intima Bioscience is studying whether knocking out an intracellular immune checkpoint gene called CISH from a patient's own tumor-infiltrating lymphocytes can enhance TCR avidity, improve neoantigen recognition, and lead to tumor regression. A phase I trial in metastatic gastrointestinal cancers kicked off earlier this year at the University of Minnesota's Masonic Cancer Center in Minneapolis.

Clinicians in China have also launched at least nine other trials of CRISPR-engineered T-cell therapies since 2017.

The various T-cell therapies under evaluation all involve gene editing ex vivo, but Eric Kmiec, PhD, of ChristianaCare's Gene Editing Institute in Newark, DE, hopes to soon begin testing an in vivo CRISPR-based treatment. He plans to disable NRF2—a gene involved in tumor progression and chemotherapy resistance—in patients with advanced non–small cell lung cancer to try to stall cancer growth and make tumors more susceptible to platinum-based chemotherapeutics.

Earlier this year, Kmiec's team described a unique stretch of tumor-specific DNA that allows for targeting NRF2 in cancer cells without affecting the gene in normal tissues—and he credits Charpentier and Doudna, who helped define the various pieces of the CRISPR machinery, for making that strategy possible (Mol Cancer Res 2020;18:891–902). “Without this fundamental molecular information,” Kmiec says, “it would've taken us much longer to develop our tumor-specific selective protocol for the disablement of the NRF2 gene in squamous cell carcinoma cells.” –Elie Dolgin

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