By MASS GENERAL BRIGHAM COMMUNICATIONS Research

2 min read

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Multiple myeloma cells. Image: Md Saiful Islam Khan/iStock/Getty Images Plus

New research has identified genetic modifications that may increase the effectiveness of immunotherapy for multiple myeloma, a difficult-to-treat blood cancer most often diagnosed in people over 65.

A team led by scientists at Harvard Medical School, Massachusetts General Hospital, and the Broad Institute of MIT and Harvard used CRISPR technology to pinpoint genes that could be edited to boost the efficacy of chimeric antigen receptor (CAR) T-cell therapy for cancer.

When the researchers edited those genes, they found that some of the modifications improved T-cell function and survival in a lab dish and in a mouse model of multiple myeloma.

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The study, published Sept. 24 in Nature and supported in part by federal funding, describes a method that could help scientists more efficiently make improvements to CAR T-cell therapy.

“Testing individual genetic modifications to find those that enhance CAR T function would take a huge amount of time and money. Our approach lets us test hundreds of changes at a time,” said co-senior author Marcela Maus, HMS professor of medicine at Mass General.

Although follow-up studies are needed to confirm the findings in humans, the scientists hope that their approach will eventually lead to better outcomes for patients with multiple myeloma — and can possibly be applied to other cancers.

Building better CAR T cells

CAR T-cell therapy is an immune-based treatment that involves retrieving a patient’s T cells, modifying them, multiplying them, and reintroducing them into the patient to fight cancer cells. In recent years, the therapy has revolutionized treatment of blood cancers, including various forms of leukemia and lymphoma.

To date, CAR T-cell therapy has not been as effective against solid tumors or in patients with relapsed or treatment-resistant multiple myeloma. In addition, the number of CAR T cells circulating in the body decreases over time, limiting their long-term activity.

In the new study, the researchers developed a CRISPR screen that targeted 135 genes in human donor-derived CAR T cells to identify genes that may improve persistence and function. The team cultured the CRISPR-edited cells in a lab dish, transferred them into a mouse model of multiple myeloma, and tracked the animals’ survival for up to 21 days.

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Analyses of the modified CAR T cells revealed that deleting the cell cycle regulator gene CDKN1B increased the CAR T cells’ proliferation, long-term persistence, and anti-tumor activity.

The researchers also observed that some genes affected the function of CAR T cells in a lab dish but not in the mouse model. Other genes boosted early proliferation of CAR T cells in the tumor microenvironment but did not provide long-term benefits.

The team’s comprehensive approach — which included screening over the life cycle of a T cell, co-culturing T cells with cancer cells, and transferring the cells to an animal model — was key to their success, the researchers said.

“We discovered important regulators in vivo that we could not have predicted from the in vitro results,” said co-senior author Robert Manguso, HMS associate professor of medicine at Mass General.

The researchers propose that future studies focus on CDKN1B in CAR T cells to determine whether modifications to the gene safely improve treatment outcomes for patients.

Authorship, funding, disclosures

Additional authors on the paper include Nelson H. Knudsen, Giulia Escobar, Felix Korell, Tamina Kienka, Celeste Nobrega, Seth Anderson, Andrew Y. Cheng, Maria Zschummel, Alexander Armstrong, Amanda Bouffard, Michael C. Kann, Sadie Goncalves, Hans W. Pope, Mitra Pezeshki, Alexander Rojas, Juliette S. M. T. Suermondt, Merle Phillips, Trisha R. Berger, Sangwoo Park, Diego Salas-Benito, Elijah P. Darnell, Filippo Birocchi, Mark B. Leick, Rebecca C. Larson, John G. Doench, Debattama Sen, and Kathleen B. Yates.

Support for the study was provided by the National Institutes of Health (grant R01CA238268), the Krantz Breakthrough Award, the German Research Foundation (DFG; 466535590), the Gilead Sciences Research Scholar Program, the CRIS Foundation Out-Back Fellowship Programme (outback2021_6), the Spanish Society of Medical Oncology, the American-Italian Cancer Foundation, and the Italian Association for Cancer Research.

Maus, Knudson, Korell, Berger, and Manguso are inventors on patents filed by Mass General and the Broad Institute on these technologies. Maus is an inventor on patents related to adoptive cell therapies, held by Mass General (some licensed to ProMab and Luminary Therapeutics) and University of Pennsylvania (some licensed to Novartis). Maus holds equity in 2SeventyBio, A2 Biotherapeutics, AffyImmune, BendBio, CARGO Therapeutics, GBM newco, Model T bio, Neximmune, and Oncternal Therapeutics. Maus receives grant/research support from Kite Pharma, Moderna, and Sobi. Maus has served as a consultant for multiple companies involved in cell therapies. Manguso has received consulting or speaking fees from Bristol Myers Squibb, Gilead Sciences, and Immunai Therapeutics; has equity ownership in OncoRev; and receives research funding from Calico Life Sciences. Leick is an inventor on patents related to adoptive cell therapies, held by Mass General, and has served as a consultant for BioNTech and Cabaletta Bio. Leick holds equity in AbbVie. Larson is an inventor on patents related to adoptive cell therapies held by Mass General, has served as a consultant for Cargo, and is now an employee of Link Cell Therapies.