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News — PHILADELPHIA – Genetically editing a cancer patient’s immune cells using CRISPR/Cas9 technology, then infusing those cells back into the patient appears safe and feasible based on early data from the first-ever clinical trial to test the approach in humans in the United States. Researchers from the have infused three participants in the trial thus far – two with multiple myeloma and one with sarcoma – and have observed the edited T cells expand and bind to their tumor target with no serious side effects related to the investigational approach. Penn is conducting the ongoing study in cooperation with the (PICI) and .

“This trial is primarily concerned with three questions: can we edit T cells in this specific way? Are the resulting T cells functional? And are these cells safe to infuse into a patient? This early data suggests that the answer to all three questions may be yes,” said the study’s principal investigator Edward A. Stadtmauer, MD, section chief of Hematologic Malignancies at Penn. Stadtmauer will present the findings next month at the 61^st American Society of Hematology Annual Meeting and Exposition in Orlando (Abstract #49).

The approach in this study is closely related to CAR T cell therapy, which engineers patients’ own immune cells to fight their cancer, but it has some key differences. Just like CAR T, researchers begin by collecting a patient’s T cells through a blood draw. However, instead of arming these cells with a receptor like CD19, the team first uses CRISPR/Cas9 editing to remove three genes. The first two edits remove a T cell’s natural receptors to make sure the immune cells bind to the right part of the cancer cells. The third edit removes PD-1, a natural checkpoint that sometimes blocks T cells from doing their job. At that point, a lentivirus is used to insert an affinity-enhanced T cell receptor (TCR), which tells the edited T cells to target an antigen called NY-ESO-1.

“Our use of CRISPR editing is geared toward improving the effectiveness of gene therapies, not editing a patient’s DNA,” said the study’s senior author Carl June, MD, the Richard W. Vague Professor in Immunotherapy and director of the Center for Cellular Immunotherapies in the Abramson Cancer Center. “We leaned heavily on our experience as pioneers of the earliest trials for modified T-cell therapies and gene therapies, as well as the strength of Penn’s research infrastructure, to make this study a reality.”

Even with that experience, moving this work into the clinic while ensuring appropriate patient safeguards meant the research team had to move through a comprehensive series of institutional and federal regulatory approval steps. This included approval by the National Institutes of Health’s Recombinant DNA Research Advisory Committee, which was charged with providing advice on safety and ethical issues associated with emerging biotechnologies. After that, plans for the trial were reviewed by the U.S. Food and Drug Administration, as well as Penn’s institutional review board and institutional biosafety committee. The whole process took more than two years.

The CRISPR-edited T cells are not active on their own like CAR T cells. Instead, they require the presence of an antigen known as HLA-A201, which is only expressed in a subset of patients. This means that patients had to be screened ahead of time to make sure their tumors are a match for the approach. Participants who met the requirements received other clinically-indicated therapy as needed while they waited for their cells to be manufactured. Once that process was completed, all three received the gene-edited cells in a single infusion after a short course of chemotherapy. Analysis of blood samples revealed that all three participants had the CRISPR-edited T cells expand and survive. While none have yet responded to the therapy, there were no treatment-related serious adverse events.

Researchers say the number of edits made to each T cell means there are multiple possible cells produced and the optimal and most active cell product remains to be determined. They are continuing to analyze patient samples and say they need longer clinical follow-up to more definitively study this emerging approach.

“Tmunity is proud to be a part of the first U.S. trial in humans with a CRISPR-edited cell therapy,” said Usman “Oz” Azam, MD, President and Chief Executive Officer of Tmunity. “These data establish a beachhead in the continued evolution of Tmunity’s innovative portfolio and provides key insights into the development of allogeneic cell therapies.”

While this phase 1 safety study continues and genetic analysis is ongoing, researchers say the feasibility and safety they’ve demonstrated so far provides optimism that the approach may be applicable across multiple areas of gene therapy research.

“Our purpose is to make sure PICI investigators have the support they need to bring bold ideas like this to life. These early findings are the first step as we determine if this new, breakthrough technology can help rewrite how we treat patients with cancer and perhaps other deadly diseases,” said Sean Parker, Founder and Chairman of PICI. “CRISPR editing could be the next generation of T cell therapy, and we are proud to be a part of the first human trial in the United States.”

Stadtmauer will present the findings Saturday, December 7 at 7:30 a.m. in Room W414AB at the Orange County Convention Center. Additional Penn authors include Adam D. Cohen, Kristy Weber, Simon F. Lacey, Vanessa E. Gonzalez, J. Joseph Melenhorst, Joseph A. Fraietta, Gabriela Plesa, Joanne Shea, Tina Matlawski, Amanda Cervini, Avery L. Gaymon, Stephanie Desjardins, Patricia Mangan, Eric Lancaster, Bruce L. Levine, Don L. Siegel, Yangbing Zhao, Wei-Ting Huang, Elizabeth Hexner.

The study was supported by the Parker Institute for Cancer Immunotherapy and Tmunity.

Editor’s note: Drs. June, Levine and Zhao are equity holders in Tmunity. Penn receives sponsored research funding from Tmunity, and as inventors of some of the licensed technology, Drs. June and Zhao, along with Penn, may receive additional financial benefits under the license in the future. Penn is also an investor in the company and holds equity interests.

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About Penn Medicine:

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the  (founded in 1765 as the nation’s first medical school) and the , which together form a $7.8 billion enterprise.

The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. Â鶹´«Ã½ & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $425 million awarded in the 2018 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center—which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. Â鶹´«Ã½ & World Report—Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Home Care and Hospice Services, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is powered by a talented and dedicated workforce of more than 40,000 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2018, Penn Medicine provided more than $525 million to benefit our community.

About the Parker Institute for Cancer Immunotherapy:

The Parker Institute for Cancer Immunotherapy (PICI) is radically changing the way cancer research is done. Founded in 2016 through a $250 million gift from Silicon Valley entrepreneur and philanthropist Sean Parker, the San Francisco-based nonprofit is an unprecedented collaboration between the country’s leading immunotherapy researchers and cancer centers, including Memorial Sloan Kettering Cancer Center, Stanford Medicine, the University of California, Los Angeles, the University of California, San Francisco, the University of Pennsylvania and The University of Texas MD Anderson Cancer Center. The institute also supports top researchers at other institutions, including City of Hope, Dana-Farber Cancer Institute, Fred Hutchinson Cancer Research Center, Icahn School of Medicine at Mount Sinai, Institute for Systems Biology and Washington University School of Medicine in St. Louis. By forging alliances with academic, industry and nonprofit partners, PICI makes big bets on bold research to fulfill its mission: to accelerate the development of breakthrough immune therapies to turn all cancers into curable diseases. Find out more at

About Tmunity

Tmunity is a private clinical-stage biotherapeutics company focused on saving and improving lives by delivering the full potential of next-generation T-cell immunotherapy to patients with devastating diseases. Integrating a foundational collaboration with the University of Pennsylvania (Penn) with the groundbreaking scientific, clinical, and manufacturing expertise, and the demonstrated track record of its founders (Carl June, MD; Bruce Blazar, MD; Bruce Levine, PhD; Yangbing Zhao, MD, PhD; Jim Riley, PhD; and Anne Chew, PhD), Tmunity represents a new center of gravity in translational T-cell medicine. The company is developing a diversified portfolio of novel treatments that exhibit best-in-class control over T-cell activation and direction in the body, with an initial focus in cancer and three programs currently in the clinic. With headquarters in Philadelphia, Tmunity utilizes laboratories and production facilities at Penn and its own dedicated cGMP manufacturing facility in East Norriton, PA, to pursue process improvement and production scale-up in support of clinical development of its T-cell therapies. For more information, visit and connect with us on social media at and .