Researchers from the University of Pennsylvania’s Abramson Cancer Center (Penn) have concluded, based on research, that genetically edited immune cells can persist, thrive, and function months after a cancer patient received them. They have demonstrated that cells once removed from an individual patient and brought back into the lab setting were able to kill the cancer months after their original manufacturing and infusion. Moreover, the cells there successfully edited in three specific ways representing the very first sanctioned investigational use of multiple edits to the human genome. As part of the very first U.S. clinical trial to test the gene-editing approach in humans, it follows the successful use of CRISPR/Cas9 technology to edit three cancer patients’ immune cells. Penn conducts this breakthrough research in collaboration with the Parker Institute for Cancer Immunotherapy and Tmunity Therapeutics.
As reported by Penn via a press release, these findings evidence the latest milestone in Penn’s history as cellular and gene therapy pioneer, including the development of the first FDA-approved CAR T cell therapy, Kymriah, for pediatric and adult blood cancer patients.
The Phase I study was a first-in-human trial proposed to test HLA-A*0201 restricted NY-ESO-1 (an antigen) redirected T cells with edited endogenous T cell receptor and PD-1. The study started in September 2018 and runs through 2033.
The Study Approach
Penn’s approach was similar to CAR T cell therapy (in which patient immune cells are engineered to fight cancer, but it has some key differences). Just like CAR T, the Penn researchers (and collaborators) began by collecting a patient’s T cells from the blood. However, rather than arming these cells with a receptor against a protein such as CD19, the team first utilized CRISPR/Cas9 editing to remove three genes. The first two edits removed a T cell’s natural receptors so they can be reprogrammed to express a synthetic T cell receptor, allowing these cells to seek out and destroy tumors. The Third edit removed PD-1, a natural checkpoint that at times may block T cells from doing their job.
In the study, the researchers were able to prove that the manufactured cells incorporated the three edited cells, establishing the first confirmation that CRISPR/Cas9 technology can be used to target multiple genes simultaneously in humans and points to new promise for this technology to target a number of diseases heretofore not treatable.
Moreover, upon knock out of the three genes, a fourth genetic modification was accomplished using a lentivirus to insert the cancer-specific synthetic T cell receptor, which informs the edited T cells to target an antigen called NY-ESO-1. What the Penn team found was that these cells (which typically survive for less than a week) via this new approach reveal that, once edited, could persist for as long as nine months. This is a powerful revelation as one of the investigators observed that earlier studies revealed the manufactured cells didn’t keep their function for long losing within days. Moving forward, the team became aware that CRISPR-edited cells kept their anti-tumor fighting capability for much longer periods after one single infusion. This breakthrough has profound implications for future use.
This study used CRISPR-edited T cells that require the cooperation of a molecule known as HLA-A*02:01, which is only expressed in a subset of patients. Consequently, as not all patients would fit the inclusion criteria, the investigators have to screen patients ahead of time to ensure there was a match. The participants who met the study criteria received only clinically indicated therapy as needed while they waited for their cells to be manufactured.
Upon completion of this process, all three patients received the gene-edited cells in a single fusion after a short course of chemotherapy. An analysis of blood samples revealed that all three participants had the CRISPR-edited T cells take root and thrive in patients while none responded to the therapy. No treatment-related serious events were observed.
A First in America
Investigators at Penn have pioneered a number of “first uses” of engineered T cells over the past decade. CRISPR technology had not previously been tested in humans in America. Because of the uncertainties and risks associated with this advanced effort, the research team had to navigate a comprehensive and rigorous series of institutional and federal regulatory approval steps, such as approval by the National Institute of Health’s Recombinant DNA Research Advisory Committee and review by the U.S. Food and Drug Administration—not to mention Penn’s institutional review board and institutional biosafety committee. The entire process took over two years. However, the work could be well worth it. Now, researchers report that the data generated from this study can open the door to later state studies to investigate and extend this approach to a broader field beyond cancer. Penn has several planned forthcoming.
A couple of researchers in this study have an equity interest in participating in commercial partner Tmunity, and they include Dr. June Levine and Yangbing Zhao.
Moreover, Tmunity provides cash funding for sponsored research with Penn. Moreover, as inventors of some of the technology, Dr. June and Dr. Zhao, along with Penn itself, may receive additional financial benefits under the license in the future. Penn is a direct equity holder in Tmunity.
About Tmunity Therapeutics (Tmunity)
Founded in 2015, Tmunity, associated with Penn, has raised $230 million. Tmunity, according to its website, is a unique biotherapeutics company because of the unrivaled depth of its scientific founders’ and management team’s experience and demonstrated field-specific track record, its mastery of the application of gene-editing and cell engineering tools in human trial settings, the maturity of its clinic-ready development programs, the readiness to scale through its manufacturing processes and facility, and the breadth of its relevant clinical, regulatory, commercial, and company-building expertise.
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 Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $7.8 billion enterprise.
Carl June, MD, the Richard W. Vague Professor in Immunotherapy and director of the Center for Cellular Immunotherapies in the Abramson Cancer Center and director of the Parker Institute for Cancer Immunotherapy at the Perelman School of Medicine at the University of Pennsylvania and the study’s senior author.
Edward A. Stadtmauer, MD, section chief of Hematologic Malignancies at Penn, who is the co-lead author on the study along with Joseph A. Fraietta.
Joseph A. Fraietta, PhD, an assistant professor of Microbiology at Penn.
Simon F. Lacey, PhD, director of the Translational and Correlative Studies Laboratory in the Center for Cellular Immunotherapies.
This study was performed in cooperation with researchers from the Stanford University School of Medicine, including Kevin R. Parker, Yanyan Qi, Ansuman T. Satpathy, and Howard Y. Chang.
Additional Penn authors include Megan M. Davis, Adam D. Cohen, Kristy L. Weber, Eric Lancaster, Patricia A. Mangan, Irina Kulikovskaya, Minnal Gupta, Fang Chen, Lifeng Tian, Vanessa E. Gonzalez, Jun Xu, In-young Jung, J. Joseph Melenhorst, Gabriela Plesa, Joanne Shea, Tina Matlawski, Amanda Cervini, Avery L. Gaymon, Stephanie Desjardins, Anne Lamontagne, January Salas-Mckee, Andrew Fesnak, Donald L. Siegel, Bruce L. Levine, Julie K. Jadlowsky, Regina M. Young, Anne Chew, Wei-Ting Hwang, Elizabeth O. Hexner, Beatriz M. Carreno, Christopher L. Nobles, Frederic D. Bushman, and Yangbing Zhao.