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 Abramson Cancer Center of the University of Pennsylvania 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 tumour target with no serious side effects related to the investigational approach.
Penn is conducting the ongoing study in cooperation with the Parker Institute for Cancer Immunotherapy (PICI) and Tmunity Therapeutics.
"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 61st American Society of Hematology Annual Meeting and Exposition in Orlando.
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 tumours 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 analyse 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."