CRISPR-edited T cells appear safe for patients with cancer
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ORLANDO — Immune cells genetically edited with CRISPR/Cas9 technology and infused back into patients with multiple myeloma and sarcoma appeared to be safe and represent a feasible therapeutic approach, according to results of a prospective phase 1 study presented at ASH Annual Meeting and Exposition.
“CRISPR technology allows us to edit genes in cells. The question is how to best use that technology to treat cancer,” Edward A. Stadtmauer, MD, section chief of hematologic malignancies and Roseman, Tarte, Harrow, and Shaffer Families’ President's Distinguished Professor at University of Pennsylvania, told Healio.. “The approach we have been undertaking is to first remove the most immunologically active cells against cancer from the patient’s blood and engineer them to be even better cancer fighters and then reinfuse these now energized cells back into the patients.”
Stadtmauer and colleagues obtained T cells from the blood of three patients — one with myxoid/round cell liposarcoma and two with multiple myeloma — and used CRISPR/Cas9 technology to remove three genes from the cells, including two T-cell receptors and PD-1. They then used a lentivirus to insert an affinity-enhanced T-cell receptor directing the edited cells to target the NY-ESO-1 antigen. The patients received the edited cells in a single infusion following a short chemotherapy course.
The CRISPR-edited cells expanded and survived in all three patients, an analysis of blood samples showed, and researchers observed no serious treatment-related adverse events.
Healio spoke with Stadtmauer about the findings, how this approach differs from chimeric antigen receptor T-cell therapy and the next steps for research.
Question: How was this study conducted, and why did you choose myeloma and sarcoma?
Answer: We modified the cells by inserting genetic material, as we would for any of the CAR T-cell therapies, to put an altered T-cell warhead on their surface that would then latch onto the tumor cells. We decided on the warhead based on what antigen is common in cancer but not in other parts of the body, so these cells focus on the cancer cells. In this case, the target was an antigen called NY-ESO-1, which is a cancer testis antigen that is uniquely expressed on certain cancer cells. We chose to target cancers with a high likelihood of having this antigen expressed. It seems to be most expressed in relapsed myeloma and in a subtype of sarcoma, and melanoma.
Q: What were the findings?
A: Given that this was the first use of CRISPR gene-edited cells to treat people with cancer, our primary goal was to demonstrate feasibility. The second goal was safety. We started with just three patients to see if we could manufacture the cells, infuse them and make sure it is safe and feasible. That’s exactly what we found with these patients. We infused these cells into the patients, and they remained at high levels there for up to 6 months.
Q: How is this different than CAR T-cell therapy?
A: For the last decade we have had the technology to insert these genes into cells. We have used a viral vector to infect T cells with genetic material that puts a primary antigen receptor warhead on their surface. This has been a very successful treatment for patients with acute lymphoblastic leukemia, non-Hodgkin lymphoma and multiple myeloma, for which we should soon have commercial CAR T cells available.
Despite these successes and high response rates, we still have patients treated with these CAR T cells who relapse or do not respond. CRISPR editing is an attempt to further enhance the activity of these cells. In addition to inserting the gene, we also used CRISPR to remove three other genes, two of which coded for the inherent T-cell receptor that’s on every T cell. The idea is that this will allow these cells to better target tumors, because there is no competition. It also removes the PD-1 gene, so these cells do not have any check on their proliferation and activity.
Q: What is next for research?
A: Once we demonstrate this approach is safe and feasible, we can treat more patients and assess the effectiveness of this for treating cancer. Even more importantly, this opens up the use of this technology for many different diseases and different cells that can be genetically modified.
One of the limitations of CAR T-cell activity is that because you are using the person’s own cells, you have to harvest them and manufacture them for several weeks. Patients who have serious diseases have difficulty being maintained during that time. If you could have an off-the-shelf product of cells that are available when a patient needs them, that could be a better way of doing this.
The problem with using someone else’s cells, however, is that they could be rejected by the patient’s body or cause unanticipated side effects. You could use the CRISPR technique to remove the genes on somebody else’s T cells that cause these side effects and manufacture bags of these cells and have them in storage for whenever a patient needs them. – by John DeRosier
Reference:
Stadtmauer EA, et al. Abstract 49. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
For more information:
Edward A. Stadtmauer , MD, can be reached at Perelman Center for Advanced Medicine, West Pavilion, 4th Floor, 3400 Civic Center Blvd., Philadelphia, PA 19104; email: stadtmae@uphs.upenn.edu.
Disclosures: Stadtmauer reports advisory/consultant roles with Amgen, Celgene, Janssen and Novartis and research funding from AbbVie, Novartis and Tmunity Therapeutics. Please see the abstract for all other authors’ relevant financial disclosures.