One-step gene-editing technique opens door to safe, effective off-the-shelf CAR T cells
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CRISPR may be the most notable name in the world of gene editing, but it’s not the only option.
One alternative is ARCUS (Precision Biosciences), which researchers at several centers are using to enhance the effectiveness of chimeric antigen receptor T-cell therapies for patients with relapsed or refractory non-Hodgkin lymphoma and B-cell acute lymphoblastic leukemia.
“The future is going to be in gene editing,” Bijal D. Shah, MD, associate professor in the department of malignant hematology at Moffitt Cancer Center, told Healio.
The ability to perform ex vivo gene editing on T cells has allowed researchers to manufacture targeted therapeutics, such as CAR T cells. It also provides the ability to augment the function of those cells, Shah said.
“We have that ability ... with CRISPR, and we have it with ARCUS,” he said.
The goal of applying novel gene-editing techniques to CAR T cells is to create off-the-shelf products developed from the cells of healthy donors rather than the heavily pretreated and potentially damaged cells used to create autologous therapies.
The result will be more effective CAR T-cell therapies for cancer that are ready as fast as a clinician can order them, Shah said.
CRISPR 2.0
ARCUS is a proprietary platform, so some details about how it differs from CRISPR are limited. However, its manufacturer describes it as a gene-editing platform focused on precision DNA edits rather than ease of design or fast turnaround.
“ARCUS nucleases have the potential to deliver safer, more specific genetic edits by leveraging the properties of a naturally occurring gene editing enzyme” that edits the DNA at a specific location, according to Precision Bioscience’s website.
“The best way to think about it is to imagine a more efficient form of CRISPR,” Shah said. “ARCUS, like CRISPR, can selectively drop a DNA message wherever you want to place it.”
The platforms diverge in the tool that is used to deliver information about where to cut and deliver the genetic payload, Shah said.
Another strength of ARCUS is its ability to deliver multiple payloads of genetic information compared with CRISPR, Shah said.
The platform allows researchers to make all alterations required in a gene-edited CAR T cell with the same tool — and all in one step. It allows them to do disrupt or knock out genes, and it also allows for the delivery of new genetic information, Shah said. The single-step gene editing allows for significant improvements in efficiency, he added.
“I jokingly call it CRISPR 2.0,” Shah told Healio. “The ability to carry this payload of genetic information [and] put it where you want it is a huge plus. Moving forward, this is not going to be restricted to CAR T-cell therapy.”
Early results
Shah is one of several researchers from multiple U.S. centers participating in a phase 1 dose-escalation study of PBCAR0191 (Precision BioSciences), an investigational allogeneic, CD19-directed CAR T-cell therapy.
PBCAR0191 is derived from healthy donor T cells and uses ARCUS gene editing to knock out the T-cell’s endogenous T-cell receptor to prevent graft-versus-host disease. Simultaneously, the gene-editing process inserts the “CAR expression cassette,” according to a preclinical proof-of-concept study published in Molecular Therapy.
The trial included cohorts of patients with relapsed or refractory B-cell ALL or NHL. Shah presented results from the NHL cohort at this year’s virtual ASCO Annual Meeting.
Results showed an 89% ORR among nine patients who received an enhanced, higher-dose lymphodepletion regimen before CAR T-cell therapy. Seven of those patients (78%) achieved a complete response to therapy by day 28 after infusion.
Five patients who received the ARCUS-edited CAR-T in the enhanced lymphodepletion group experienced cytokine release syndrome; however, researchers reported no cases of grade 3 or greater CRS in either treatment group, regardless of lymphodepletion regimen.
Additionally, no GVHD cases occurred in the NHL cohort.
Shah called the results “extraordinary,” adding that the response rates in the study were “parallel to what we see with the autologous CAR-T therapy in relapsing non-Hodgkin’s lymphoma.”
Shah said the therapy provides significant reductions in disease burden using a product that is ready for infusion into the patient within days.
“[They] have the ability to be delivered within a week of signing consent,” he told Healio. “We’ve taken a 6- to 8-week process down to a week.”
Looking forward
As with patients who received autologous CD19-directed CAR-T cells, many patients who received PBCAR0191 experienced disease progression within 3 months of therapy receipt, particularly those patients with high tumor burden. This likely reflects both T-cell and NK-cell recovery from the effects of lymphodepletion, leading to rapid elimination of the allogeneic CAR T cells.
This has fostered the testing and implementation of enhanced lymphodepletion strategies, including the use of higher doses of fludarabine and cytarabine. “With this approach, we see significant increases in expansion and lifespan of the CAR T cells, which underlies the improvements in response,” Shah said.
The utility of allogeneic CAR T cells is that they can serve as a fast and effective bridging strategy that increases the likelihood that the next line of therapy will be more effective and durable, Shah said. This could include the subsequent use of autologous CD19-directed CAR T cells or hematopoietic stem cell transplant.
“For me, [this] is the most efficient and easy bridge to an allogeneic transplant for a patient with relapsed leukemia that I can imagine,” he said.
Similarly, the ease of access and low toxicity could allow for allogeneic CAR T cells to be used to consolidate response to a prior treatment regimen.
Challenges regarding durability of remission are being met with the development of novel allogeneic CAR T cells — so-called “stealth cells” that may bypass endogenous T cell- and NK cell-mediated rejection, potentially allowing for less intensive lymphodepletion and a more persistently active product, according to Shah.
New techniques in gene editing — including ARCUS — have made this efficiency possible and produced a therapy that is faster, less toxic and highly effective in the months following infusion, Shah said. These characteristics lend themselves to becoming a highly appealing therapy, he added.
References:
Bijal S, et al. Abstract 7516. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
MacLeod DT, et al. Mol Ther. 2017;doi:10.1016/j.ymthe.2017.02.005.
For more information:
Bijal D. Shah, MD, MS, can be reached at Moffitt Cancer Center Magnolia Campus, 12902 USF Magnolia Drive, Tampa, FL 33612; email: bijal.shah@moffitt.org.
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