1. Jenks, Susan

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A novel "switchable" CAR T-cell therapy for blood cancers moved into early clinical trials recently after gaining Fast Track designation from the FDA. The organization approved the investigational therapy's use in a Phase I study for the treatment of patients with relapsed or refractory B-cell malignancies, including non-Hodgkin's lymphoma and chronic lymphocytic leukemia. Preclinical studies have shown better control and versatility in targeting these cancers, while also mitigating dangerous side effects, such as cytokine release syndrome, when the immune system overreacts to these genetically engineered immune system cells.

CAR T-Cell Therapy. ... - Click to enlarge in new windowCAR T-Cell Therapy. CAR T-Cell Therapy

"Our approach is very different from traditional CAR-T therapy," said Travis Young, PhD, Vice President of Biologics and leader of the CAR-T program at the California Institute for Biomedical Research (Calibr), a translational research arm of the Scripps Research Institute.


"Our CAR-T cells have no specificity for any endogneous human target," a platform design that potentially enables investigators to target well-known cancer antigens and newly discovered ones, Young noted, rather than just a single target at a time.


For the research now underway, however, all of the patients will be positive for CD19, a common biomarker in many, but not all, B-cell malignancies and the dominant target of at least three FDA-approved drugs on the market.


According to Young, the "ballpark goal" for Calibr's study is to enroll about 36 patients across five centers in the United States, including the University of California, San Diego and the City of Hope in Los Angeles, among others. No numbers were availabe yet for how many patients have been enrolled in the study.


In the dual-component therapy, Young said patients first receive their own altered T cells, then the switchable antibody, which forms a bridge to the CD19 positive target cells. While the cells serve as the system's hardware, he likens the switchable antibody-an adapter molecule-to software, which can be programmed to wherever they're needed, as tumors evolve.


That capability, Young suggests, might prove useful to treating solid tumors in the future, which generally tend to be more immunosuppressive than blood cancers and the microenvironments inside them more complex. It also might broaden the donor pool to include donor T cells, expanding the therapy to far more patients. "There's no reason to expect that our concept wouldn't work the same way with allogeneic cells," Young said.


Maksim Mamonkin, PhD, Assistant Professor at the Center for Cell and Gene Therapy at Baylor College of Medicine, described this research approach as "very attractive" in the adoptive cell therapy field. Not only is the concept of controlling the specificity of the adopted transferred cells "on the fly" an appealing one, he said, but making the activity of CAR-T cells contingent on the presence of a switchable antibody could allow "at least some control over the duration and magnitude of the on-target activity," which is important to protecting healthy tissues.


While this clinical study wil help answer many questions in the field, Mamonkin said a number of specific issues first need to be resolved.


* Will the local and systemic concentrations of the switchable antibody be sufficient to produce robust and durable anti-tumor responses?


* Will the expansion and persistence of the switchable CAR-T therapy improve on "hardwired" recognition of specific tumor targets in conventional CAR-T therapy?


* How immunogenic is this system, particularly the modified antibody?



Meanwhile, the FDA's Fast Track designation does not necessarily translate into quicker development of the Calibr product.


"It's a great validation that the agency understands the therapy and our platform," Young said. But, primarily the designation carries with it a closer interaction with the federal agency on the study design and patient safety, as testing moves along in the months ahead, he concluded.


Susan Jenks is a contributing writer.


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