Genetic Engineering & Biotechnology News

JUL 2018

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26 | JULY 2018 | Genetic Engineering & Biotechnology News | They obliged their developers to stretch their own capabili- ties while staying in touch with the latest research findings. Nonetheless, Yescarta and Kymriah, both of which are FDA- approved immunotherapies, are limited to treating hemato- logical tumors, or "liquid" tumors—as are many of the CAR T-cell therapies currently in development. Such therapies spare developers the arduous climbing that awaits those who would position CAR T-cell therapies to engage solid tumors. CAR T cells have difficulty grappling with solid tumors several reasons: CAR T cells may search in vain for a unique tumor-associated antigen; they may expire, fail to prolifer- ate, or simply languish, dawdling rather than converging on tumor sites; they may struggle to cope with tumor cell heterogeneity and antigen loss; or they may succumb to the immunosuppressive and metabolically hostile tumor micro- environment. How might CAR T cells overcome these difficulties? That question was asked repeatedly, in different contexts, by members of the cell therapy community who participated in the CAR-T Congress: Maximizing the Potential of CAR-T Therapy. At this event, provisional answers included novel infusion strategies, improved targeting and control of CAR T cells, the adoption of alternative receptor technologies, and the generation of alternative CAR-carrying cells. The most interesting suggestions from this event are sum- marized in this article. As varied as these suggestions are, they all aim to combine two powers: the power of an anti- body to recognize its specific antigen, and the power of a T cell to deliver a vigorous immune response. Addressing Logistical Challenges "CAR T-cell therapy has proven to be very effective with- in the context of liquid tumors," said Sadik Kassim, Ph.D., vice president, process and analytical development, Mustang Bio. "But the major challenge in the field has been getting the clinical response to a CAR T-cell therapy within a solid tumor setting." In his CAR-T Congress presentation, Dr. Kassim drew on lessons from Mustang Bio's collaboration with the City of Hope Beckman Research Institute and Medical Center. Specifically, he referenced a recent study led by the City of Hope's Stephen J. Forman, M.D., and Behnam Badie, M.D. The study, which appeared in the New England Journal of Medicine, suggested that while a leukemia or lymphoma may be impacted by a single systemic infusion of tumor- specific CAR T cells, solid tumors may require multiple, regional infusions. To flesh out this notion, City of Hope investigators described a novel administration approach against multifocal glioblastoma, one of the most lethal can- cers. Multifocal glioblastoma has a five-year survival of about 5%—due in part to the brain's sequestration behind the blood-brain barrier. After tumor resection, CAR T cells specific for the inter- leukin-13 receptor α chain variant 2 (IL13Rα2) were infused weekly directly into the cavity created by removal of the primary tumor. Subsequently, the therapy was administered weekly into the cerebral ventricles, which allowed systemic distribution within the nervous system. "Even though they administered at a certain location, they observed a regression of the tumor at a distal site, in the spinal cord," noted Dr. Kassim. "The point is, within the context of solid tumors, the trafficking of the CAR T cells is probably going to be important. One aspect of that is the route of administration." If single-infusion protocols are inadequate against solid tumors, monotherapies may be insufficient as well. Treat- ment may require a checkpoint antibody, for example, or something to promote inflammation. Preconditioning regi- mens have yet to be optimized. "What will it take for the CAR T cell, post infusion, to really take and start expand- ing," asked Dr. Kassim, "and what would give the cells room? Those protocols are still being investigated." Targeting Liquid and Solid Tumors Finding (and hitting) the right target can be difficult. "The antigens that are present in solid tumors are usually expressed in other tissues of the body, or there is great het- erogeneity," said Peggy Sotiropoulou, Ph.D., R&D manager, Celyad. "Consequently, the antigens are not expressed in all the tumor cells." She added that tumors that do express the antigens may reside in an immunosuppressive microenviron- CAR T Cells Show Solid Progress Josh P. Roberts The lowest-hanging fruits of chimeric antigen receptor (CAR) T-cell therapy are already being plucked. Yet even these fruits, which include Kite Pharma's Yescarta and Novartis' Kymriah, cannot be described as easy pickings. Translational Medicine Special Issue: Human Gene Therapy—Chimeric Antigen Receptor (CAR)-Modified T Cells: Beyond Inspired Outcomes The May issue of Human Gene Therapy is focused on CAR T-cell research and therapies. The issue's editorial ("Driving CARs across New Borders") notes the following: "Undoubtedly, the explosiveness of CAR potential holds promise for diverse scientific disciplines, as different specialties bring expertise that can further advance this immunotherapy. For example, while T cells are an obvious choice for CAR engineering, other cell lineages have attributes that might be advantageous for the treatment of distinct patient populations. "Harrer et al. review efforts to extend the CAR paradigm by engineering subsets such as natural killer, natural killer T, myeloid, and hematopoietic stem cells. "The new generation of effective cellular immunotherapy is upon us. Despite recent remarkable successes, we still have much to do to develop immunotherapy to its full potential." n The special May issue containing ten full access articles, including the editorial, can be found at: CAR Engineering—It's Not Just for T Cells

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