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CAR T-Cell Therapy Shows Signs of Anti-Tumor Activity in Pediatric Neuroblastoma Patients

NEW YORK – A handful of pediatric patients with relapsed or refractory neuroblastoma have shown signs of responding to autologous CAR T-cell therapy directed at GD2, according to a paper published Wednesday in Science Translational Medicine.

The GD2 directed therapy evaluated in the present Phase I trial sponsored by Cancer Research UK is also under development at UK-based Autolus Therapeutics. In this small study, researchers evaluated the feasibility — as well as the safety, tolerability, and recommended Phase II dose — of the treatment they referred to as 1RG-CART.

The autologous cell-based therapy involves harvesting patients' T cells and modifying them to target GD2, a marker commonly expressed on neuroblastomas, before infusing them back into the patient. The product was successfully manufactured for all 17 pediatric cancer patients initially enrolled in the trial, even though five patients could not receive the treatment due to disease progression. The remaining 12 patients were treated in separate cohorts defined by dose escalation and the intensity of the lymphodepleting regimen they received before getting CAR T-cell treatment.

None of the patients met the standard criteria for achieving an objective response. Among the six patients who received a higher dose of CAR T cells, the investigators noted signs of clinical activity, such as the regression of soft tissue and bone marrow disease. However, these responses were heterogenous, the researchers noted, with only some tumor regions shrinking or disappearing after CAR T-cell treatment, but others not.

"Given the patchy and transient nature of antitumor activity that we observed, modifications to enhance T cell persistence systemically, but particularly within the tumor, will likely be required to induce sustained and complete responses," wrote the study authors led by Karin Straathof of UCL Great Ormond Street Institute of Child Health in the UK.

Heading into the study, the investigators noted that neurotoxicity was a key safety concern since GD2 is commonly expressed not only on neuroblastomas, but also on healthy cells in the brain and pain fibers. Moreover, GD2 monoclonal antibody therapy has been associated with neurotoxicity. That said, the "second-generation" GD2-directed CAR T cells used in this clinical trial included a co-expressed "suicide-gene" that could be targeted with rituximab (Pfizer's Ruxience) to effectively delete the 1RG-CART therapy should the patient experience severe toxicities.

While patients did experience other toxicities, they were manageable, and none were due to the treatments attacking healthy, GD2-expressing cells.

While the researchers acknowledged that further improvements to this treatment will be necessary to achieve objective and complete responses, they concluded, "the evidence that we present indicates the capacity for GD2-directed CAR-T cells to enter the solid tumor environment, expand with associated but manageable cytokine release syndrome, and induce local tumor necrosis without off-target toxicity."