Adaptimmune cell therapy shows ‘persistent anti-tumor effects’

Adaptimmune Therapeutics (ADAP) announced that data from the pilot study of NY-ESO SPEAR T-cells in synovial sarcoma will be published in Cancer Discovery. GlaxoSmithKline (GSK) exercised its option to exclusively license the right to research, develop, and commercialize NY-ESO SPEAR T-cell therapy program in September 2017. Transition of this program to GSK is ongoing. Median duration of response of 30.9 weeks, overall response rate of 50%, and 60% among the ten patients who received the target dose of at least one billion transduced cells, there was one confirmed complete response and five confirmed partial responses, median time to initial response of 6.2 weeks. Median progression-free survival was 15 weeks, the current estimate of the median overall survival is approximately 120 weeks among the twelve patients in Cohort 1. Maximal effects of chemotherapy are typically observed within four weeks of treatment; however, seven patients experienced continued decreases in tumor burden following the four week evaluation point, and maximal antitumor responses occurred in four patients more than three months post-infusion, there was also demonstration of transient increases in the size of metastatic lesions consistent with lymphocyte-induced inflammation followed by regression as well as trafficking of SPEAR T-cells into the tumor bed, indicating that, unlike currently available immune therapies, these cells can kill cancer cells in previously non-inflamed tumors. The majority of adverse events were consistent with those typically experienced by cancer patients undergoing cytotoxic chemotherapy or other cancer immunotherapies, there were no fatal serious adverse events in this treatment cohort, the most common adverse events greater than or equal to grade 3 were lymphopenia, leukopenia, neutropenia, anemia, hypophosphatemia, and thrombocytopenia, five patients experienced cytokine release syndrome of grades 1, 2, and 3, CRS occurred within a median of four days post-infusion and the median duration of CRS was ten days. Another safety assessment was monitoring for lentivirus that is used for gene transfer during manufacturing. Polymerase chain reaction was performed and all patients were found to be negative for replication-competent lentivirus. Clonality assessment was carried out to exclude insertional oncogenesis as a mechanism for persistence, and all analyzed samples showed high levels of SPEAR T-cell polyclonality with the absence of dominant clones indicating that oncogenesis is not a mechanism of persistence. SPEAR T-cells were detectable in all patients following infusion, with peak levels measured within the first ten days. Peak NY-ESO vector copy levels were statistically significantly higher in responders compared to non-responders. Among seven patients for whom monitoring continued beyond 200 days, circulating SPEAR T-cells were readily detectable. Persisting pools comprised largely central memory and stem cell memory subsets that remained virtually negative for exhaustion markers such as PD-1 and LAG-3 for the duration of the analysis period. CD8+ SPEAR T-cells were isolated from the pre-infusion product and at post-infusion time points, and analyzed for cytokine production in an in vitro assay with NY-ESO expressing target cells; cytokine staining showed production of various cytokines by SPEAR T-cells in vitro indicating that SPEAR T-cells are polyfunctional both pre- and post-infusion SPEAR T-cells from patient 202 were isolated and placed in an in vitro killing assay 28 months after infusion and found to kill NY-ESO expressing target cells without addition of exogenous cytokines.

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