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Adoptive cell therapy using cultured tumor infiltrating lymphocytes for Japanese patients with refractory melanoma

ABSTRACT: Three patients who failed immune-checkpoint inhibitors were treated with the adoptive cell therapy using ex vivo cultured tumor infiltrating lymphocytes (TIL-ACT), which was composed of preparation of TIL culture, lympho-depleting non-myeloablative preconditioning, TIL infusion, and following relatively low dose intravenous IL-2 administration. Then we evaluated treatment feasibility, safety and clinical response. To further investigate the relationship between the tumor microenvironment and the patient's clinical course, we performed gene expression analysis of the pre-treatment tumor cells and immunohistochemistry of the tumor tissue focusing on delineating the immune components and immunologic milieu within the tumor. Together with the results of genomic and immunological analysis of ex vivo cultured TILs by flowcytometry and quantitative real-time polymerase chain reaction, we considered the various immunostimulating or immunosupprrsive factors giving influence on the effects of the conducted TIL-ACT.

ORGANISM(S): Homo sapiens

PROVIDER: GSE155389 | GEO | 2021/08/18

REPOSITORIES: GEO

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Project description:Recent reports have detailed the efficacy of the adoptive cell transfer (ACT) of autologous anti-tumor lymphocytes for the treatment of patients with melanoma refractory to standard therapy. Here we report the microarray analysis of tumor infiltrating lymphocytes (TIL) generated from twenty-eight melanoma patients enrolled in a treatment protocol that combines non-myeloablative lymphodepletion followed by adoptive cell transfer. The patients were divided into two groups Ÿ twelve who experienced an objective response according to RECIST criteria and sixteen who did not. Using several methods of data analysis, no consistent overt changes in gene expression, pathways or classical markers of lymphocyte development were detected between TIL administered to responding versus non-responding patients. Only one non Y chromosome gene, phosphoserine phophatase-like (PSPHL), was found to be over expressed primarily in lymphocytes that did not result in tumor regression and seemed to negatively correlate with in vivo survival of transferred TIL. As persistence of lymphocyte clonotypes in vivo was correlated with patient response, cyro-preserved treatment TIL cultures were bead-separated into in vivo persisting and non-persisting fractions. Subsequent microarray analysis of these persisting and non-persisting clonotypes also did not reveal any consistent differences in gene expression. Finally, to determine if the lymphocytes used in our adoptive cell transfer studies had similar gene expression profiles, the twenty-eight TIL samples were compared to 10 samples generated through limiting dilution cloning from an early ACT trial. This analysis revealed differences in the gene expression of lymphocytes that have been used in these two different ACT trials. However, the inability to find differential gene expression in tumor infiltrating lymphocytes that correlate to patient response or persistence suggests that differences affecting these clinical events lie in host or tumor factors rather than transferred cells. Keywords: cell type comparison design

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Adoptive cell therapy using cultured tumor infiltrating lymphocytes for Japanese patients with refractory melanoma

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