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Gene Expression of Human Lymphocytes Used For ACT of Metastatic Melanoma

ABSTRACT: 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE6592 | GEO | 2007/12/15

SECONDARY ACCESSION(S): PRJNA98905

REPOSITORIES: GEO

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Project description:The optimal T cell attributes for the adoptive immunotherapy of cancer and viral diseases are currently unclear. Recent adoptive transfer clinical trials using ex vivo expanded tumor infiltrating lymphocytes has provided evidence that differentiated effector T cells can mediate durable responses in selected cancer patients. The capacity of these transferred cells to persist in the host was found to strongly correlate with their clinical activity. Thus, there is significant interest in identifying intrinsic markers that define antigen specific effector T cells that can develop into long-lived memory cells rather than undergoing apoptosis after infusion in humans. We recently reported the long term persistence of ex vivo expanded tumor specific CD8+ T effector clones in refractory metastatic melanoma patients after adoptive T cell transfer. By utilizing these highly homogeneous clone populations, we sought to define the pre-infusion cellular and molecular attributes associated with their effector to memory transition. Comparative transcriptional profiling found the pre-infusion clone mRNA expression levels of the IL-7 receptor (IL-7Ra) and the proto-oncogene, c-myc, directly correlated with the level of clonal persistence after adoptive transfer in humans. The predictive value of these markers was further established by utilizing IL-7R protein, induced pSTAT5, and c-myc mRNA expression to prospectively identify human tumor specific effector clones that could engraft after controlled adoptive transfer into highly immunodeficient mice. These findings support that IL-7R and c-myc expression are valuable cell intrinsic markers that can predict the fate of effector CD8+ T cells after adoptive transfer. We used microarrays to compare the pre-infusion gene expression profile of melanoma-specific CD8+ T cell clones that would eventually either persist or not after adoptive transfer in humans. We derived ten melanoma-specific CD8+ T cell clones and determined their degree of persistence after adoptive therapy into patients. We performed microarray on the pre-infusion samples of six persisting and four non-persisting clones to obtain a comparative gene signature profile.

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Gene Expression of Human Lymphocytes Used For ACT of Metastatic Melanoma

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