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Long-Term TIL Engraftment and Clonal Expansion After Multiple TIL and Anti-PD-1 Therapy: A Five-Year Immunogenomic Case Study

ABSTRACT: Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) can achieve durable responses in metastatic melanoma and other indications, but the long-term clonal dynamics after multiple administration and synergy with checkpoint blockade are still to be explored. We present a longitudinal case study of a prostate cancer patient treated with serial TIL infusions and delayed anti-PD-1 therapy, analyzed using high-throughput T-cell receptor (TCR) sequencing from serial blood and tumor samples over five years. TIL-derived clonotypes exhibited sustained persistence and clonal expansion in blood, with peaks corresponding to clinical response. Multiple TIL administration increased the patient exposure to the therapy, improving its pharmacokinetics profile over time. Notably, anti-PD-1 therapy administered six months post-first TIL administration further expanded both previously infused and novel TIL-derived clonotypes, coinciding with durable complete response. Serial tracking revealed stable levels of TIL-derived clonotypes up to five years post-treatment, with persistent tumor infiltration. T-cell clonotype expansion was associated with decreased TCR diversity and increased frequency of hyperexpanded clones, suggesting selective amplification of tumor-reactive populations. Our findings provide mechanistic insight into the long-term persistence and reactivation of TIL-derived immunity and illustrate the potent synergy between adoptive transfer and delayed PD-1 blockade, supporting the integration of longitudinal immunogenomic monitoring in personalized immunotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE295713 | GEO | 2025/12/04

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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Long-Term TIL Engraftment and Clonal Expansion After Multiple TIL and Anti-PD-1 Therapy: A Five-Year Immunogenomic Case Study

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