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E - Disease Models and Clinical Applications -> Cancer – Targeted Gene and Cell Therapy

847: Characterization of the Transcriptomic and T-Cell Receptor (TCR) Clonal Heterogeneity of Tumor-Infiltrating Lymphocyte (TIL) Therapy Infusion Products by Single-Cell Sequencing and Correlative Analyses With Clinical Efficacy in Patients with Advanced Cutaneous Melanoma

Type: Oral Abstract Session

Presentation Details
Session Title: Cell-based Cancer Immunotherapies II
Location: Salon G
Start Time: 5/18/2022 15:45
End Time: 5/18/2022 16:00

Introduction: Autologous TIL products made from tumor digests produced high clinical response rates (67% overall response rate; 19% complete responses) and a safety profile consistent with lymphodepletion and high-dose interleukin-2 in a retrospective analysis of a single-center compassionate use clinical series of 21 patients with advanced cutaneous melanoma (Hawkins RE, et al. Cancer Res. 2021;81[13 suppl]:LB150). Using single-cell and bulk sequencing techniques, this translational subanalysis characterizes TIL therapy infusion product composition, mediators of cell-cell interactions, TCR repertoire, and correlates these findings with clinical efficacy. Methods: Suitable patients underwent resection of ≥1 cm3 of tumor tissue for TIL production. Quantitative disease assessments were conducted and analyzed retrospectively per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 when feasible. TIL products were characterized using RNA-based bulk TCR sequencing and paired single-cell RNA and TCR sequencing techniques. TCR repertoire clonality was assessed using multiple metrics, including Gini coefficient. Descriptive statistical testing was performed using Wilcoxon test; P values were not adjusted for multiplicity. Results: As of December 31, 2019, 21 patients underwent treatment; data are reported for patients with assessable products (n=20 for RNA-based bulk TCR sequencing, and n=18 for paired single-cell RNA and TCR sequencing). Analysis of the single-cell RNA sequencing data identified several cell subpopulations with distinct transcriptional signatures previously undescribed in TIL products, including MX1+OAS1+ T cells, 2 subsets of mixed gamma/delta CD8+ T cells, and CD8+ regulatory T cells. The combined frequency of MX1+OAS1+ T cells and apoptotic CD8+ T cells was significantly lower among responders versus nonresponders (P=.0012). Transcriptional state of the MX1+OAS1+ TIL subpopulation may be maintained by the IRF7 transcription factor, as suggested by gene regulatory network analysis. Among all patients, analyses of molecules involved in cell-cell interaction identified potentially detrimental signaling interactions, including the TGFβ, galectin, Fas ligand, and MIF pathways, among different TIL product subpopulations. Analysis of the bulk TCR sequencing data suggested that higher clonality of TIL product TCR repertoire (α, β, γ, δ) was associated with response (all P≤.02). TIL products made from different patients shared little similarity in TCR repertoire, and overall, the majority of TCRs were previously undescribed. Joint analysis of the single-cell RNA and TCR sequencing data suggested that higher clonality was observed among EOMES+ TIL product subpopulations and that higher clonality among CD62L+ TIL product subpopulations was associated with response (P=.0012). Conclusions: This subanalysis characterized TIL therapy infusion products using single-cell and bulk sequencing techniques and may identify actionable TIL therapy improvements, which may improve outcomes for patients with advanced cutaneous melanoma. Collectively, these findings suggest that a significant fraction of the clonotypes contained in TIL infusion products are unique to each patient, highlighting a potential benefit of TIL therapy versus more targeted T-cell therapies. These hypothesis-generating data may identify TIL therapy improvement opportunities and potential response biomarkers that warrant further study.

Jinzhou Yuan, Gray Kueberuwa, Yizhou Jiang, Leyuan Bao, Michelle Le Brocq, Catherine Sharpe, John S. Bridgeman, Ryan D. Guest, Zachary J. Roberts, Robert E. Hawkins, Paul B. Robbins, Rubén Alvarez-Rodríguez

Instil Bio, Inc, Dallas, TX
  J. Yuan: 1; Commercial Interest i.e. Company X; Instil Bio, Inc.. 1; What was received? i.e. Honorarium; Employment and stock or other ownership. 1; For what role? i.e. Speaker; Employee.

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