Characterization of dynamic changes in tumor-infiltrating lymphocytes (TIL) after neoadjuvant administration of CUE-101, an HPV16 E7-HLA-IL2 fusion protein, to patients with HPV+ locally advanced oropharyngeal squamous cell carcinoma (LA-OPSCC).
Year: 2025
Type: conference-abstract
Abstract: 6055 Background: CUE-101 is a novel fusion protein designed to selectively engage and expand HPV16-specific T-cells to promote an anti-tumor immune response in HPV+ malignancies. CUE-101 is comprised of the HPV16 E7 11-20 epitope, HLA-A*0201, and a reduced affinity human IL2. In this single-arm Phase 2 trial (NCT04852328), CUE-101 is administered to HLA-A*0201+ patients with HPV16+ LA-OPSCC in three schedules (A, B, and C) before curative-intent surgery and adjuvant therapy or definitive chemoradiation therapy. Primary endpoints were safety of CUE-101 and changes in the frequency of HPV16 E7 11-20 -specific CD8+ T cells in blood and tumor. Correlates in TIL for Schedules A and B are presented here. Methods: CUE-101 (4 mg/kg IV) was administered 14 days (Schedule A), 14 and 7 days (Schedule B), or 7 days (Schedule C) before curative-intent treatment. Biopsies of the primary tumor were collected before CUE-101 administration and within 2 days prior to curative-intent therapy. Single-cell RNA and T-cell receptor (TCR) sequencing (scRNAseq, 10X Genomics) was performed on fresh sorted CD8 T-cells. HPV16 E7 11-20 dextramer staining and flow cytometry assessed reactivity to HPV E7. Multiplex immunofluorescent (mIF) tissue staining with a 30-marker Phenocycler panel (Akoya Biosciences) assessed tumor, myeloid, and T-cell states. Changes in T-cell clonal frequency were significant if fold change >2 and fisher exact test adjusted p <0.05. Changes in cell populations after treatment were evaluated by two-tailed paired student’s t-test. Results: Of 20 total patients enrolled, paired biopsies from 13 of sufficient quality were analyzed by scRNAseq, flow cytometry, and mIF. In a joint analysis of Schedules A (n=7) and B (n=6), we identified multiple T-cell clones that significantly expanded following CUE-101 treatment, representing 4-51% (mean 18.3%) of tumor-infiltrating CD8 cells by scRNAseq. Among these, we found significant enrichment for phenotypes of chronic T cell activation (PD1+CD39+, often associated with tumor reactivity, p =0.041). In agreement with this finding, flow cytometry of TIL showed increased CD8+CD39+ cells (mean 10.9%, p =0.026) among CD45 cells, and a small increase in NK cells (1.7%, p =0.005). Absolute cell counts by mIF confirmed these trends. Direct dextramer staining of TIL samples has not specifically identified HPV E7 11-20 reactive T cells pre- or post-treatment, therefore cloning of TCRs from expanded T-cells is being performed to enable functional testing of HPV reactivity. Conclusions: Significant clonal expansion of intra-tumoral CD8 T-cells with signatures associated with tumor reactivity were observed within 2 weeks of CUE-101 administration in HPV16+ LA OPSCC. Studies in blood and of T-cell specificities are ongoing. Clinical trial information: NCT04852328 .
Source: Journal of Clinical Oncology
Authors: Jesse M Zaretsky, Riley Mullins, Thomas F. Barrett, Peter John Oppelt, Jessica C. Ley, Emily Stoller, Porter Bischoff, Ryan Jackson, Patrik Pipkorn, Richard A. Harbison, Wade Thorstad, Nikhil Rammohan, Jennifer F. De Los Santos, Michael Moravan, Anthony J. Apicelli, Steven N. Quayle, Matteo Levisetti, Anish Suri, Douglas Adkins, Sidharth Puram
Institution: Washington University in St. Louis
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4410804916