Enhanced melanoma-specific cytotoxic T-cell expansion and the clinical outcomes with simlukafusp alfa and pembrolizumab following checkpoint inhibitor progression
9 affiliations
- 1Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
- 2Roche Holdings Inc, South San Francisco, California, USA
- 3Oncology Biomarker Development, Genentech Inc, South San Francisco, California, USA
- 4Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany
- 5Department of Biostatistics, F Hoffmann-La Roche Ltd, Basel, Switzerland
- 6Oncology Department, Vall d’Hebron University Hospital, Barcelona, Spain
- 7Vall d’Hebron Institut d’Oncologia, Barcelona, Spain
- 8Department of General Medical Oncology Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
- 9Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland
Abstract
Background: Despite advances in checkpoint inhibitor (CPI) therapy, a substantial proportion of patients with advanced melanoma experience disease progression, and the capacity of CD8+ cytotoxic T lymphocytes (CTLs) specific for wild-type melanoma-associated antigens to persist and remain functionally inducible after CPI failure is poorly understood. Here we report exploratory translational analyses from the BP41054 Phase I trial investigating the combination of simlukafusp alfa (FAP-IL2v), a tumor stroma-targeted IL-2 variant, with pembrolizumab in CPI-experienced patients with advanced melanoma.
Methods
Peripheral blood mononuclear cells from a subset of 33 CPI-experienced patients were profiled at baseline (C1D1_pre) and on treatment (C2D8) using quantitative immunophenotyping and a panel of 28 melanoma-associated peptide–HLA tetramers spanning 14 antigens and multiple HLA alleles. Antigen-specific CTLs were further characterized functionally by ex vivo peptide challenge and interferon (IFN)-γ intracellular staining. Associations with progression-free survival (PFS) were assessed as exploratory endpoints.
Results: Treatment was associated with increased circulating natural killer cells and CD8+ T cells, including effector memory and terminally differentiated effector subsets, as assessed in peripheral blood. CTLs specific for 11 unique peptide-major histocompatibility complexes were identified, with increased frequencies detected during treatment in a subset of patients. These antigen-specific CTLs demonstrated functional activity as indicated by IFN-γ production on peptide challenge, though responses were variable across peptide specificities and patients, and direct cytotoxic activity was not assessed. Signs of incomplete functional rescue, including persistent co-expression of exhaustion markers, were observed. In exploratory descriptive analyses, patients whose antigen-specific CTL diversity increased on treatment had a longer median PFS than those in whom diversity was reduced; with three patients per group, these outcomes are reported descriptively, without formal statistical comparison. Baseline melanoma-associated immunity did not predict clinical outcome.
Conclusions: These hypothesis-generating findings indicate that melanoma-specific CD8+ T-cell immunity persists and remains inducible in CPI-experienced patients, supporting the rationale for strategies that re-engage residual antitumor immunity. Validation in larger cohorts with paired tumor and blood sampling will be required to establish clinical relevance.
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BibTeX
@article{junker2026enhanced,
title = {{Enhanced melanoma-specific cytotoxic T-cell expansion and the clinical outcomes with simlukafusp alfa and pembrolizumab following checkpoint inhibitor progression}},
author = {Fabian Junker and Martine Darwish and Mahesh Yadav and Christin Habigt and Tobias Bergauer and David Dejardin and José Duarte and Eva Muñoz-Couselo and Oliver Bechter and Volker Teichgräber and Nino Keshelava and Anton Kraxner and Jehad Charo},
journal = {Journal for Immunotherapy of Cancer},
year = {2026},
month = nov,
doi = {10.1136/jitc-2026-015065},
url = {https://doi.org/10.1136/jitc-2026-015065},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Enhanced melanoma-specific cytotoxic T-cell expansion and the clinical outcomes with simlukafusp alfa and pembrolizumab following checkpoint inhibitor progression
AU - Fabian Junker
AU - Martine Darwish
AU - Mahesh Yadav
AU - Christin Habigt
AU - Tobias Bergauer
AU - David Dejardin
AU - José Duarte
AU - Eva Muñoz-Couselo
AU - Oliver Bechter
AU - Volker Teichgräber
AU - Nino Keshelava
AU - Anton Kraxner
AU - Jehad Charo
PY - 2026
DA - 2026/11/02
JO - Journal for Immunotherapy of Cancer
DO - 10.1136/jitc-2026-015065
UR - https://doi.org/10.1136/jitc-2026-015065
AB - Background: Despite advances in checkpoint inhibitor (CPI) therapy, a substantial proportion of patients with advanced melanoma experience disease progression, and the capacity of CD8+ cytotoxic T lymphocytes (CTLs) specific for wild-type melanoma-associated antigens to persist and remain functionally inducible after CPI failure is poorly understood. Here we report exploratory translational analyses from the BP41054 Phase I trial investigating the combination of simlukafusp alfa (FAP-IL2v), a tumor stroma-targeted IL-2 variant, with pembrolizumab in CPI-experienced patients with advanced melanoma. Methods Peripheral blood mononuclear cells from a subset of 33 CPI-experienced patients were profiled at baseline (C1D1_pre) and on treatment (C2D8) using quantitative immunophenotyping and a panel of 28 melanoma-associated peptide–HLA tetramers spanning 14 antigens and multiple HLA alleles. Antigen-specific CTLs were further characterized functionally by ex vivo peptide challenge and interferon (IFN)-γ intracellular staining. Associations with progression-free survival (PFS) were assessed as exploratory endpoints. Results: Treatment was associated with increased circulating natural killer cells and CD8+ T cells, including effector memory and terminally differentiated effector subsets, as assessed in peripheral blood. CTLs specific for 11 unique peptide-major histocompatibility complexes were identified, with increased frequencies detected during treatment in a subset of patients. These antigen-specific CTLs demonstrated functional activity as indicated by IFN-γ production on peptide challenge, though responses were variable across peptide specificities and patients, and direct cytotoxic activity was not assessed. Signs of incomplete functional rescue, including persistent co-expression of exhaustion markers, were observed. In exploratory descriptive analyses, patients whose antigen-specific CTL diversity increased on treatment had a longer median PFS than those in whom diversity was reduced; with three patients per group, these outcomes are reported descriptively, without formal statistical comparison. Baseline melanoma-associated immunity did not predict clinical outcome. Conclusions: These hypothesis-generating findings indicate that melanoma-specific CD8+ T-cell immunity persists and remains inducible in CPI-experienced patients, supporting the rationale for strategies that re-engage residual antitumor immunity. Validation in larger cohorts with paired tumor and blood sampling will be required to establish clinical relevance.
SN - 2051-1426
ER -