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Overcoming resistance to programmed cell death protein 1 (PD-1) blockade with allogeneic invariant natural killer T-cells (iNKT)

Oncogene volume 43, pages 758–762 (2024)Cite this article

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Abstract

Gastric cancer is the 5th most common malignancy worldwide with only 36% of patients with metastatic disease surviving beyond 5 years. Despite therapeutic improvements with the advent of immune checkpoint inhibitors, most patients with gastric cancer develop disease progression related to tumor resistance. Novel immunotherapeutic approaches, including invariant natural killer (iNKT) cells, are in clinical development and represent potential therapeutic options to overcome resistance. AgenT-797 is an allogeneic human unmodified iNKT derived from healthy donors. Activation of iNKT cells by tumor lipid antigens can trigger direct cytotoxicity and promote indirect anti-tumor immune responses such as recruitment and activation of T cells, NK cells, and dendritic cells through secretion of cytokines and IFNγ. We describe immune modulation leading to durable tumor response in a patient with microsatellite instability-high (MSI-H) advanced gastric adenocarcinoma treated with agent-797 after progression on standard chemotherapy and anti-PD-1 therapy.

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Fig. 1
Fig. 2: Genomic and imaging analysis of tumor biopsies.
Fig. 3: RNAseq gene expression analysis of screening and on-treatment (D15) tumor biopsies.

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Authors and Affiliations

  1. Legorreta Cancer Center at Brown University, Lifespan Cancer Institute, Providence, RI, USA

    Matthew J. Hadfield, Howard Safran & Benedito A. Carneiro

  2. Agenus, Inc, Lexington, MA, USA

    Marco A. Purbhoo, Joseph E. Grossman & Jennifer S. Buell

Authors
  1. Matthew J. Hadfield
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  2. Howard Safran
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  3. Marco A. Purbhoo
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  4. Joseph E. Grossman
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  5. Jennifer S. Buell
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  6. Benedito A. Carneiro
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Contributions

MJH, MAP, and BAC were responsible for writing the report, extracting and analyzing data, interpreting results, and updating reference lists. HS, JEG, and JSB contributed to the design and writing of the report, interpreted the results, and provided feedback on the manuscript.

Corresponding author

Correspondence to Benedito A. Carneiro.

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Competing interests

MJH, HS: No conflicts of interest. MAP, JEG, JSB: Employee and stockholder of Agenus. BC: Institutional support for clinical trial from Mink Therapeutics.

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Hadfield, M.J., Safran, H., Purbhoo, M.A. et al. Overcoming resistance to programmed cell death protein 1 (PD-1) blockade with allogeneic invariant natural killer T-cells (iNKT). Oncogene 43, 758–762 (2024). https://doi.org/10.1038/s41388-024-02948-y

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  • DOI: https://doi.org/10.1038/s41388-024-02948-y

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