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Cited by 24Pancreatic and Hepatic Oncology ResearchImmunotherapy and Immune ResponsesPancreatitis Pathology and Treatment

A Phase 2 Randomized Placebo-Controlled Adjuvant Trial of GI-4000, a Recombinant Yeast Expressing Mutated RAS Proteins in Patients with Resected Pancreas Cancer

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Muscarella, Peter, Bekaii-Saab, Tanios, McIntyre, Kristi, Rosemurgy, Alexander, Ross, Sharona B., Richards, Donald A., Fisher, William E., Flynn, Patrick J. +9 more·2021·Journal of Pancreatic Cancer
DOI 10.1089/pancan.2020.0021PMC PMC7997807
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Abstract

Purpose: GI-4000, a series of recombinant yeast expressing four different mutated RAS proteins, was evaluated in subjects with resected ras-mutated pancreas cancer. Methods: Subjects (n = 176) received GI-4000 or placebo plus gemcitabine. Subjects' tumors were genotyped to identify which matched GI-4000 product to administer. Immune responses were measured by interferon-γ (IFNγ) ELISpot assay and by regulatory T cell (Treg) frequencies on treatment. Pretreatment plasma was retrospectively analyzed by matrix-assisted laser desorption/ionization-time-of-flight (MALDI-ToF) mass spectrometry for proteomic signatures predictive of GI-4000 responsiveness. Results: GI-4000 was well tolerated, with comparable safety findings between treatment groups. The GI-4000 group showed a similar pattern of median recurrence-free and overall survival (OS) compared with placebo. For the prospectively defined and stratified R1 resection subgroup, there was a trend in 1 year OS (72% vs. 56%), an improvement in OS (523.5 vs. 443.5 days [hazard ratio (HR) = 1.06 [confidence interval (CI): 0.53–2.13], p = 0.872), and increased frequency of immune responders (40% vs. 8%; p = 0.062) for GI-4000 versus placebo and a 159-day improvement in OS for R1 GI-4000 immune responders versus placebo (p = 0.810). For R0 resection subjects, no increases in IFNγ responses in GI-4000–treated subjects were observed. A higher frequency of R0/R1 subjects with a reduction in Tregs (CD4+/CD45RA+/Foxp3low) was observed in GI-4000–treated subjects versus placebo (p = 0.033). A proteomic signature was identified that predicted response to GI-4000/gemcitabine regardless of resection status. Conclusion: These results justify continued investigation of GI-4000 in studies stratified for likely responders or in combination with immune check-point inhibitors or other immunomodulators, which may provide optimal reactivation of antitumor immunity. ClinicalTrials.gov Number: NCT00300950.

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  • These vaccines are designed to induce antigen-presenting cells to display mutant KRAS, stimulating attacks by cytotoxic T-cells against cancer cells expressing mutant KRAS neoantigen.

    “These vaccines are designed to induce antigen-presenting cells to display mutant KRAS, stimulating attacks by cytotoxic T-cells against cancer cells expressing mutant KRAS neoantigen [78,79,80].”

    From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [78]

  • Vaccination can train the immune system to attack cells expressing mutant KRAS.

    “Vaccination can train the immune system to attack cells expressing mutant KRAS.”

    From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [78]

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Authors
Muscarella, P., Bekaii-Saab, T., McIntyre, K., Rosemurgy, A., Ross, S. B., Richards, D. A., Fisher, W. E., Flynn, P. J., Mattson, A., Coeshott, C., Roder, H., Roder, J., Harrell, F. E., Cohn, A., Rodell, T. C., Apelian, D., & for the GI-4000 in Pancreas Cancer Study Group
Affiliations
  • The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
  • Mayo Clinic Cancer Center, Phoenix, Arizona, USA.
  • Texas Oncology, US Oncology Research, Dallas, Texas, USA.
  • AdventHealth Tampa (US)
  • Texas Oncology (US)
  • Baylor College of Medicine (US)
  • Minnesota Oncology (US)
  • Smuggler Mountain Group (SMG, Inc.), Aspen, Colorado, USA.
  • Biodesix, Inc., Boulder, Colorado, USA.
  • Vanderbilt University (US)
  • Rocky Mountain Cancer Centers (US)
Corresponding author
Rodell, Timothy C.
ORCID
Venue
Journal of Pancreatic Cancer
Publisher
SAGE Publications
Published
2021-03-01
Volume
7
Issue
1
Pages
8-19
ISSN
2475-3246 (ISSN-L)
DOI
10.1089/pancan.2020.0021
PMC
PMC7997807
OpenAlex
W3137688201
Cited by
24
References
42
Citations by year
2026: 4 · 2025: 7 · 2024: 5 · 2023: 4 · 2022: 4
FWCI
1.18
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Pancreatic Cancer (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Topics
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
Keywords
recombinant yeast, RAS mutations, pancreatic cancer, adjuvant therapy, gemcitabine, interferon-gamma, regulatory T cells, tumor-infiltrating lymphocytes, R1 resection, R0 resection, recurrence-free survival, overall survival, immune checkpoint inhibitors, cancer immunotherapy

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