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.
Highlights
Mutations in the ras oncogene occur in conserved locations, codons 12, 13, and 61,3 and the number of mutations that can occur is limited to a few predominant amino acid substitutions
The primary reasons for screened subjects failing to enroll included either the lack of a K-ras mutation in their tumor or the presence of a mutation not represented in the GI-4000 products
Given the current promise of immunotherapy and interest in strategies to target cancer patients likely to respond to treatments, we believe continued investigation of GI-4000 is warranted, with further prospective studies stratified for likely responders
Summary
The ras oncogene and its RAS protein gene product contain the most common oncogene-related mutations in human cancer, with 90% of pancreas cancers harboring mutant RAS proteins.[1,2] Mutations in the ras oncogene occur in conserved locations, codons 12, 13, and 61,3 and the number of mutations that can occur is limited to a few predominant amino acid substitutions. These yeast cells can activate dendritic cells and generate T cell cytotoxicity against target cells expressing viral and cancer antigens.[17,18,19,20,21,22,23]
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