Treatment of Ras mutation-bearing solid tumors using whole recombinant S. cerevisiae yeast expressing mutated Ras: Preliminary safety and immunogenicity results from a phase 1 trial.

Published

Journal Article

2571 Background: A number of tumors express activating, transforming mutations at codons 12 and 61 in the ras oncogene. We have previously shown that whole heat-inactivated recombinant S. cerevisiae expressing mutated Ras proteins induce protective cellular immunity as well as complete remission of established, carcinogen-induced, ras mutation-bearing lung tumors in mice (Cancer Res 64, 5084, 2004). METHODS: GI-4014, GI-4015 and GI-4016 are recombinant yeast, each expressing a truncated and modified human Ras protein containing one of the three most common mutations at codon 12 (G12V, G12C, or G12D respectively) and the two most common mutations at codon 61 (Q61R and Q61L). In a four center Phase 1 trial, patients with advanced colorectal, pancreatic or non-small cell lung cancer, who have failed at least first line chemotherapy, have tumor samples subjected to genomic sequencing of the K-, H- and N-ras genes. If the tumor contains one of the target mutations, the subject receives 5 subcutaneous weekly doses of the corresponding product and is followed for an additional 56 days for safety, immunogenicity and tumor response. RESULTS: 32 patients have been consented, of whom 9 had ras mutations in their tumors, 7 of which were contained in one of the three products. Six patients have been treated. Of 3 low-dose patients in whom cellular assay data are available, two have shown mutation-specific T cell responses by proliferation and cytokine secretion assays. No treatment-related serious adverse events have occurred and possibly treatment-related adverse events have been limited to mild fever and malaise in one subject. CONCLUSIONS: Recombinant yeast represent a novel vector for generating antigen-specific immune responses. Early data in humans suggest that, even at the lowest dose, these vectors generate mutation-specific cellular responses with an acceptable safety profile [Table: see text].

Full Text

Duke Authors

Cited Authors

  • Cohn, A; Morse, MA; O'Neil, B; Bellgrau, D; Duke, RC; Franzusoff, AJ; Munson, S; Ferraro, J; Rodell, TC

Published Date

  • June 2005

Published In

Volume / Issue

  • 23 / 16_suppl

Start / End Page

  • 2571 -

PubMed ID

  • 27945865

Pubmed Central ID

  • 27945865

Electronic International Standard Serial Number (EISSN)

  • 1527-7755

Language

  • eng

Conference Location

  • United States