The immunological and clinical effects of mutated ras peptide vaccine in combination with IL-2, GM-CSF, or both in patients with solid tumors

J Transl Med. 2014 Feb 24;12:55. doi: 10.1186/1479-5876-12-55.

Abstract

Background: Mutant Ras oncogenes produce proteins that are unique to cancer cells and represent attractive targets for vaccine therapy. We have shown previously that vaccinating cancer patients with mutant ras peptides is feasible and capable of inducing a specific immune response against the relevant mutant proteins. Here, we tested the mutant ras peptide vaccine administered in combination with low dose interleukin-2 (IL-2) or/and granulocyte-macrophage colony-stimulating factor (GM-CSF) in order to enhance the vaccine immune response.

Methods: 5000 μg of the corresponding mutant ras peptide was given subcutaneously (SQ) along with IL-2 (Arm A), GM-CSF (Arm B) or both (Arm C). IL-2 was given SQ at 6.0 million IU/m²/day starting at day 5, 5 days/week for 2 weeks. GM-CSF was given SQ in a dose of 100 μg/day one day prior to each ras peptide vaccination for 4 days. Vaccines were repeated every 5 weeks on arm A and C, and every 4 weeks on arm B, for a maximum of 15 cycles or until disease progression.

Results: We treated 53 advanced cancer patients (38 with colorectal, 11 with pancreatic, 1 with common bile duct and 3 with lung) on 3 different arms (16 on arm A, 18 on arm B, and 19 on arm C). The median progression free survival (PFS) and overall survival (OS) was 3.6 and 16.9 months, respectively, for all patients evaluable for clinical response (n = 48). There was no difference in PFS or OS between the three arms (P = 0.73 and 0.99, respectively). Most adverse events were grade 1-2 toxicities and resolved spontaneously. The vaccine induced an immune response to the relevant ras peptide in a total of 20 out of 37 evaluable patients (54%) by ELISPOT, proliferative assay, or both. While 92.3% of patients on arm B had a positive immune response, only 31% of patients on arm A and 36% of patients on arm C had positive immune responses (P = 0.003, Fisher's exact test).

Conclusions: The reported data showed that IL-2 might have a negative effect on the specific immune response induced by the relevant mutant ras vaccine in patients with advanced cancer. This observation deserves further investigations.

Trial registration: NCI97C0141.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Aged
  • Amino Acid Sequence
  • Cancer Vaccines / adverse effects
  • Cancer Vaccines / therapeutic use*
  • Enzyme-Linked Immunospot Assay
  • Granulocyte-Macrophage Colony-Stimulating Factor / therapeutic use*
  • Humans
  • Immunity / immunology
  • Interleukin-2 / therapeutic use*
  • Middle Aged
  • Molecular Sequence Data
  • Neoplasms / drug therapy*
  • Neoplasms / immunology*
  • Neoplasms / prevention & control
  • T-Lymphocytes, Regulatory / immunology
  • Treatment Outcome
  • Vaccines, Subunit / adverse effects
  • Vaccines, Subunit / chemistry
  • Vaccines, Subunit / therapeutic use*
  • ras Proteins / genetics*

Substances

  • Cancer Vaccines
  • Interleukin-2
  • Vaccines, Subunit
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • ras Proteins