Related Experiment Videos
A phase I vaccine trial with peptides reflecting ras oncogene mutations of solid tumors
S N Khleif1, S I Abrams, J M Hamilton
1Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Abstract:
Mutations in the ras genes occur in 20% of all human cancers. These genes, in turn, produce mutated proteins that are unique to cancer cells, rendering them distinguishable from normal cells by the immune system. Thus, mutated Ras proteins may form potential targets for immune therapy. We conducted a phase I/pilot clinical trial in patients with advanced cancers to test the toxicity and the ability to induce an immune response by vaccination with 13-mer mutated Ras peptides reflecting codon 12 mutations. These peptides corresponded to each of the patient's own tumor Ras mutation. Patients were vaccinated monthly x3 subcutaneously with the specific Ras peptide along with Detox adjuvant (RiBi ImmunoChem Research, Inc., Hamilton, MT, U.S.A.) at one of five different peptide dose levels (100, 500, 1,000, 1,500, and 5,000 micrograms). Three out of 10 evaluable patients generated a mutant Ras specific CD4+ and/or CD8+ T-cell immune response. The CD8+ cytotoxic cells specific for Gly to Val mutation at codon 12 were capable of lysing an HLA-A2-matched tumor cell line carrying the corresponding mutant but not the wild-type ras gene. The treatment has been well tolerated with no evidence of serious acute or delayed systemic side effects on any of the five dose levels. We demonstrated that we can generate in cancer patients specific T-lymphocyte responses that detect single amino acid differences in Ras oncoproteins. Neither the immune responses nor the minor side effects seen were found to be dose dependent. This approach may provide a unique opportunity for generating a tumor-directed therapy. Also, in vitro stimulation of these cells with the corresponding peptide generated specific T-cell lines that could be used for adoptive immune therapy.
Insights
Cancer immunotherapy targeting Ras mutations is feasible. Vaccinating patients with mutated Ras peptides induced specific T-cell responses, showing potential for novel cancer treatments without dose dependency or significant side effects.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Ras gene mutations are prevalent in human cancers (20%).
- Mutated Ras proteins are tumor-specific, presenting potential targets for immune system recognition and therapeutic intervention.
- Current cancer treatments lack specificity, leading to significant side effects.
Purpose of the Study:
- To evaluate the safety and immunogenicity of a novel cancer vaccine targeting Ras mutations.
- To determine if vaccination with mutated Ras peptides can elicit a tumor-specific immune response in cancer patients.
- To explore the potential of Ras peptide vaccination as a new form of cancer immunotherapy.
Main Methods:
- A Phase I/pilot clinical trial was conducted involving patients with advanced cancers.
- Patients received subcutaneous vaccinations of 13-mer mutated Ras peptides (codon 12) combined with Detox adjuvant at varying doses (100-5,000 µg).
- Immune responses were assessed by measuring T-cell activation (CD4+ and CD8+), and cytotoxic activity against tumor cells was evaluated in vitro.
Main Results:
- Three out of 10 evaluable patients developed mutant Ras-specific CD4+ and/or CD8+ T-cell responses.
- CD8+ cytotoxic T-cells demonstrated the ability to lyse tumor cells with the specific Ras mutation (Gly to Val at codon 12) but not wild-type cells.
- The treatment was well-tolerated across all dose levels, with no significant dose-dependent immune responses or systemic side effects observed.
Conclusions:
- Vaccination with mutated Ras peptides can successfully generate specific T-lymphocyte responses in cancer patients.
- This approach allows for the detection of single amino acid differences in Ras oncoproteins, offering a highly targeted therapy.
- Mutated Ras peptides represent a promising strategy for developing personalized cancer vaccines and adoptive immunotherapies.