Abstract
In mice, injection of messenger RNA (mRNA) coding for tumor-associated antigens can induce antitumor immune responses and therefore offers a broadly applicable immunotherapy approach. We injected intradermally protamine-stabilized mRNAs coding for Melan-A, Tyrosinase, gp100, Mage-A1, Mage-A3, and Survivin in 21 metastatic melanoma patients. In 10 patients keyhole limpet hemocyanin (KLH) was added to the vaccine. Granulocyte macrophage colony-stimulating factor was applied as an adjuvant. Endpoints were toxicity and immune responses. No adverse events more than grade II have been observed. During treatment the frequency of Foxp3+/CD4+ regulatory T cells was significantly decreased upon mRNA vaccination in peripheral blood of the patients in the KLH arm, whereas myeloid suppressor cells (CD11b+HLA-DR lo monocytes) were reduced in the patients not receiving KLH. A reproducible increase of vaccine-directed T cells was observed in 2 of 4 immunologically evaluable patients. One of 7 patients with measurable disease showed a complete response. In conclusion, we show here that direct injection of protamine-protected mRNA is feasible and safe. The significant influence of the treatment on the frequency of immunosuppressive cells, the increase of vaccine-directed T cells upon treatment in a subset of patients together with the demonstration of a complete clinical response encourage further clinical investigation of the protamine-mRNA vaccine.
Trial registration: ClinicalTrials.gov NCT00204607.
Publication types
- Clinical Trial, Phase I
- Clinical Trial, Phase II
- Randomized Controlled Trial
- Research Support, Non-U.S. Gov't
MeSH terms
- Adolescent
- Adult
- Aged
- Antigens, Neoplasm / genetics*
- Antigens, Neoplasm / immunology*
- Antigens, Neoplasm / metabolism
- Antigens, Neoplasm / therapeutic use
- Bone Neoplasms / immunology*
- Bone Neoplasms / metabolism
- Bone Neoplasms / secondary
- Bone Neoplasms / therapy*
- CD11b Antigen
- CD4 Antigens
- Cancer Vaccines*
- Cell Proliferation
- Feasibility Studies
- Female
- Forkhead Transcription Factors
- Granulocyte-Macrophage Colony-Stimulating Factor / administration & dosage
- HLA-DR Antigens
- Hemocyanins / metabolism
- Humans
- Immunotherapy, Active*
- Injections, Intradermal
- Lung Neoplasms / immunology*
- Lung Neoplasms / metabolism
- Lung Neoplasms / secondary
- Lung Neoplasms / therapy*
- Male
- Melanoma / immunology*
- Melanoma / metabolism
- Melanoma / pathology
- Melanoma / therapy*
- Melanoma-Specific Antigens
- Middle Aged
- Myeloid Cells / immunology
- Myeloid Cells / metabolism*
- Myeloid Cells / pathology
- Neoplasm Proteins / genetics*
- Neoplasm Proteins / immunology*
- Neoplasm Proteins / metabolism
- Neoplasm Proteins / therapeutic use
- Neoplasm Staging
- Protamines / metabolism
- RNA, Messenger / genetics
- RNA, Messenger / metabolism
- RNA, Messenger / therapeutic use
- Remission Induction
- T-Lymphocytes, Regulatory / immunology
- T-Lymphocytes, Regulatory / metabolism*
- T-Lymphocytes, Regulatory / pathology
Substances
- Antigens, Neoplasm
- CD11b Antigen
- CD4 Antigens
- Cancer Vaccines
- FOXP3 protein, human
- Forkhead Transcription Factors
- HLA-DR Antigens
- Melanoma-Specific Antigens
- Neoplasm Proteins
- PRM1 protein, human
- Protamines
- RNA, Messenger
- Granulocyte-Macrophage Colony-Stimulating Factor
- Hemocyanins
- keyhole-limpet hemocyanin
Associated data
- ClinicalTrials.gov/NCT00204607