Direct injection of protamine-protected mRNA: results of a phase 1/2 vaccination trial in metastatic melanoma patients.
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.
Weide
Benjamin
B
Department of Dermatology, Division of Dermatooncology, University of Tübingen, Tübingen, Germany. benjamin.weide@med.uni-tuebingen.de
Pascolo
Steve
S
Scheel
Birgit
B
Derhovanessian
Evelyna
E
Pflugfelder
Annette
A
Eigentler
Thomas K
TK
Pawelec
Graham
G
Hoerr
Ingmar
I
Rammensee
Hans-Georg
HG
Garbe
Claus
C
D000293:Adolescent; D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000556:secondary / Q000628:therapy*; D039481:CD11b Antigen; D015704:CD4 Antigens; D019496:Cancer Vaccines; D049109:Cell Proliferation; D005240:Feasibility Studies; D005260:Female; D051858:Forkhead Transcription Factors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage; D006684:HLA-DR Antigens; D006433:Hemocyanins / Q000378:metabolism; D006801:Humans; D016233:Immunotherapy, Active; D007271:Injections, Intradermal; D008175:Lung Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000556:secondary / Q000628:therapy*; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D058950:Melanoma-Specific Antigens; D008875:Middle Aged; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000627:therapeutic use; D009367:Neoplasm Staging; D011479:Protamines / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D012074:Remission Induction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D000951:Antigens, Neoplasm; D039481:CD11b Antigen; D015704:CD4 Antigens; D019496:Cancer Vaccines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006684:HLA-DR Antigens; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; C082073:PRM1 protein, human; D011479:Protamines; D012333:RNA, Messenger; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin