Phase I/II combined chemoimmunotherapy with carcinoembryonic antigen-derived HLA-A2-restricted CAP-1 peptide and irinotecan, 5-fluorouracil, and leucovorin in patients with primary metastatic colorectal cancer.
OBJECTIVE
We conducted a phase I/II randomized trial to evaluate the clinical and immunologic effect of chemotherapy combined with vaccination in primary metastatic colorectal cancer patients with a carcinoembryonic antigen-derived peptide in the setting of adjuvants granulocyte macrophage colony-stimulating factor, CpG-containing DNA molecules (dSLIM), and dendritic cells.


METHODS
HLA-A2-positive patients with confirmed newly diagnosed metastatic colorectal cancer and elevated serum carcinoembryonic antigen (CEA) were randomized to receive three cycles of standard chemotherapy (irinotecan/high-dose 5-fluorouracil/leucovorin) and vaccinations with CEA-derived CAP-1 peptide admixed with different adjuvants [CAP-1/granulocyte macrophage colony-stimulating factor/interleukin-2 (IL-2), CAP-1/dSLIM/IL-2, and CAP-1/IL-2]. After completion of chemotherapy, patients received weekly vaccinations until progression of disease. Immune assessment was done at baseline and after three cycles of combined chemoimmunotherapy. HLA-A2 tetramers complexed with the peptides CAP-1, human T-cell lymphotrophic virus type I TAX, cytomegalovirus (CMV) pp65, and EBV BMLF-1 were used for phenotypic immune assessment. IFN-gamma intracellular cytokine assays were done to evaluate CTL reactivity.


RESULTS
Seventeen metastatic patients were recruited, of whom 12 completed three cycles. Therapy resulted in five complete response, one partial response, five stable disease, and six progressive disease. Six grade 1 local skin reactions and one mild systemic reaction to vaccination treatment were observed. Overall survival after a median observation time of 29 months was 17 months with a survival rate of 35% (6 of 17) at that time. Eight patients (47%) showed elevation of CAP-1-specific CTLs. Neither of the adjuvants provided superiority in eliciting CAP-1-specific immune responses. During three cycles of chemotherapy, EBV/CMV recall antigen-specific CD8+ cells decreased by an average 14%.


CONCLUSIONS
The presented chemoimmunotherapy is a feasible and safe combination therapy with clinical and immunologic efficacy. Despite concurrent chemotherapy, increases in CAP-1-specific T cells were observed in 47% of patients after vaccination.
Weihrauch
Martin R
MR
Center for Experimental Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. martin.weihrauch@uni-koeln.de
Ansén
Sascha
S
Jurkiewicz
Elke
E
Geisen
Caroline
C
Xia
Zhinan
Z
Anderson
Karen S
KS
Gracien
Edith
E
Schmidt
Manuel
M
Wittig
Burghardt
B
Diehl
Volker
V
Wolf
Juergen
J
Bohlen
Heribert
H
Nadler
Lee M
LM
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017252:CD3 Complex / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002272:Carcinoembryonic Antigen / Q000097:blood / Q000276:immunology*; D015179:Colorectal Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D005472:Fluorouracil / Q000008:administration & dosage; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage; D015789:HLA-A2 Antigen / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000008:administration & dosage; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D011446:Prospective Studies; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome
D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D002272:Carcinoembryonic Antigen; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D007376:Interleukin-2; D009842:Oligopeptides; D000077146:Irinotecan; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin