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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

Authors' Affiliations: ¹ Center for Experimental Medicine, Dana-Farber Cancer Institute, Harvard Medical School; ² Department of Medicine, Harvard Medical School; ³ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; ⁴ Department I of Internal Medicine, University of Cologne; ⁵ Axiogenesis GmbH, Cologne, Germany; ⁶ Mologen AG; ⁷ Institute of Molecular Biology and Bioinformatics, Center of Biochemistry and Biophysics, Charité-Universitaetsmedizin Berlin, Berlin, Germany; and ⁸ Aventis Pharma Deutschland GmbH, Bad Soden, Germany

Requests for reprints: Martin R. Weihrauch, Dana-Farber Cancer Institute, Room D542, 44 Binney Street, Boston, MA 02115. Phone: 617-632-5191; Fax: 617-632-6024; E-mail: martin.weihrauch{at}uni-koeln.de.

Purpose: 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.

Experimental Design: 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- 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.