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

Martin R. Weihrauch, Sascha Arisén, Elke Jurkiewicz, Caroline Geisen, Zhinan Xia, Karen Anderson, Edith Gracien, Manuel Schmidt, Burghardt Wittig, Volker Diehl, Juergen Wolf, Heribert Bohlen, Lee M. Nadler

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Abstract

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-γ 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.

Original languageEnglish (US)
Pages (from-to)5993-6001
Number of pages9
JournalClinical Cancer Research
Volume11
Issue number16
DOIs
StatePublished - Aug 15 2005
Externally publishedYes

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irinotecan
HLA-A2 Antigen
Leucovorin
Carcinoembryonic Antigen
Fluorouracil
Colorectal Neoplasms
Vaccination
Peptides
Drug Therapy
Granulocyte-Macrophage Colony-Stimulating Factor
Interleukin-2
Cytomegalovirus
Human Herpesvirus 4
CD8 Antigens
T-Lymphocytes
Dendritic Cells
Disease Progression
Research Design
Therapeutics
Survival Rate

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. / Weihrauch, Martin R.; Arisén, Sascha; Jurkiewicz, Elke; Geisen, Caroline; Xia, Zhinan; Anderson, Karen; Gracien, Edith; Schmidt, Manuel; Wittig, Burghardt; Diehl, Volker; Wolf, Juergen; Bohlen, Heribert; Nadler, Lee M.

In: Clinical Cancer Research, Vol. 11, No. 16, 15.08.2005, p. 5993-6001.

Research output: Contribution to journalArticle

Weihrauch, Martin R. ; Arisén, Sascha ; Jurkiewicz, Elke ; Geisen, Caroline ; Xia, Zhinan ; Anderson, Karen ; Gracien, Edith ; Schmidt, Manuel ; Wittig, Burghardt ; Diehl, Volker ; Wolf, Juergen ; Bohlen, Heribert ; Nadler, Lee M. / 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. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 16. pp. 5993-6001.
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abstract = "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-γ 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.",
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T1 - 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

AU - Weihrauch, Martin R.

AU - Arisén, Sascha

AU - Jurkiewicz, Elke

AU - Geisen, Caroline

AU - Xia, Zhinan

AU - Anderson, Karen

AU - Gracien, Edith

AU - Schmidt, Manuel

AU - Wittig, Burghardt

AU - Diehl, Volker

AU - Wolf, Juergen

AU - Bohlen, Heribert

AU - Nadler, Lee M.

PY - 2005/8/15

Y1 - 2005/8/15

N2 - 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-γ 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.

AB - 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-γ 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.

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