Carcinoembryonic Antigen-loaded Dendritic Cells in Advanced Colorectal Cancer Patients

Study Overview
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Brief Summary
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Dendritic cells (DCs) are the professional antigen-presenting cells of the immune system. As such they are currently used in clinical vaccination protocols in cancer patients. We evaluate the ability of mature DCs pulsed with carcinoembryonic antigen (CEA)-peptide (arm A) or electroporated with CEA-mRNA (arm B) to induce CEA-specific T cell responses in patients with resectable liver metastases from colorectal cancer. To evaluate immune responses, CEA-specific T cell reactivity is monitored in peripheral blood, resected abdominal lymph nodes, tumor tissue and biopsies of vaccination sites and post-treatment DTH skin tests. Patients are vaccinated intradermally and intravenously with CEA-peptide pulsed mature DCs three times prior to resection of liver metastases. In 2007 a side-study has been added (arm C), in which patients with stage III or high-risk stage II colorectal cancer that are amenable for standard adjuvant oxaliplatin/capecitabine therapy are vaccinated with CEApeptide-pulsed DCs. Also in this group, safety and immune responses in peripheral blood and the DTH-skin test are the primary endpoints. Results are compared with the results obtained in arm A.

Official Title
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Induction of Specific T Cell Responses in Colorectal Cancer Patients With Liver Metastases Upon Vaccination With Autologous Dendritic Cells Pulsed With CEA-peptide or Electroporated With CEA-RNA: Evaluation of in Vivo Immune Response.

Conditions
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Colorectal Cancer, Liver Metastases

Intervention / Treatment
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* Biological: CEA-loaded dendritic cell vaccine


Participation Criteria
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Eligibility Criteria
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For arm A and B Inclusion Criteria: Histological documented evidence of colorectal cancer. Primary tumor surgically removed, recurrence(s) in the liver. Planned surgical excision of liver metastases. HLA-A2.1 phenotype according to lymphocyte HLA typing. Expression of CEA on primary tumor. ECOG performance status 0-1, life expectancy > 3 months. Age 18-75 years. WBC > 3.0 x 109/l, lymphocytes > 0.8 x 109/l, platelets > 100 x 109/l, serum creatinine < 150 μmol/l, serum bilirubin < 25 μmol/l. Expected adequacy of follow-up. Written informed consent. Exclusion Criteria: Clinical signs of extra hepatic metastases, in patients with a clinical suspicion of other metastases diagnostic tests should be performed to exclude this. Prior chemotherapy, immunotherapy, or radiotherapy within three months before planned surgical excision is allowed. A history of myocardial infarction, angina pectoris, cardiac arrhythmias, cerebrovascular accidents, transient ischemic attacks or severe hypertension (exclusion criteria for autologous blood donation) Concomitant use of corticosteroids or other immunosuppressive agents. A history of any second malignancy in the past five years excluding adequately treated basal carcinoma of skin or carcinoma in situ of cervix. Serious concomitant disease, active infections. Specifically, patients with autoimmune disease or organ allografts and patients with a history of HBsAg or HIV are excluded. A known allergy to shell fish. Pregnant or lactating women. For arm C (side-study) inclusion criteria: histological proof of colorectal cancer HLA-A0201 positive stage III (T1-4N1-2M0) cancer or high risk stage II (T4 and/or poor differentiation in histology and/or perforation and/or obstruction and/or venous invasion and/or histological analysis of ≤10 lymph nodes) ≤ 8 weeks since surgical resection of primary colorectal tumor Age 18-75 years WHO performance 0-1 (Karnofsky 100-70%) WBC ≥ 3.0x109/l Platelets ≥ 100x109/l Hb ≥ 6 mmol/l Total bilirubin ≤ 2x UNL ASAT and ALAT ≤ 3x UNL Serum creatinine ≤ 1.5 x UNL Expected adequacy of follow-up Signed written informed consent exclusion criteria A history of second malignancy within the last 5 years. Adequately treated basal carcino¬ma of skin or carcinoma in situ of cervix is acceptable within this period Serious concomitant disease. Autoimmune disease or organ grafts. Other serious concomitant diseases preventing the safe administration of study drugs or likely to interfere with the study assessments. A known allergy to shell fish (contains KLH) Pregnant or lactating women

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A<br>Dendritic cells pulsed with CEA-peptide | Biological: CEA-loaded dendritic cell vaccine<br>* Carcinoembryonic antigen (either peptide or mRNA) loaded dendritic cells.<br>|
| Experimental: B<br>Dendritic cells electroporated with CEA-mRNA | Biological: CEA-loaded dendritic cell vaccine<br>* Carcinoembryonic antigen (either peptide or mRNA) loaded dendritic cells.<br>|
| Experimental: C<br>Dendritic cells pulsed with CEA-peptide, in combination with oxaliplatin/capecitabine | Biological: CEA-loaded dendritic cell vaccine<br>* Carcinoembryonic antigen (either peptide or mRNA) loaded dendritic cells.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| immunological response against carcinoembryonic antigen and the control protein KLH |  | During the study | 
| Toxicity |  | During the study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dendritic cells, Colorectal cancer, Carcinoembryonic antigen, Vaccine, Immunotherapy