Vaccination of Melanoma Patients With Dendritic Cells Loaded With Allogeneic Apoptotic-Necrotic Melanoma Cells

Melanoma Clinical Trial

Official title:

Phase I Clinical Trial of a Therapeutic Vaccine Composed of Autologous Dendritic Cells Loaded With Allogeneic Apoptotic Tumor Cells in Patients With Melanoma Stages IIB, IIC, III and IV

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00515983
• Other study ID #: 4484/04
• Status: Completed
• Phase: Phase 1
• First received: August 10, 2007
• Last updated: August 10, 2007
• Start date: October 2004
• Est. completion date: December 2005

Study information

• Verified date: August 2007
• Source: José Mordoh, M.D., Ph.D.
• Contact: n/a
• Is FDA regulated: No
• Health authority: Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
• Study type: Interventional

Clinical Trial Summary

Background: Sixteen melanoma patients (1 stage IIC, 8 stage III, and 7 stage IV) were treated in a Phase I study to evaluate safety and immune responses, with a vaccine (DC/Apo-Nec) composed of autologous dendritic cells (DCs) loaded with a mixture of apoptotic/necrotic melanoma cell lines (Apo-Nec).

Methods: PBMC were obtained from leukapheresis and DCs were generated from monocytes cultured in the presence of GM-CSF and IL-4 in serum-free medium. Immature DCs (iDCs) were loaded with gamma-irradiated Apo-Nec cells and injected id without adjuvant. Cohorts of four patients were given four vaccines with 5, 10, 15, or 20 x106 DC/Apo-Nec per vaccine, two weeks apart.

Results: The vaccine was well tolerated in all patients. Toxicity to vaccine was mild, and the toxicity-limiting dose has not been reached. We found that 42.3 ±13.7 % melanoma patients´ iDCs were able to phagocyte Apo-Nec cells wich induced DCs maturation, as evidenced by increased expression of CD83, CD80, CD86, HLA class I and II compared to iDCs. Also, after phagocytosis, a 75.2 ±16 % reduction in Dextran-FITC endocytosis was observed compared to iDCs. CCR7 was upregulated upon Apo-Nec phagocytosis in DCs from all patients and accordingly in vitro DC/Apo-Nec cells were able to migrate towards MIP-3 beta. The DTH score increased significatively in the patients after the first vaccination and slightly decreased by the fourth vaccine (Mann-Whitney Test, p<0.05). For patient #1 a positive DTH reaction was detected to her own tumor irradiated cells. The presence of CD8+ T lymphocytes specific to gp100 and Melan A/MART-1 Ags were studied by tetramers binding in HLA-A*0201 patients (7 /15 patients) before and after vaccination. Two patients who remain NED increased Ags their specific T lymphocytes after vaccination. No humoral responses to Apo-Nec cells were detected. With a mean follow-up of 44.5 months post-surgery, the stage IIC pt is NED, 7/8 stage III pts are NED and 7/7 stage IV patients have progressed.

Conclussions: We conclude that DC/Apo-Nec vaccine is well tolerated, it induces specific immunity against melanoma Ags and in stage III patients it may prolong disease-free survival, affording protection from relapse in an adjuvant setting.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 16
• Est. completion date: December 2005
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 17 Years to 60 Years

Eligibility

Inclusion Criteria:

• histologically confirmed cutaneous melanoma stages IIB, IIC, III or IV (AJCC)

• pts with minimal or non-detectable disease (NED) after surgery as asserted by CAT scans. Melanoma pts with unknown primary tumor site could be included in the study

• life expectancy > 6 months

• ages:from 15 to 60 years

• performance status (ECOG) 0 or 1

• pts with stage III disease had to be previously treated with IFN-alpha, and either finished the treatment or suspended it due to disease progression, toxicity or other clinical reasons. Alternatively, those pts who had not started IFN-alpha within six months after surgery could be included in this study

• a suitable venous access for the leukapheresis procedure

• laboratory eligibility criteria included: hemoglobin > 10 gr %; WBC count > 4800/mm3, platelets > 150.000/mm3, total and direct bilirubin, serum oxalacetic transaminase and glutamic pyruvic transaminase < 1.5 fold the upper normal value; LDH < 450 mU/ml

• absence of pregnancy, with serum ßHCG determined one week before vaccination in premenopausal women

• serum creatinine < 1.4 mg %

• no chemotherapy, radiotherapy or any biological treatments during the previous month

• no concurrent medication with corticosteroids or NSAIDs

• l no active brain metastases m- normal ECG

• all pts gave written informed consent before inclusion in the Study.

Exclusion Criteria:

• Ocular melanoma or melanoma of mucosa

• Active brain metastases

• Other previous carcinoma (with the exeption of cervical or in situ basal cells carcinoma adequately treated)

• Pregnant or breast-feeding women

• Cardiac Arythmia, severe heart disease.

• Bacterial, mycotic or viral serious infections ( > grade 2 according to NCI common toxicity criteria)

• HIV, B or C Hepatitis previous infection

• Primary or secondary immunodeficiencies

• Other diseases that require treatment with regular corticoids or non steroids anti-inflammatory drugs or COX-2 inhibitors

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Melanoma

Intervention

Biological:
• DC/Apo-Nec

Locations

Country	Name	City	State
Argentina	Instituto Médico Alexander Fleming	Buenos Aires	Capital Federal

Sponsors (1)

Lead Sponsor	Collaborator
José Mordoh, M.D., Ph.D.

Country where clinical trial is conducted

Argentina, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Toxicity measured according to the NCI-Common Toxicity Criteria.		115 days follow up per Subject (Trial duration)
Primary	Induction of immune responses associated to different vaccine doses		115 days follow up per subject (Trial duration)
Secondary	Feasibility		115 days follow up per subject (Trial duration)