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

NCT00515983 | Completed Phase 1

• 1 other identifier: 4484/04
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Melanoma

Keywords

melanoma; dendritic cells; apoptotic/necrotic cells; therapeutic vaccine

Outcome Measures

Primary Outcomes (2)

• Toxicity measured according to the NCI-Common Toxicity Criteria.

  115 days follow up per Subject (Trial duration)

• Induction of immune responses associated to different vaccine doses

  115 days follow up per subject (Trial duration)

Secondary Outcomes (1)

• Feasibility

  115 days follow up per subject (Trial duration)

Interventions

DC/Apo-Nec BIOLOGICAL

Eligibility Criteria

• Age: 17 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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 βHCG 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

You may not qualify if:

• 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

Sponsors & Collaborators

• José Mordoh, M.D., Ph.D.: lead

Study Sites (1)

Instituto Médico Alexander Fleming

Buenos Aires, Buenos Aires F.D., 1426, Argentina

Location

Related Publications (1)

• von Euw EM, Barrio MM, Furman D, Levy EM, Bianchini M, Peguillet I, Lantz O, Vellice A, Kohan A, Chacon M, Yee C, Wainstok R, Mordoh J. A phase I clinical study of vaccination of melanoma patients with dendritic cells loaded with allogeneic apoptotic/necrotic melanoma cells. Analysis of toxicity and immune response to the vaccine and of IL-10 -1082 promoter genotype as predictor of disease progression. J Transl Med. 2008 Jan 25;6:6. doi: 10.1186/1479-5876-6-6.

  PMID: 18221542 DERIVED

MeSH Terms

Conditions

Melanoma

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• José Mordoh, MD,PhD

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: August 10, 2007
• First Posted: August 14, 2007
• Study Start: October 1, 2004
• Study Completion: December 1, 2005
• Last Updated: August 14, 2007

Record last verified: 2007-08

Locations

AR (1)