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

August 10, 2007 updated by: José Mordoh, M.D., Ph.D.

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

16

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Argentina
    • Capital Federal
      • Buenos Aires, Capital Federal, Argentina, 1426
        • Instituto Medico Alexander Fleming

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

17 years to 60 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 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
  • 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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: Single

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Toxicity measured according to the NCI-Common Toxicity Criteria.
Time Frame: 115 days follow up per Subject (Trial duration)
115 days follow up per Subject (Trial duration)
Induction of immune responses associated to different vaccine doses
Time Frame: 115 days follow up per subject (Trial duration)
115 days follow up per subject (Trial duration)

Secondary Outcome Measures

Outcome Measure
Time Frame
Feasibility
Time Frame: 115 days follow up per subject (Trial duration)
115 days follow up per subject (Trial duration)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

José Mordoh, M.D., Ph.D.

Investigators

  • Study Director: José Mordoh, MD,PhD

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2004

Study Completion (Actual)

December 1, 2005

Study Registration Dates

First Submitted

August 10, 2007

First Submitted That Met QC Criteria

August 10, 2007

First Posted (Estimate)

August 14, 2007

Study Record Updates

Last Update Posted (Estimate)

August 14, 2007

Last Update Submitted That Met QC Criteria

August 10, 2007

Last Verified

August 1, 2007

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 4484/04

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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