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

J

José Mordoh, M.D., Ph.D.

Status and phase

Completed
Phase 1

Conditions

Melanoma

Treatments

Biological: DC/Apo-Nec

Study type

Interventional

Funder types

Other

Identifiers

NCT00515983
4484/04

Details and patient eligibility

About

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.

Enrollment

16 patients

Sex

All

Ages

17 to 60 years old

Volunteers

No Healthy Volunteers

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

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

Single Blind

Trial contacts and locations

1

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Data sourced from clinicaltrials.gov

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