Peripheral blood CD4+ T-cell response before postoperative active immunotherapy correlates with clinical outcome in metastatic melanoma

• Published in: Annals of surgical oncology 2004-10, Vol.11 (10), p.892-899
• Main Authors: Hsueh, Eddy C, Famatiga, Estela, Shu, Sherry, Ye, Xing, Morton, Donald L
• Format: Article
• Language: English
• Subjects: Aged; Biomarkers, Tumor - analysis; Cancer Vaccines - immunology; Cancer Vaccines - therapeutic use; CD4-Positive T-Lymphocytes - immunology; Cells, Cultured; Clinical outcomes; Coculture Techniques; Female; Flow Cytometry; Humans; Immunotherapy, Active; Interferon-gamma - biosynthesis; Interleukin-4 - biosynthesis; Male; Melanoma - immunology; Melanoma - pathology; Melanoma - surgery; Middle Aged; Multivariate Analysis; Prognosis; Skin Neoplasms - immunology; Skin Neoplasms - pathology; Skin Neoplasms - surgery; Survival Analysis; Treatment Outcome
• ISSN: 1068-9265; 1534-4681
• DOI: 10.1245/ASO.2004.02.018

Canvaxin polyvalent specific active immunotherapeutic (CancerVax Corp., Carlsbad, CA) is a minimally toxic adjuvant after resection of regional metastatic melanoma. Because Canvaxin immunotherapeutic requires induction of an immune response, we hypothesized that survival would be directly correlated with cellular immune responses to Canvaxin cells prior to immunization. We randomly selected 54 patients from a study of Canvaxin therapy after complete resection of American Joint Committee on Cancer (AJCC) stage III melanoma. Peripheral blood lymphocytes (PBLs) collected before immunotherapy were co-cultured with Canvaxin cells; cellular response was determined by flow cytometric measurement of the production of intracellular interleukin 4 (IL4) or interferon gamma (IFNgamma) by CD4(+) T-cells. Results were calculated as percent positive for double staining of CD4(+) plus IL4(+) or CD4(+) plus IFNgamma(+). The mean (+/- SD) increase in cytokine-producing CD4(+) T-cells after Canvaxin stimulation was 4.8 +/- 2.3% for an IFN response and 5.1 +/- 2.0% for an IL4 response. Both increases were significantly correlated with overall survival by univariate analysis (P = .0471 for IFNgamma and 0.002 for IL4). There was no significant correlation between unstimulated IFNgamma/IL4 responses and overall survival. Multivariate analysis showed that a CD4(+) T-cell IL4 response before Canvaxin therapy was a significant independent prognostic variable. In vitro cellular immune response to Canvaxin cells directly correlates with survival after subsequent initiation of immunotherapy for AJCC stage III melanoma. This finding will be evaluated in a multicenter phase III trial of Canvaxin plus bacille Calmette-Guerin (BCG) versus placebo plus BCG after resection of stage III melanoma.