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Journal of Clinical Oncology, Vol 22, No 18 (September 15), 2004: pp. 3834-3835 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.99.019
Maturation Matters: Importance of Maturation for Antitumor Immunity of Dendritic Cell VaccinesTumor Vaccine Program, New York University Cancer Institute, New York University School of Medicine, New York, NY To the Editor: Slingluff et al1 compared in a prospective randomized phase II trial two vaccine approaches for the treatment of 26 patients with advanced melanoma. The primary end point of this trial was clinical response rate according to the Response Evaluation Criteria in Solid Tumors criteria. In addition, immune monitoring assays were performed to assess peptide-specific immune responses in blood and draining sentinel immunized node (SIN). Patients received several melanoma-associated, major histocompatibility I-restricted peptides with a tetanus helper peptide either in an emulsion of granulocyte macrophage colony-stimulating factor (GM-CSF) and Montanide adjuvant (arm 2) or pulsed onto dendritic cells (arm 1). Dendritic cells (DCs) were generated from autologous blood monocytes by in vitro culture with interleukin (IL) -4 and GM-CSF and displayed an immature phenotype. The investigators found a significantly higher presence of cytotoxic T lymphocytes in the SIN of the GM-CSF arm. There were no statistically significant differences in T-cell responses in the peripheral blood or in clinical benefit between the two groups, though potentially confounding factors were present (previous treatments, concurrent low-dose IL-2, additional booster vaccinations, nonblinded arms). The authors conclude that multipeptide vaccines with GM-CSF and adjuvant deserve further investigation. In our view, the use of immature DCs in this trial does not establish the inferiority of DC-based vaccination. It has been definitively demonstrated that the efficacy of DC vaccines is critically dependent on the maturation state of the cells. Maturation is a terminal differentiation process that transforms DCs from poorly immunostimulatory cells specialized for antigen capture into cells specialized for T-cell stimulation. DC maturation is accompanied by reduced phagocytic uptake, migration to lymphoid tissues, and enhanced T-cell activation potential. Maturation is induced by stimuli that alert the resting DC to the presence of pathogens, inflammation, or tissue injury. This can be exploited in cancer vaccines either ex vivo by the addition of such stimuli (IL-1, IL-6, tumor necrosis factor [TNF] alpha, and prostaglandin E-2 are commonly used) to DC cultures or in situ maturation through the injection of immature DCs into adjuvant-treated skin. A direct comparison of peptide-loaded immature and mature DCs in patients with metastatic melanoma has shown that only mature DCs induce antigen-specific cytolytic effector responses.2 An analysis of several published melanoma vaccine trials indicated that TNF alpha-induced maturation of DCs correlated with favorable clinical outcomes.3 In addition, immature DCs might not only fail to immunize, but can induce tolerance to presented antigens.4 In situ matured DCs might have superior migratory and immunostimulatory capacities when compared with DCs matured ex vivo.5 In summary, Slingluff et al1 present an elegant study comparing two vaccine adjuvants. However, since immature DCs are now known to be less potent than matured DCs, no conclusion in regard to the better adjuvant can be drawn. Although optimal DC preparations are not yet defined for use in cancer immunotherapy, we believe that the incorporation of matured DCs into protocols is important in the search for the most effective vaccine adjuvant. Authors' Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Served as an officer or member of the Board of a company: Nina Bhardwaj, Cerus. REFERENCES
1. Slingluff CL, Petroni GR, Yamshchikov, et al: Clinical and immunologic results of a randomized phase II trial of vaccination using four melanoma peptides either administered in granulocyte-macrophage colony-stimulating factor in adjuvant or pulsed on dendritic cells. J Clin Oncol 21:4016–4026, 2003 2. Jonuleit H, Giesecke-Tuettenberg A, Tuting T, et al: A comparison of two types of dendritic cells as adjuvants for the induction of melanoma-specific T-cell responses in humans following intranodal injection. Int J Cancer 93:243–251, 2001[CrossRef][Medline] 3. McIlroy D, Gregoire M: Optimizing dendritic cell-based anticancer immunotherapy: Maturation does have clinical impact. Cancer Immunol Immunother 52:583–591, 2003[CrossRef][Medline]
4. Dhodapkar MV, Steinman RM, Krasovsky J, et al: Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J Exp Med 193:233–238, 2001
5. Nair S, McLaughlin C, Weizer A: Injection of immature dendritic cells into adjuvant-treated skin obviates the need for ex vivo maturation. J Immunol 171:6275–6282, 2003 Related Reply
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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