Multicenter phase II study of matured dendritic cells pulsed with melanoma cell line lysates in patients with advanced melanoma

Antoni Ribas, Luis H Camacho, Sun Min Lee, Evan M Hersh, Charles K Brown, Jon M Richards, Maria Jovie Rodriguez, Victor G Prieto, John A Glaspy, Denise K Oseguera, Jackie Hernandez, Arturo Villanueva, Bartosz Chmielowski, Peggie Mitsky, Nadège Bercovici, Ernesto Wasserman, Didier Landais, Merrick I Ross, Antoni Ribas, Luis H Camacho, Sun Min Lee, Evan M Hersh, Charles K Brown, Jon M Richards, Maria Jovie Rodriguez, Victor G Prieto, John A Glaspy, Denise K Oseguera, Jackie Hernandez, Arturo Villanueva, Bartosz Chmielowski, Peggie Mitsky, Nadège Bercovici, Ernesto Wasserman, Didier Landais, Merrick I Ross

Abstract

Background: Several single center studies have provided evidence of immune activation and antitumor activity of therapeutic vaccination with dendritic cells (DC) in patients with metastatic melanoma. The efficacy of this approach in patients with favorable prognosis metastatic melanoma limited to the skin, subcutaneous tissues and lung (stages IIIc, M1a, M1b) was tested in a multicenter two stage phase 2 study with centralized DC manufacturing.

Methods: The vaccine (IDD-3) consisted 8 doses of autologous monocyte-derived matured DC generated in serum-free medium with granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin-13 (IL-13), pulsed with lysates of three allogeneic melanoma cell lines, and matured with interferon gamma. The primary endpoint was antitumor activity.

Results: Among 33 patients who received IDD-3 there was one complete response (CR), two partial responses (PR), and six patients had stable disease (SD) lasting more than eight weeks. The overall prospectively defined tumor growth control rate was 27% (90% confidence interval of 13-46%). IDD-3 administration had minimal toxicity and it resulted in a high frequency of immune activation to immunizing melanoma antigens as assessed by in vitro immune monitoring assays.

Conclusions: The administration of matured DC loaded with tumor lysates has significant immunogenicity and antitumor activity in patients with limited metastatic melanoma.

Clinical trial registration: NCT00107159.

Figures

Figure 1
Figure 1
Antitumor response in patient 093-020. a) Evolution of subcutaneous scalp metastases. b) Evolution of subauricular nodal metastases.
Figure 2
Figure 2
Antitumor response and pathologic analysis in patients 095-050 (a-c) and patient 095-200. a) Baseline picture of skin metastasis in the right lower extremity. b) Close-up pictures of the evolution of target lesion 6 in patient 095-050. c) H&E image of the pathologic analysis of a residually pigmented skin lesion from target lesion 6 on week 32, demonstrating melanophages and no evidence of active melanoma. d) Baseline lesions in patient 095-200. e) The lesions at week 40 were smaller but retained pigmentation. No viable tumor was detected upon biopsy.
Figure 3
Figure 3
Examples of flow cytometric analysis with double staining for CD107a (y axis) and interferon gamma (x axis) by in vitro sensitized (IVS) peripheral blood mononuclear cells (PBMC) from two patients with an objective response to IDD-3 vaccination. a) Samples from patient 093-020. b) Samples from patient 095-050. Detection of melanA-specific CD8 T cells with tetramers is also shown for this patient.

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