Results of a phase I clinical study using autologous tumour lysate-pulsed monocyte-derived mature dendritic cell vaccinations for stage IV malignant melanoma patients combined with low dose interleukin-2

Abstract

We conducted a pilot study to assess the feasibility and efficacy of immunotherapy for stage IV malignant melanoma patients resistant to conventional therapies involving vaccination with mature dendritic cells (mDCs) combined with administration of low dose interleukin-2. Autologous monocytes were harvested from a single apheresis and cultured for 7 days with granulocyte-macrophage colony-stimulating factor and interleukin-4, yielding immature dendritic cells (iDCs), which were then cryopreserved until use. For 4 days prior to vaccination, iDCs were exposed to autologous tumour lysate combined with tumour necrosis factor-alpha to induce terminal differentiation into mDCs. Patients were then vaccinated weekly with 107 mDCs for 10 weeks and given 350-700 kIU of interleukin-2 three times per week. Of the 10 patients in the study, one showed stable disease, seven showed progressive disease, and two showed mixed responses, including partial tumour regression, and were therefore given 20 additional injections. Only minimal adverse events were noted, including localized skin reactions and mild fever (NIH-CTC grade 0-1). Median survival from the first vaccination was 240 days (range 31-735 days). In vitro, melanoma patient-derived dendritic cells (DCs) showed reduced cell surface expression of CD1a antigen on iDCs and reduced CD86 and HLA-DR expression on mDCs. In addition, antigen uptake, chemotaxis and antigen presentation were all attenuated in DCs from the patients. In summary, although improvement of clinical efficacy will require further research, autologous tumour lysate-pulsed monocyte-derived mDCs could be safely harvested, cryopreserved and administrated to patients without obvious complications.

Route of Administration Modulates the Induction of Dendritic Cell Vaccine–Induced Antigen-Specific T Cells in Advanced Melanoma Patients

“…In half of the patients, we coadministered IL-2 because of its capacity to stimulate the growth and expansion of antigen-specific cytotoxic T lymphocytes. IL-2 has been used alone or in combination with other treatments for melanoma (23)(24)(25)(26)44). Our data indicate that in intradermally vaccinated patients, IL-2 has no prominent effect, neither on the presence of tetramer-positive T cells nor on the occurrence of functional antigen-specific T cells.…”

“…Although true clinical benefit of low-dose IL-2 has not been unequivocally proven in melanoma (23)(24)(25)(26), it has been suggested that low-dose IL-2 may enhance proliferation of antigen-specific T cells after DC vaccination (27,28). Therefore, we also examined whether concomitant treatment with low-dose IL-2 increases the efficacy of the DC vaccine.…”

Dendritic cell–based immunotherapy targeting Wilms’ tumor 1 in patients with recurrent malignant glioma

“…If frozen tumor tissues were stored, a tumor lysate was prepared for loading DCs as previously described. 20,24 DCs were prepared as previously described. 9,18,31,34 According to the vaccination protocol, the DCs were cryopreserved until the day of administration.…”

TAPCells, the Chilean dendritic cell vaccine against melanoma and prostate cancer

“…(Boczkowski et al, 1996;Nestle et al, 1998;Rosenberg et al, 1998;Svane et al, 2003;Ridgway, 2003;Schadendorf et al, 2006). As an alternative, DCs pulsed or loaded with tumors or tumor lysates from the same patient have been used to induce stronger and longer immune responses against tumors (O´Rourke et al, 2003;Nagayama et al, 2003;Hersey et al, 2004;Trefzer et al, 2005). This strategy has the advantage of providing tumor antigens capable of being presented in MHC class I and class II molecules by DCs, thus reducing the tumor escape.…”