ASH Melanoma vaccine abstract:
[2903] Immunologic Gene Therapy: A Phase I/II Trial Utilizing Autologous Dendritic Cells Transduced with gp100- and Melan A/MART-1-Encoding Adenoviruses in Advanced Melanoma.
Frank G. Haluska, Mark A. Goldberg, G. Linette, Eric Jonasch, F. S. Hodi, Charles C. Cunningham, John Nemunaitis, Iain Webb, Christopher Stowell, Sixun Yang. Massachusetts General Hospital, Boston, MA; U.S. Oncology, Inc., Houston, TX; Dana-Farber Cancer Institute, Boston, MA; Genzyme Molecular Oncology, Framingham, MA
Dendritic cells (DCs) are potent antigen-presenting cells (APCs). Several studies have demonstrated the safety of ex-vivo culture of DCs for human administration, but the optimal method of introducing antigen onto DCs has yet to be determined. We have studied the genetic modification of DCs ex-vivo with an adenoviral (Ad) vector encoding antigens recognized by cytotoxic T lymphocytes (CTL) and expressed in a high proportion of melanomas: melanoma rejection antigens Melan A/MART-1 and gp100. Preclinical data from a murine B16 melanoma active treatment model have confirmed tumor inhibition and prolonged survival in association with the development of a CTL response with this approach. Low-dose recombinant Interleukin-2 (rIL-2) may enhance this antigen-specific immunity. In this study we transduced granulocyte monocyte colony-stimulating factor (GM-CSF)- and rIL-4-derived autologous DCs ex-vivo with Ad vectors encoding Melan A/MART-1 and gp100 (modified DCs), then subcutaneously (SC) administered the modified DCs either alone or with low-dose rIL-2, in 3 dose cohorts based on the number of DCs. The safety, cellular immune response, and therapeutic efficacy of the modified DCs alone and in conjunction with low-dose rIL-2 were evaluated. Eligible adult patients with histologically confirmed Stage III or IV primary cutaneous melanoma whose metastatic tumor tissue expressed both Melan A/MART-1 and gp100, as demonstrated by immunohistochemistry, were allowed to participate in this study. Each patient was assigned to 1 of 6 dose groups at 1 of 3 dose levels: 7.5 x 106, 22.5 x 106, or 50 x 106 modified DCs every 21 days into each extremity, with or without rIL-2 (0.9 x 106 IU/m2 daily on Days 4 through 19 of each 21-day treatment cycle). Patients returned to the clinic for safety and immunological analyses weekly for the first 21-day treatment cycle and every 21 days thereafter, for a total of 6 21-day treatment cycles. RESULTS: 27 patients were enrolled, and 17 are evaluable at the time of this report. Of the 17 evaluable patients (11 M/6 F, ages 23 to 77), 12 were confirmed to be human leukocyte antigen-A2 (HLA-A2) positive. Overall, therapy was well tolerated. To date, serious adverse experiences possibly related to the study drug include 2 patients with asymptomatic areas of retinal hypopigmentation observed in study-related ophthalmologic examinations. This effect may be immunologically mediated. Other immunologic findings included 3 patients who developed vitiligo. Additional vaccination-related immunologic data to be reported will include antigen-specific reactivity, delayed type hypersensitivity (DTH)-like reactions, and vaccination site reactions. There were 12 stage IV and 5 stage III patients at screening. We observed the following responses: at follow-up (3 months following study completion), complete response n=1 (5.9%); at study completion (21 days following the 6th vaccination), partial response n=1 (5.9%), stable disease n=1 (5.9%). Seven (7) patient deaths have been recorded. The study is ongoing.
Keywords: Stage III/IV melanoma\ Autologous dendritic cells transduced with adenoviruses encoding melan A/MART-1 and gp100\ Interleukin-2 |
