Vaccination of Patients with Metastatic Renal Carcinoma with Dendritic Cell/Tumor Fusions Following Debulking Nephrectomy
Jacalyn Rosenblatt, MD1, Andrew Wagner, MD1, Michael Atkins, MD1, David McDermott, MD1, Cho Daniel, MD1, Baldev Vasir, PhD2, Zekui Wu, MD2, Lynne Uhl, MD1, Somaya Poorvi, BA1, Heidi Mills, BA1, Brett Glotzbecker, MD1, Donna Fitzgerald, PA1, Karen Lowe, RN1, Dilani Dombogado, BA1, Evan Barnathan, BA1, Kerry Wellenstein, BA1, Martin Sanda, MD1, William DeWolf, MD1, Donald Kufe, MD2, David Avigan, MD1.
1Beth Israel Deaconess Medical Center, Boston, MA, USA, 2Dana Farber Cancer Institute, Boston, MA, USA.
BACKGROUND: We have developed a cancer vaccine in which patient derived tumor cells are fused with autologous dendritic cells (DCs) such that a broad array of tumor antigens are presented in the context of DC mediated costimulation. In animal models, vaccination with DC/tumor fusions resulted in the regression of metastatic disease. Response to vaccination may be further enhanced by tumor cytoreduction, minimizing tumor mediated immune suppression.
METHODS: We are conducting a phase I trial in which patients with metastatic renal cell carcinoma (RCC) undergo vaccination with autologous DC/RCC fusions following debulking nephrectomy. An initial cohort underwent vaccination with DC/RCC fusions alone and, in the absence of significant toxicity, a subsequent cohort underwent vaccination in conjunction with GM-CSF. RCC were isolated from nephrectomy specimens that underwent mechanical and chemical digestion and cryopreserved as single cell suspensions. DCs were generated from adherent mononuclear cells isolated from leukapheresis collections cultured for 5 days with GM-CSF and IL-4 and matured by exposure to TNFα for 48-72 hours. Fusion cells were quantified by determining the percentage of cells that co-expressed unique DC and RCC antigens following coculture of RCC and DCs with polyethylene glycol. As a measure of their potency as antigen presenting cells, DC/RCC fusions effectively stimulated allogeneic T cell proliferation ex vivo.
RESULTS: To date, fourteen patients have undergone therapy following successful vaccine generation. Vaccination has been well tolerated with the only vaccine associated toxicity being administration site reactions and a transient modest increase in the ANA titer not associated with clinical manifestations of autoimmunity in a single patient. Circulating tumor reactive T cells were determined pre-vaccination and at serial time points post-vaccination by determining the percentage of CD4 and CD8 T cells that expressed IFNγ following ex vivo exposure to autologous tumor lysate. Vaccination resulted in a dramatic increase in the levels of circulating tumor reactive T cells, with a mean fold increase was 11 and 108 for CD4 and CD8+ T cells, respectively. Of 14 patients evaluable for clinical response, 3 patients demonstrated a partial response and 4 patients experienced stable disease.
CONCLUSIONS: In preliminary analysis, vaccination with DC/RCC fusions following nephrectomy was feasible, well tolerated, and associated with immunologic and clinical responses.