LPS-activated dendritic cell vaccine in combination with immunomodulatory dose of cytoxan in patients with stage IV melanoma: Phase I/IIa clinical trial.

Abstract

TPS313 Background: Our studies demonstrate that patients with stage IV melanoma who undergo DC vaccination mount an immune response to tumor antigens presented on the vaccines. However, only a fraction of patients experience durable clinical responses (∼10-15% CR and PR combined). Two immune parameters appear linked to clinical outcome: 1) objective clinical response is associated with induction of melanoma-specific effector cells; and 2) all patients display melanoma-specific Tregs that may counteract effector cells. Thus, we need to identify the next generation DC vaccines able to tilt the balance toward strong effector cells that can overcome Tregs control and combination therapies that would permit to further limit Tregs. Our pre-clinical results demonstrate that LPS (TLR4 ligand) is superior to poly I:C (TLR3) and/or a mixture of inflammatory cytokines in priming IFN-DCs to secrete IL12p70 upon interaction with T cells. LPS-activated IFN-DCs loaded with killed allogeneic melanoma cells induce stronger proliferation of autologous CD8+ T cells. Thus, such vaccine is expected to induce stronger and more diverse immune responses in patients, thereby leading to better clinical outcomes. Methods: We have initiated a phase I/II clinical trial (IRB #006-025; BB-IND #12919) enrolling patients with stage IV melanoma. Patients receive seven injections of DC vaccine generated from monocytes by culturing with GM- CSF and Type I interferon, loaded with killed allogeneic Colo829 melanoma cells and activated with lipopolysaccharide (LPS). Patients receive cyclophosphamide 300 mg/m2, administered intravenously 24 hours prior to DC vaccinations #1, 3, 5, 6 and 7. The trial is based on an initial toxicity evaluation in the first 10 patients on top of a 2-stage response rule–1/19 to continue and 5/30 to accept. The trial is expected to accrue a total of 33 subjects. The primary endpoints of this trial are the rate of objective clinical response and the safety/feasibility of the vaccination preparation. To date 21 patients have been accrued of which 18 received DC vaccinations. No significant financial relationships to disclose.