Pilot Clinical Trial of Type 1 Dendritic Cells Loaded with Autologous Tumor Lysates Combined with GM-CSF, Pegylated IFN, and Cyclophosphamide for Metastatic Cancer Patients

Abstract

Twenty-four patients with metastatic cancer received two cycles of four daily immunizations with monocyte-derived dendritic cells (DC). DC were incubated with preheated autologous tumor lysate and subsequently with IFN-α, TNF-α, and polyinosinic:polycytidylic acid to attain type 1 maturation. One DC dose was delivered intranodally, under ultrasound control, and the rest intradermally in the opposite thigh. Cyclophosphamide (day -7), GM-CSF (days 1-4), and pegIFN alpha-2a (days 1 and 8) completed each treatment cycle. Pretreatment with cyclophosphamide decreased regulatory T cells to levels observed in healthy subjects both in terms of percentage and in absolute counts in peripheral blood. Treatment induced sustained elevations of IL-12 in serum that correlated with the output of IL-12p70 from cultured DC from each individual. NK activity in peripheral blood was increased and also correlated with the serum concentration of IL-12p70 in each patient. Circulating endothelial cells decreased in 17 of 18 patients, and circulating tumor cells markedly dropped in 6 of 19 cases. IFN-γ-ELISPOT responses to DC plus tumor lysate were observed in 4 of 11 evaluated cases. Tracing DC migration with [(111)In] scintigraphy showed that intranodal injections reached deeper lymphatic chains in 61% of patients, whereas with intradermal injections a small fraction of injected DC was almost constantly shown to reach draining inguinal lymph nodes. Five patients experienced disease stabilization, but no objective responses were documented. This combinatorial immunotherapy strategy is safe and feasible, and its immunobiological effects suggest potential activity in patients with minimal residual disease. A randomized trial exploring this hypothesis is currently ongoing.

NK Cells: Key to Success of DC-Based Cancer Vaccines?

“…Four of five patients who responded to the DC vaccine had a highly activated NK cell phenotype, in comparison with none of the nonresponders. Extensive NK cell monitoring in a subsequent phase II trial is ongoing.All studies with tumor lysate-pulsed DC vaccination, alone [98, 99] or as a part of combination therapy [100,101], led to NK cell changes (Table 3). Di Nicola and colleagues found a positive correlation between an increased frequency of CD56 dim CD16 ϩ NK cells and clinical response post-DC vaccination [98].…”

Modeling Tumor Response after Combined Administration of Different Immune-Stimulatory Agents

“…Vaccine administration in combination with different coadjuvants to potentiate the triggered immune response or to inhibit the immunosuppressive mechanism developed by the tumor have proven to increase preclinical and clinical efficacy achieved in immunotherapy (Ghiringhelli et al, 2007;Alfaro et al, 2011;Mkrtichyan et al, 2011;Ge et al, 2012;Hong et al, 2012).…”

“…Different alternatives to increase the immunologic efficacy of immunotherapy have been discussed (Finn, 2003;Rosenberg et al, 2004;Copier et al, 2009). Among them, inhibition of the immunosuppressive mechanisms elicited by the tumor through depletion of the Treg cell population has shown promising results using drugs such as anti-CD25 antibodies or low doses of cyclophosphamide (CTX) (Onizuka et al, 1999 ;Ghiringhelli et al, 2007;Alfaro et al, 2011). Another approach widely studied has been the activation of antigen-presenting cells (especially dendritic cells) or other cells of the innate immune system to increase the number and/or avidity of the antigen-specific T cells with adjuvants such as Toll-like receptor (TLR) ligands or coadministration of different cytokines to potentiate and promote cell survival (Brody et al, 2010;Landrigan et al, 2011;Hong et al, 2012).…”

Células dendríticas especializadas en presentación de antígenos exógenos a linfocitos T citotóxicos

“…Existen estudios experimentales que indican que se puede conseguir presentación cruzada por parte de la subpoblación CD8α -mediante su activación a través de TLRs o FcR 95-98 y se ha observado que son necesarias para la presentación cruzada de antígenos derivados de Saccharomyces cerevisae 99 (Tabla 1). Las células dendríticas CD11c + derivadas de suspensiones de médula ósea en cultivos de diferenciación en presencia de GM-CSF son capaces de presentar antí-genos proteicos o en cuerpos apoptóticos fagocitados a linfocitos T citotóxicos con efectos terapéuticos frente a tumores 100 (Tabla 1). Tabla 1.…”