IRX-2, a Novel In Vivo Immunotherapeutic, Induces Maturation and Activation of Human Dendritic Cells In Vitro

Abstract

IRX-2 is a uniform, well-defined set of natural cytokines currently in Phase II clinical trials for squamous cell carcinoma of the head and neck (HNSCC). In preliminary clinical studies of HNSCC patients, IRX-2 therapy has shown promising results, increasing overall survival of patients from 32% to 61% at 48 months. Although it is known that specific cytokines in IRX-2 enhance T cell activity [e.g., interleukin-2 (IL-2), interferon-gamma, IL-1beta], we chose to investigate the influence of IRX-2 on monocyte-derived dendritic cells (Mo-DCs) isolated from human peripheral blood in an effort to further understand the clinical findings. We show here that IRX-2 treatment of human monocyte-derived DC resulted in morphologic, phenotypic, and functional changes consistent with the development of mature activated DC. Specifically, IRX-2-treated DC increased expression of CD83 and CCR7, markers for DC maturation and migration, respectively, and increased the expression of HLA-DR, CD54, and the costimulatory molecules CD86 and CD40, which are critical mediators of T cell activation. Functional changes in DC induced by IRX-2 included a reduced endocytic capacity, increased ability to stimulate T cells and increased IL-12 cytokine production. These results provide a plausible mechanistic explanation for the in vivo clinical activity of IRX-2 and an additional rationale for the use of IRX-2-based immunotherapy in patients.

T-helper and T-regulatory cells modulation in head and neck squamous cell carcinoma

“…[56][57][58] Recent approaches tried to modulate immune response by directly targeting molecules involved in the interactions between cancer and the immune system. In particular, several experimental pieces of evidence have demonstrated that Treg eradication by chemical drugs or specific antibodies is a promising strategy to induce a significant anticancer immune response.…”

Increased lymphocyte infiltration in patients with head and neck cancer treated with the IRX-2 immunotherapy regimen

“…Potentially, IRX-2 consisting of several cytokines stimulates multiple immune cell types and could be active through several molecular mechanisms. In vitro studies have shown that IRX-2 treatment of dendritic cells results in the up-regulation of markers associated with antigen presentation [38]. IRX-2 also causes an increase in both CD83 protein expression and the percentage of cells expressing CD83, a marker for DC maturation.…”

CD167 Acts as a Novel Costimulatory Receptor in T-Cell Activation

“…This finding may also have implications for the treatment of transplant-associated immune responses, because the allogeneic MLR is an in vitro model of allograft rejection. 41,42 Costimulation is a critical process not only for initiating activation of resting T cells but also for differentiating primed cells into effector T cells. 43 Effector T cells play a critical role in controlling pathologic immune responses, including infections and allergic and autoimmune disorders.…”