IRX-2, a novel in vivo immunotherapeutic, induces maturation and activation of human dendritic cells in vitro.
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.
Egan
James E
JE
IRX Therapeutics, Inc., Farmingdale, NY 11735, USA.
Quadrini
Karen J
KJ
Santiago-Schwarz
Frances
F
Hadden
John W
JW
Brandwein
Harvey J
HJ
Signorelli
Kathy L
KL
D015703:Antigens, CD / Q000378:metabolism; D002454:Cell Differentiation; D048430:Cell Shape / Q000187:drug effects; D016207:Cytokines / Q000276:immunology* / Q000494:pharmacology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
D015703:Antigens, CD; C515370:CCR7 protein, human; D016207:Cytokines; C114857:IRX 2; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D018664:Interleukin-12