Lymph node histology in head and neck cancer: impact of immunotherapy with IRX-2

Meneses, Abelardo; Verástegui, Emma; Barrera, José Luís; Garza, Jaime de la; Hadden, John W.

doi:10.1016/s1567-5769(03)00017-1

Cited by 28 publications

(21 citation statements)

References 19 publications

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“…Schilling et al [39] have recently shown that IRX-2 reverses, in vitro, the DC defects of HNSCC subjects. Kast et al [40] have shown that whereas Langerhan’s cells infected with the HPV virus do not show evidence of activation, this can be reversed by incubation with IRX-2 (MK personal communication). Also, NCM may reverse the sinus histiocytosis (reduction in size, depletion of T cells and intrasinusoidal accumulation of immature dendritic cells that are FASCIN+ CD68+ CD83− CD86−) seen in draining lymph nodes of HNSCC subjects (Signorelli, Quadrini-unpublished data).…”

Section: Discussionmentioning

confidence: 99%

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

Berinstein¹,

Wolf

Naylor³

et al. 2011

Cancer Immunol Immunother

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Twenty-seven subjects with squamous cell cancer of the head and neck received the neoadjuvant IRX-2 immunotherapy regimen prior to surgery in a Phase 2 trial. Pretreatment tumor biopsies were compared with the primary tumor surgical specimens for lymphocyte infiltration, necrosis and fibrosis, using hematoxylin and eosin stain and immunohistochemistry in 25 subjects. Sections were examined by three pathologists. Relative to pretreatment biopsies, increases in lymphocyte infiltration (LI) were seen using H and E or immunohistochemistry. CD3+ CD4+ T cells and CD20+ B cells were primarily found in the peritumoral stroma and CD3+ CD8+ T cells and CD68+ macrophages were mainly intratumoral. LI in the surgical specimens were associated with reductions in the primary tumor size. Improved survival at 5 years was correlated with high overall LI in the tumor specimens. Neoadjuvant IRX-2 immunotherapy regimen may restore immune responsiveness presumably by mobilizing tumor infiltrating effector lymphocytes and macrophages into the tumor.

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Section: Discussionmentioning

confidence: 99%

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

Berinstein¹,

Wolf

Naylor³

et al. 2011

Cancer Immunol Immunother

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“…The delivery of IRX-2 to tumor-draining lymph nodes (LN) of HNC patients reduced pain and dysphagia, decreased tumor size and, in some patients, prolonged disease-free and overall survival [1, 2]. IRX-2 also increased the number of circulating naive and memory T cells [3], enriched T cells in tumor-draining LN [4], and promoted lymphocyte infiltrations into the tumors [5]. In addition, in vitro studies showed that IRX-2 enhanced dendritic cell (DC) maturation [6] and protected cytotoxic T lymphocytes from tumor-induced apoptosis [7].…”

Section: Introductionmentioning

confidence: 99%

IRX-2, a novel biologic, favors the expansion of T effector over T regulatory cells in a human tumor microenvironment model

et al. 2011

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IRX-2, a natural cytokine biological with multiple components, has been used in preclinical and clinical studies to promote antitumor activity of T lymphocytes. To define cellular mechanisms responsible for antitumor effects of IRX-2, its ability to induce effector T cells (Teff) was examined in a model simulating the tumor microenvironment. An in vitro model containing conventional CD4+CD25− cells co-cultured with autologous immature dendritic cells, irradiated tumor cells, and cytokines was used to study differentiation and expansion of regulatory T cells (Treg) and Teff in the presence and absence of IRX-2. Phenotype, suppressor function, signaling, and cytokine production were serially measured using flow cytometry, Western blots, CFSE-based suppressor assays, and Luminex-based analyses. The presence of IRX-2 in the co-cultures promoted the induction and expansion of IFN-γ+Tbet+ Teff and significantly (p < 0.01) decreased the induction of inducible IL-10+TGF-β+ Treg. The responsible mechanism involved IFN-γ-driven T cell polarization towards Teff and suppression of Treg differentiation. In an in vitro model simulating the human tumor microenvironment, IRX-2 promoted Teff expansion and antitumor activity without inducing Treg. Thus, IRX-2 could be considered as a promising component of future antitumor therapies.

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“…Sinus histiocytosis (also called sinus hyperplasia) is a lymph node pathology in cancer patients that is characterized by an accumulation of myeloid-related cells in the lymph node with markers characteristic of immature DC and macrophages. 29,30 Preliminary data suggest that immunotherapy with IRX-2 in HNSCC patients converts DC in the lymph nodes from an immature CD86 À /83 + non-antigen presenting phenotype into activated and mature CD86 + /83 + DC. 30 Additionally, IRX-2 treatment induces nodal expansion that results in an increase in the both the size of the lymph nodes and the density of T cells within the node.…”

mentioning

confidence: 99%

“…29,30 Preliminary data suggest that immunotherapy with IRX-2 in HNSCC patients converts DC in the lymph nodes from an immature CD86 À /83 + non-antigen presenting phenotype into activated and mature CD86 + /83 + DC. 30 Additionally, IRX-2 treatment induces nodal expansion that results in an increase in the both the size of the lymph nodes and the density of T cells within the node. 30 A plausible mechanism for the increased T cell infiltration of tumors and conversion of the DC in the lymph nodes to a mature and functionally active state is that IRX-2 treatment overcomes the tumor-induced immunosuppressive effects on APC and T cell interactions by directly activating and maturing the DC population and ensuring effective activation of T cells.…”

mentioning

confidence: 99%

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

Egan¹,

Quadrini²,

Santiago‐Schwarz

et al. 2007

Journal of Immunotherapy

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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.

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Lymph node histology in head and neck cancer: impact of immunotherapy with IRX-2

Cited by 28 publications

References 19 publications

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

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

IRX-2, a novel biologic, favors the expansion of T effector over T regulatory cells in a human tumor microenvironment model

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

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