A trial of IRX-2 in patients with squamous cell carcinomas of the head and neck

Hadden, John W.; Verástegui, Emma; Barrera, José Luís; Kurman, Michael R.; Meneses, Abelardo; Zinser, Juan W; Garza, Jaime de la; Hadden, Elba M.

doi:10.1016/s1567-5769(03)00029-8

Cited by 29 publications

(35 citation statements)

References 22 publications

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“…Early recognition of immunosuppression in HNSCC patients resulted in clinical trials testing available immunostimulatory strategies including interleukin (IL)-2 and interferon (IFN)-α2a. While local IL-2 based therapies were associated with favorable local and systemic immune activation [12,13], as well as a positive randomized phase III study in operable HNSCC [14], the feasibility of tumoral injection has hampered development outside of select academic centers. The systemic combination of IL-2 and IFN-α2a demonstrated modest clinical activity with excess toxicity in recurrent/metastatic disease, and was abandoned [15].…”

Section: Introductionmentioning

confidence: 99%

Promising systemic immunotherapies in head and neck squamous cell carcinoma

2013

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SUMMARY Patients with head and neck squamous cell carcinoma (HNSCC) demonstrate poor survival and significant treatment morbidity with standard therapy. The immune profile in HNSCC, whether caused by carcinogen exposure or human papillomavirus (HPV), is notably immunosuppressive. Early clinical trials of immunotherapy in HNSCC were troubled by systemic toxicity or difficulties in local administration. Now, interest in immunotherapy has been revitalized by mechanistic insights into immune evasion by HNSCC, coupled to ongoing development of novel immunotherapies. This review will summarize immune escape mechanisms in HNSCC, namely downregulation of tumor antigen (TA) presentation, aberrant regulation of the signal transducer and activator of transcription (STAT) family, the immunosuppressive cytokine milieu, and dysregulation of immune effector cells. Therapeutic strategies hypothesized to specifically counter HNSCC immunosuppression will then be discussed. We will survey TA-targeted monoclonal antibodies (mAb), including the prototype cetuximab, as well as adjunctive strategies to enhance antibody-dependent cell-mediated cytotoxicity. We will review immunomodulation to restore STAT1/STAT3 activation balance. Examples of mAb therapy to block immunosuppressive cytokines, such as interleukin-6 or VEGF, will be provided. mAbs which release co-inhibitory T cell receptors such as CTLA-4 and PD-1, overexpressed in HNSCC, also hold therapeutic promise. Finally, we will describe principles for therapeutic vaccination in HPV-associated HNSCC, where non-host TAs such as viral oncoproteins represent ideal targets, and HPV-negative HNSCC, where p53 is a promising target. Insights into immunosuppression in HNSCC have elucidated mechanistic targets for immunotherapy. Rational clinical investigation may lead to effective stand alone or combinatorial treatment approaches.

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Section: Introductionmentioning

confidence: 99%

Promising systemic immunotherapies in head and neck squamous cell carcinoma

2013

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“…Preclinical studies have shown that this cytokine cocktail is active on multiple immune cell types, inducing dendritic cell maturation, T cell activation, and NK cell stimulation [104,105,106,107]. Phase I and II trials have demonstrated that IRX-2 is safe and generally well-tolerated, although some patients may develop potentially serious adverse effects including anemia and lymphopenia [108,109]. In addition, a Phase II study of 42 head and neck cancer patients treated with IRX-2 plus chemoradiotherapy demonstrated higher OS and longer time to recurrence compared to contemporary off-study controls [108].…”

Section: Immunomodulatorsmentioning

confidence: 99%

“…Phase I and II trials have demonstrated that IRX-2 is safe and generally well-tolerated, although some patients may develop potentially serious adverse effects including anemia and lymphopenia [108,109]. In addition, a Phase II study of 42 head and neck cancer patients treated with IRX-2 plus chemoradiotherapy demonstrated higher OS and longer time to recurrence compared to contemporary off-study controls [108]. IRX-2 treatment was associated with symptomatic improvement in 57% of patients [108], suggesting that IRX-2 may be an efficacious treatment to augment traditional chemoradiotherapy and surgery for head and neck cancers.…”

Section: Immunomodulatorsmentioning

confidence: 99%

Novel Immunotherapeutic Approaches for Head and Neck Squamous Cell Carcinoma

Bann

Deschler

Goyal

2016

Cancers

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The immune system plays a key role in preventing tumor formation by recognizing and destroying malignant cells. For over a century, researchers have attempted to harness the immune response as a cancer treatment, although this approach has only recently achieved clinical success. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and is associated with cigarette smoking, alcohol consumption, betel nut use, and human papillomavirus infection. Unfortunately, worldwide mortality from HNSCC remains high, partially due to limits on therapy secondary to the significant morbidity associated with current treatments. Therefore, immunotherapeutic approaches to HNSCC treatment are attractive for their potential to reduce morbidity while improving survival. However, the application of immunotherapies to this disease has been challenging because HNSCC is profoundly immunosuppressive, resulting in decreased absolute lymphocyte counts, impaired natural killer cell function, reduced antigen-presenting cell function, and a tumor-permissive cytokine profile. Despite these challenges, numerous clinical trials testing the safety and efficacy of immunotherapeutic approaches to HNSCC treatment are currently underway, many of which have produced promising results. This review will summarize immunotherapeutic approaches to HNSCC that are currently undergoing clinical trials.

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“…Initial clinical trials have shown that IRX-2-based immunotherapy in patients with HNSCC increased both apparent disease-free survival time and overall survival. 28 Histologic analysis of tumor samples of patients treated with IRX-2 revealed a decrease in tumor cell density and an increase in tumor infiltrating lymphocytes as compared with case-matched untreated patients. 28 In patients with HNSCC, the lymph nodes are often distinguished by T cell depletion and sinus histiocytosis.…”

mentioning

confidence: 94%

“…28 Histologic analysis of tumor samples of patients treated with IRX-2 revealed a decrease in tumor cell density and an increase in tumor infiltrating lymphocytes as compared with case-matched untreated patients. 28 In patients with HNSCC, the lymph nodes are often distinguished by T cell depletion and sinus histiocytosis. 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.…”

mentioning

confidence: 94%

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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A trial of IRX-2 in patients with squamous cell carcinomas of the head and neck

Cited by 29 publications

References 22 publications

Promising systemic immunotherapies in head and neck squamous cell carcinoma

Promising systemic immunotherapies in head and neck squamous cell carcinoma

Novel Immunotherapeutic Approaches for Head and Neck Squamous Cell Carcinoma

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

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