Combination Immunotherapy of Squamous Cell Carcinoma of the Head and Neck

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

doi:10.1001/archotol.126.3.345

Cited by 30 publications

(15 citation statements)

References 21 publications

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“…These local changes were, in turn, accompanied by a delayed tumor recurrence and an increase in overall survival as compared to historical controls. 12,21 Another effect of IRX-2 was the restoration and normalization of lymphocyte counts in preclinical studies in mice and in lymphopenic HNSCC patients, respectively, especially in combination with thymosin- α 1. 20 …”

Section: Discussionmentioning

confidence: 99%

IRX-2, a novel immunotherapeutic, protects human T cells from tumor-induced cell death

et al. 2009

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IRX-2 is a cytokine-based biologic agent that has the potential to enhance antitumor immune responses. We investigated whether IRX-2 can protect T cells from tumor-induced apoptosis. Tumor-derived microvesicles (MV) expressing FasL were purified from supernatants of tumor cells and incubated with activated CD8+ T cells. MV induced significant CD8+ T-cell apoptosis, as evidenced by Annexin binding (64.4±6.4%), caspase activation (58.1±7.6%), a loss of mitochondrial membrane potential (82.9±3.9%) and DNA fragmentation. T-cell pretreatment with IRX-2 prevented apoptosis. IRX-2-mediated cytoprotection was dose and time dependent and was comparable to effects of IL-2, IL-7 or IL-15. IRX-2 prevented MV-induced downregulation of JAK3 and TCRζ chain and induced STAT5 activation in T cells. IRX-2 prevented MV-induced Bax and Bim upregulation (P<0.005–0.05), prevented cytochrome c release and Bid cleavage, and concurrently restored the expression of Bcl-2, Bcl-xL, FLIP and Mcl-1 (P<0.005–0.01) in T cells. In addition, IRX-2 reversed MV-induced inhibition of the PI3K/Akt pathway. An Akt inhibitor (Akti-1/2) abrogated protective effects of IRX-2, suggesting that Akt is a downstream target of IRX-2 signaling. Thus, ex vivo pretreatment of CD8+ T cells with IRX-2 provided potent protection from tumor-induced apoptosis. IRX-2 application to future cancer biotherapies could improve their effectiveness by bolstering T-cell resistance to tumor-induced immunosuppression.

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Section: Discussionmentioning

confidence: 99%

IRX-2, a novel immunotherapeutic, protects human T cells from tumor-induced cell death

et al. 2009

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“…Nevertheless, immunotherapeutic agents have been used to treat SCC. In a phase two trial of SCC of head and neck patients treated with a natural cytokine mixture, that was expected to stimulate anti tumour specific immune responses, lesions were reduced in size and in some patients completely disappeared (Barrera et al, 2000). Inflammatory mononuclear cell infiltrates were found in association with oral premalignant lesions and SCC (Migliorati et al, 1986).…”

Section: Discussionmentioning

confidence: 99%

Increase in immune cell infiltration with progression of oral epithelium from hyperkeratosis to dysplasia and carcinoma

Gannot

Vered

et al. 2002

Br J Cancer

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In the present study, epithelium derived lesions of various pathological manifestations were examined histologically and immunohistochemically for mononuclear cell infiltration. The infiltrate under the transformed epithelium of oral lesions, was examined for differences in the composition of immune mononuclear cells as the epithelium moves from hyperkeratosis through various degrees of dysplasia to squamous cell carcinoma. The study was performed on 53 human tongue tissues diagnosed as hyperkeratosis (11 cases), mild dysplasia (nine cases), moderate and severe dysplasia (14 cases) and squamous cell carcinoma (19 cases). A similar analysis was performed on 30 parotid gland tissues diagnosed as pleomorphic adenoma (14 cases) and carcinoma ex-pleomorphic adenoma (16 cases). Immunohistochemical analysis of various surface markers of the tumour infiltrating immune cells was performed and correlated with the transformation level as defined by morphology and the expression of p53 in the epithelium. The results revealed that, in the tongue lesions, the changes in the epithelium from normal appearance to transformed were accompanied by a corresponding increase in the infiltration of CD4, CD8, CD14, CD19+20, and HLA/DR positive cells. The most significant change was an increase in B lymphocytes in tongue lesions, that was in accordance with the transformation level (P50.001). In the salivary gland, a significant number of cases did not show an infiltrate. In cases where an infiltrate was present, a similar pattern was observed and the more malignant tissues exhibited a higher degree of immune cell infiltration.

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“…Tumor infiltration by cytotoxic CD3 + CD8 + CTLs has been attributed a positive prognostic value in cohorts of breast carcinoma patients (n = 1334), positively correlating with tumor grade and inversely correlating with age at diagnosis, estrogen receptor as well as progesterone receptor positivity; 44 differentiated thyroid carcinoma patients (n = 398); 45 subjects affected by oral squamous cell carcinoma (n = 132); 46 glioblastoma patients vaccinated with DC-based immunotherapy (n = 23); 47 subjects affected by esophageal carcinoma (n = 70); 48 non-small cell lung carcinoma (NSCLC) patients (n = 199), highlighting a preponderant prognostic value for T cells infiltrating cancer nests and the tumor stroma; 49 subjects affected by melanoma (n = 264 and n = 285), a setting in which T-cell infiltration appears to convey independent prognostic information; 50 , 51 surgically resected HCC patients (n = 44); 52 Merkel cell carcinoma patients (n = 146); 53 subjects affected by colorectal carcinoma (CRC) (n = 447, n = 276, n = 41, n = 93, n = 152, n = 97; n = 160 and n = 470); 54 - 61 ovarian carcinoma patients who underwent surgical resection (n = 70); 62 prostatic adenocarcinoma patients (n = 325); 63 and subjects affected by muscle-invasive urothelial carcinoma (n = 69) 64 . Similarly, increased intratumoral levels of both CD3 + CD8 + CTLs and not better characterized CD3 + CD4 + helper T cells have been associated with improved clinicopathological parameters in cohorts of head and neck carcinoma (HNC) patients treated with IRX-2-based immunotherapy (n = 15, n = 42 and n = 27); 65 - 67 esophageal cancer patients who underwent tumor resection (n = 122 and n = 181), a setting in which NK-cell accumulation also conveyed prognostic information; 68 , 69 surgically resected NSCLC patients (n = 335), highlighting a prominent prognostic value for CD4 + cells accumulating at stromal, as opposed to epithelial, sites; 70 subjects affected by melanoma; 71 surgically resected HCC patients (n = 163); 72 pancreatic adenocarcinoma patients (n = 80), correlating with an intense infiltration by DCs; 73 gallbladder cancer patients treated with curative surgery (n = 110), a setting in which also DC, but not NK-cell, infiltration, conveyed prognostic information; 74 prostate carcinoma patients undergoing radical prostatectomy (n = 188), a setting in which B-cell infiltration also provided prognostic insights; 75 vulval intraepithelial neoplasia patients receiving therapeutic human papillomavirus vaccination combined with the Toll-like receptor (TLR) 7 agonist imiquimod (n = 19), 76 and patients affected by various solid tumors (including breast carcinoma, melanoma and renal cell carcinoma, RCC) undergoing IL-2-based immunotherapy 77 . Of note, CD3 + CD4 + and CD8 + cells (together with CD20 + and CD57 + cells) have been shown to preferentially accumulate at the margins of breast carcinoma lesions ablated by high intensity focused ultrasound (n = 23 patients), as opposed to similar lesions removed by radical mastectomy (n = 25) …”

Section: T Lymphocytesmentioning

confidence: 99%

Trial watch

et al. 2012

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Solid tumors are constituted of a variety of cellular components, including bona fide malignant cells as well as endothelial, structural and immune cells. On one hand, the tumor stroma exerts major pro-tumorigenic and immunosuppressive functions, reflecting the capacity of cancer cells to shape the microenvironment to satisfy their own metabolic and immunological needs. On the other hand, there is a component of tumor-infiltrating leucocytes (TILs) that has been specifically recruited in the attempt to control tumor growth. Along with the recognition of the critical role played by the immune system in oncogenesis, tumor progression and response to therapy, increasing attention has been attracted by the potential prognostic and/or predictive role of the immune infiltrate in this setting. Data from large clinical studies demonstrate indeed that a robust infiltration of neoplastic lesions by specific immune cell populations, including (but not limited to) CD8+ cytotoxic T lymphocytes, Th1 and Th17 CD4+ T cells, natural killer cells, dendritic cells, and M1 macrophages constitutes an independent prognostic indicator in several types of cancer. Conversely, high levels of intratumoral CD4+CD25+FOXP3+ regulatory T cells, Th2 CD4+ T cells, myeloid-derived suppressor cells, M2 macrophages and neutrophils have frequently been associated with dismal prognosis. So far, only a few studies have addressed the true predictive potential of TILs in cancer patients, generally comforting the notion that—at least in some clinical settings—the immune infiltrate can reliably predict if a specific patient will respond to therapy or not. In this Trial Watch, we will summarize the results of clinical trials that have evaluated/are evaluating the prognostic and predictive value of the immune infiltrate in the context of solid malignancies.

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Combination Immunotherapy of Squamous Cell Carcinoma of the Head and Neck

Cited by 30 publications

References 21 publications

IRX-2, a novel immunotherapeutic, protects human T cells from tumor-induced cell death

IRX-2, a novel immunotherapeutic, protects human T cells from tumor-induced cell death

Increase in immune cell infiltration with progression of oral epithelium from hyperkeratosis to dysplasia and carcinoma

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