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Neoadjuvant Immunotherapy of Oral Squamous Cell Carcinoma Modulates Intratumoral CD4/CD8 Ratio and Tumor Microenvironment: A Multicenter Phase II Clinical Trial

József Tímár, Andrea Ladányi, Csaba Forster-Horváth, Júlia Lukits, Balázs Döme, Éva Remenár, Mária Gdény, Miklós Kásler, Beáta Bencsik, Gábor Répássy, György Szabó, Norbert Velich, Zsuzsa Suba, János Él, Zsuzsa Balatoni, Károly Pócza, Béla Zemplén, Paul Chretien, Eyal Talor

From the National Institute of Oncology; Departments of Otolaryngology and Head and Neck Surgery and Dentistry and Oral Surgery, Semmelweis University; Department of Otolaryngology and Head and Neck Surgery, Uzsoki Hospital; District Hospital, Gyr, Budapest, Hungary; and CEL-SCI Corporation, Vienna, VA

Address reprint requests to Eyal Talor, PhD, CEL-SCI Corporation, 4820-C Seton Dr, Baltimore, MD 21215; e-mail: etalor{at}cel-sci.com

PURPOSE: To investigate the clinicopathologic effects of local neoadjuvant Leukocyte Interleukin Injection (LI) regimen in oral squamous cell carcinoma (OSCC) patients. Treatment regimen included LI 800 IU/d as interleukin-2 (IL-2), administered half peritumorally and half perilymphatically five times per week for 3 weeks; low-dose cyclophosphamide; indomethacin; zinc; and multivitamins.

PATIENTS AND METHODS: Thirty-nine patients diagnosed with T2-3N0-2M0 OSCC participated in the pathology portion of this phase II multicenter study (19 LI-treated patients and 20 historical controls). Clinical responses were determined by imaging. Paraffin-embedded tumor samples were obtained at surgery for all patients. Surgery for the LI-treated group was performed between days 14 and 54 after the end of treatment. Histologic evaluation, pathologic staging, necrosis, and American Joint Committee on Cancer grading were performed from hematoxylin and eosin sections. Immunohistochemistry and morphometry determined cellular infiltrate.

RESULTS: Two pathologically complete, two major (> 50%), and four minor responses (> 30% but < 50%) resulted from LI treatment (overall response rate, 42%). Histopathology showed that the intratumoral CD4⁺:CD8⁺ ratio was low (< 1) in patients not treated with LI (controls). An increase in tumor-infiltrating CD4⁺ and a decrease of CD8⁺ T cells was observed in LI-treated patients, leading to a significantly (P < .05) higher intratumoral CD4⁺:CD8⁺ ratio (> 2.5). This was paralleled by dendritic cell transition from tumor surface toward stromal interface (P < .05), with macrophage decrease and neutrophil accumulation, multifocal microscopic necrosis, and significant (P < .05) increase in tumor stroma of LI-treated patients compared with controls.

CONCLUSION: LI-treated OSCC patients were characterized by a markedly altered composition of tumor-infiltrating mononuclear cells, increased CD4⁺:CD8⁺ ratio, and increased tumor stroma to epithelial ratio, all of which were distinct from controls.

Supported in part by the Ministry of Education (NKFP 1/48/2001, J.T. and M.K.).

Previously published in abstract form (with modifications) in the ASCO Proceedings (Proc Am Soc Clin Oncol 22:189s, 2004 [abstr 2605]).

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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