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

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 we...

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Published in:	Journal of clinical oncology Vol. 23; no. 15; pp. 3421 - 3432
Main Authors:	TIMAR, Jozsef, LADDNYI, Andrea, SZABO, György, VELICH, Norbert, SUBA, Zsuzsa, ELÖ, Jdnos, BALATONI, Zsuzsa, POSZA, Kdroly, ZEMPLEN, Béla, CHRETIEN, Paul, TALOR, Eyal, FORSTER-HORVATH, Csaba, LUKITS, Julia, DOME, Baldzs, REMENDR, Eva, GÖDENY, Mdria, KDSLER, Miklos, BENCSIK, Bedta, REPASSY, Gabor
Format:	Journal Article
Language:	English
Published:	Baltimore, MD American Society of Clinical Oncology 20-05-2005 Lippincott Williams & Wilkins
Subjects:	Adult Aged Aged, 80 and over Biological and medical sciences Biopsy, Needle Carcinoma, Squamous Cell - drug therapy Carcinoma, Squamous Cell - mortality Carcinoma, Squamous Cell - pathology CD4-CD8 Ratio Cyclophosphamide - therapeutic use Dose-Response Relationship, Drug Drug Administration Schedule Drug Therapy, Combination Female Follow-Up Studies Humans Immunohistochemistry Immunotherapy - methods Indomethacin - therapeutic use Injections, Intralesional Interleukin-2 - therapeutic use Male Maximum Tolerated Dose Medical sciences Middle Aged Mouth Neoplasms - drug therapy Mouth Neoplasms - mortality Mouth Neoplasms - pathology Neoadjuvant Therapy Neoplasm Staging Otorhinolaryngology. Stomatology Survival Rate Treatment Outcome Tumors Upper respiratory tract, upper alimentary tract, paranasal sinuses, salivary glands: diseases, semeiology Cancerology Treatment Stomatology Immunotherapy Phase II trial T-Lymphocyte Oral cavity disease Malignant tumor Oral squamous cell carcinoma Microenvironment
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Summary:	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. 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. 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. 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.
ISSN:	0732-183X 1527-7755
DOI:	10.1200/JCO.2005.06.005