Neoadjuvant immunotherapy of oral squamous cell carcinoma modulates intratumoral CD4/CD8 ratio and tumor microenvironment: A multicenter phase II clinical trial

J. Tímár, A. Ladányi, Csaba Forster-Horváth, Júlia Lukits, B. Döme, E. Remenár, Mária Godény, M. Kásler, Beáta Bencsik, G. Répássy, György Szabó, Norbert Velich, Z. Suba, János Élõ, Zsuzsa Balatoni, Károly Pócza, Béla Zemplén, Paul Chretien, Eyal Talor

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Abstract

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.

Original languageEnglish
Pages (from-to)3421-3432
Number of pages12
JournalJournal of Clinical Oncology
Volume23
Issue number15
DOIs
Publication statusPublished - 2005

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CD4-CD8 Ratio
Phase II Clinical Trials
Tumor Microenvironment
Interleukins
Immunotherapy
Squamous Cell Carcinoma
Leukocytes
Injections
Neoplasms
Necrosis
Hematoxylin
Eosine Yellowish-(YS)
Indomethacin
Paraffin
Cyclophosphamide
Dendritic Cells
Multicenter Studies
Interleukin-2
Zinc
Neutrophils

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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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. / Tímár, J.; Ladányi, A.; Forster-Horváth, Csaba; Lukits, Júlia; Döme, B.; Remenár, E.; Godény, Mária; Kásler, M.; Bencsik, Beáta; Répássy, G.; Szabó, György; Velich, Norbert; Suba, Z.; Élõ, János; Balatoni, Zsuzsa; Pócza, Károly; Zemplén, Béla; Chretien, Paul; Talor, Eyal.

In: Journal of Clinical Oncology, Vol. 23, No. 15, 2005, p. 3421-3432.

Research output: Contribution to journalArticle

Tímár, J. ; Ladányi, A. ; Forster-Horváth, Csaba ; Lukits, Júlia ; Döme, B. ; Remenár, E. ; Godény, Mária ; Kásler, M. ; Bencsik, Beáta ; Répássy, G. ; Szabó, György ; Velich, Norbert ; Suba, Z. ; Élõ, János ; Balatoni, Zsuzsa ; Pócza, Károly ; Zemplén, Béla ; Chretien, Paul ; Talor, Eyal. / Neoadjuvant immunotherapy of oral squamous cell carcinoma modulates intratumoral CD4/CD8 ratio and tumor microenvironment : A multicenter phase II clinical trial. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 15. pp. 3421-3432.
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abstract = "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.",
author = "J. T{\'i}m{\'a}r and A. Lad{\'a}nyi and Csaba Forster-Horv{\'a}th and J{\'u}lia Lukits and B. D{\"o}me and E. Remen{\'a}r and M{\'a}ria God{\'e}ny and M. K{\'a}sler and Be{\'a}ta Bencsik and G. R{\'e}p{\'a}ssy and Gy{\"o}rgy Szab{\'o} and Norbert Velich and Z. Suba and J{\'a}nos {\'E}l{\~o} and Zsuzsa Balatoni and K{\'a}roly P{\'o}cza and B{\'e}la Zempl{\'e}n and Paul Chretien and Eyal Talor",
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T1 - Neoadjuvant immunotherapy of oral squamous cell carcinoma modulates intratumoral CD4/CD8 ratio and tumor microenvironment

T2 - A multicenter phase II clinical trial

AU - Tímár, J.

AU - Ladányi, A.

AU - Forster-Horváth, Csaba

AU - Lukits, Júlia

AU - Döme, B.

AU - Remenár, E.

AU - Godény, Mária

AU - Kásler, M.

AU - Bencsik, Beáta

AU - Répássy, G.

AU - Szabó, György

AU - Velich, Norbert

AU - Suba, Z.

AU - Élõ, János

AU - Balatoni, Zsuzsa

AU - Pócza, Károly

AU - Zemplén, Béla

AU - Chretien, Paul

AU - Talor, Eyal

PY - 2005

Y1 - 2005

N2 - 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.

AB - 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.

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