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Terry Y. Shibuya, MD; Wei-Zen Wei, PhD; Michelle Zormeier, MD; John Ensley, MD; Wael Sakr, MD; Robert H. Mathog, MD; Robert J. Meleca, MD; George H. Yoo, MD; Carl H. June, MD; Bruce L. Levine, PhD; Lawrence G. Lum, MD

Arch Otolaryngol Head Neck Surg. 2000;126:473-479.

Objectives  To test whether T-cell CD3 responses are altered in patients with advanced-stage head and neck squamous cell carcinoma (HNSCC) and whether anti-CD3/anti-CD28 (CD3/CD28) bead stimulation could reverse CD3 unresponsiveness.

Design  Anti-CD3 (CD3) monoclonal antibody immobilized on tissue culture plastic was used to stimulate lymph node mononuclear cells (LNMCs) and peripheral blood mononuclear cells (PBMCs) from patients with advanced-stage HNSCC. Proliferation, T-cell phenotype, and cytokines were measured during 8-day in vitro stimulation. Immune-enhancing properties of CD3/CD28 beads were also tested on LNMCs and PBMCs. Cytotoxicity of bead-activated T cells (ATCs) was measured against autologous and allogeneic HNSCC.

Results  Six patients were nonresponders to CD3 stimulation defined by tritium (³H) incorporation of less than 3500 cpm, whereas 11 patients were responders with ³H incorporation of 3500 cpm or more. Responders produced higher levels of interleukin (IL)–12 and interferon (IFN-) after CD3 stimulation than nonresponders. No phenotypic or clinical differences were identified between groups. Stimulation with CD3/CD28 beads enhanced IFN- and IL-2 produced by both groups. Bead ATCs were generated from PBMCs of patient 11 in the responder group and lysed (± SD) 100% ± 1% of autologous tumor and 49% ± 1% of allogeneic tumor. Bead ATCs from LNMCs of this patient lysed 58% ± 1% of autologous tumor and 63% ± 1% of allogeneic tumor.

Conclusions  A subpopulation of patients with HNSCC who are nonresponders to CD3 stimulation has been identified, showing reduced proliferation and IL-12 and IFN- secretion. Nonresponders stimulated with CD3/CD28 beads reversed immune unresponsiveness and induced a type 1 cytokine response. Bead-generated ATCs from patient 11 in the responder group lysed autologous and allogeneic HNSCC in vitro, suggesting a possible effective immunotherapeutic modality in the treatment of HNSCC.

From the Departments of Otolaryngology–Head and Neck Surgery (Drs Shibuya, Zormeier, Mathog, Meleca, and Yoo), Immunology-Microbiology (Dr Wei), Medicine (Dr Ensley), and Pathology (Dr Sakr), Wayne State University School of Medicine, and the Karmanos Cancer Institute (Drs Wei, Ensley, and Sakr), Detroit, Mich; the Departments of Molecular and Cellular Engineering and Medicine, University of Pennsylvania Cancer Center, Philadelphia (Drs June and Levine); and the Immunotherapy Research and Treatment Institute, St Luke's Medical Center, Milwaukee, Wis (Dr Lum).

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