Cancer Therapy Vol 4, page 81 Cancer Therapy Vol 4, 81-98, 2006
Cancer immunotherapy Review Article
Carole L. Berger*, Joshua Shofner, Juan Gabriel Vasquez, Kavita Mariwalla and Richard L. Edelson Yale University, School of Medicine, Department of Dermatology and Comprehensive Cancer Center
__________________________________________________________________________________ *Correspondence: Carole L. Berger, Ph. D. Yale University, School of Medicine, Department of Dermatology, 333 Cedar Street, New Haven CT 06520; Tel: (203) 737-4024; Fax (203) 785-7637; E-mail: carole.berger@yale.edu Key words: Cancer immunotherapy, Cutaneous T cell lymphoma, Dendritic cells, CD4 and CD8 T cells, immunity, T regulatory cells, Heat shock proteins, immune response, CTCL cells, malignancy, Treg cells, Cytokine therapy, Monoclonal antibody therapy Abbreviations: 8-methoxypsoralen, (8-MOP); antibody-dependent cellular cytotoxicity, (ADCC); antigen presenting cells, (APC); cutaneous T cell lymphoma, (CTCL); cytotoxic T lymphocyte antigen-4, (CTLA-4); dendritic cell, (DC); epidermal growth factor receptor, (EGFR); extracorporeal photopheresis, (ECP); glucocorticoid-induced TNF receptor, (GITR); granulocyte-monocyte colony stimulating factor, (GMCSF); heat shock protein-peptide complexes, (HSPPC); heat shock proteins, (HSP); interleukin 10, (IL10); Keyhole Limpet Hemocyanin, (KLH); Langerhans cell, (LC); lipopolysaccharide, (LPS); monocyte conditioned media, (MCM); natural killer T cells, (NKT); nuclear factor-!B, (NF-!B); pattern recognition receptors, (PRR); psoralen and ultraviolet light therapy, (PUVA); receptor activator of NF-!B, (RANK); T cell receptor, (TCR); TNF-related activation induced cytokine, (TRANCE); Toll-like receptors, (TLR); T-regulatory cells, (Treg); Transimmunization, (TI); ultraviolet A, (UVA); vascular epidermal growth factor, (VEGF); X-linked syndrome, (IPEX) Received: 27 October 2005; Accepted: 11 November 2005; electronically published: March 2006
Abstract This article reviews current advances in the immunotherapy of cancer with a particular focus on our experience with cutaneous T cell lymphoma. We have developed an in vitro model of the growth of this malignancy that has enabled us to decipher the clinical phenotype of the disease and identified new targets for therapeutic intervention. Our studies in this disease can provide a road map for translational immunotherapy, whereby, the clinical features of the disease provide leads that can be followed in the laboratory and the investigational results can be used to interpret the clinical findings. This bidirectional partnership between the clinic and the bench can be exploited to develop a better understanding of cancer and may yield more targeted and less toxic forms of immunotherapy.
advances in basic science can inform the search for relevant treatments. We will then selectively review other forms of immunotherapy that show particular promise in the treatment of CTCL and a variety of other cancers.
I. Introduction Over the past few years the long sought goal of effective, non-toxic cancer immunotherapy has become tantalizingly within reach as our understanding of the immune system and the cells that mediate immunity and tolerance have been clarified by molecular and biologic advances. We are progressing towards the crafting of therapies to improve the treatment of a variety of malignancies and techniques that will aid in diagnosis and monitoring. This review will highlight promising new forms of immunotherapy and demonstrate how a better understanding of the functioning of the immune system has translated into novel therapies for cancer. As a case in point, we will first focus on our studies in cutaneous T cell lymphoma (CTCL) which have elucidated the immunobiology of the disease and identified potential therapeutic targets (Berger et al, 2002a, 2005). Our studies in this disease serve to illustrate the paradigm that
A. Cutaneous T cell lymphoma CTCL is a clonal malignant expansion of antigenexperienced CD4 T cells that localize in the epidermis in direct association with an immature member of the dendritic cell (DC) series, the Langerhans cell (LC, Figure 1). The clonality of the malignant T cells has been confirmed at the phenotypic and molecular level by the demonstration that the CTCL cells all carry an identical T cell receptor (TCR) and by karyotypic and polymerase chain analysis which revealed clonal abnormalities unique for individual patients (Berger et al, 1988; Charley et al, 1990; Volkenandt et al, 1994). These phenotypic and genetic profiles can be used for disease diagnosis and 81