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9 Diagnostic Approaches for Selecting Patient-Customized Therapies, Obviating Tumor Variability to Maximize Therapeutic Effect Chih-Sheng Chiang, Nathalie Kertesz, and Zheng Liu Division of Translational Medicine, MannKind Corporation, Valencia, California, U.S.A. NEED FOR DIAGNOSTIC INFORMATION TO GUIDE TARGETED THERAPY (THERANOSTICS) One of the promising concepts for improving health care utilizing the considerable knowledge gained in the past century is personalized medicine or individualized medicine. Basically, the promise is that therapeutic efficacy can be maximized while minimizing side effects if treatments are designed according to the relevant genotype and phenotype information of the individual (1). Another aspect of personalized medicine is monitoring the evolution of the disease (including the effects of treatment and changes of the disease target itself) and adjusting further therapy accordingly. In order to obtain the relevant information of the individual and monitor the disease evolution, appropriate diagnostic methods need to be applied. Therefore, the approach of utilizing relevant diagnostic information to guide therapy (known as theranostics) has become an essential component of personalized medicine. 181
182 Chiang et al. Cancer is a very complex collection of diseases. Not only are there multiple organ types and histotypes, but also the underlying molecular variations in each type of cancer are numerous (2,3). Genomic instability has been observed in most types of tumors, and mutations accumulate at accelerated rates in cancer cells. Therefore, cancer of the same type will be different from one patient to the next (4). Moreover, there is considerable heterogeneity within the same type of cancer in a single patient. That is, within the same patient, some cancer cells would have different characteristics from other cancer cells (4). The limited efficacy and lack of standardization of conventional chemotherapy have lead to the development and implementation of alternative strategies for the treatment of malignant diseases. The role of immune surveillance in the control of tumor growth has sparked a large amount of attention on immunotherapy (5). Another factor that has placed immunotherapy on the forefront of new cancer therapies is the significant progress in the identification of human tumor–associated antigens (6) and in the characterization of the molecular steps leading to an immune response (7). Immunotherapy of cancer generally targets tumor-associated antigens (TAA) frequently expressed in cancers but seldom in normal tissues. In passive immunotherapy, an immunologically active molecule such as monoclonal antibody is provided by the treatment. Thus, loss or downregulation of target antigen expression by a tumor cell would allow it to escape the immunity generated or provided by immunotherapy. In active immunotherapy, a substance capable of inducing the patients’ own immunity to the targeted antigens is provided by the treatment. The emphasis has been on T cell–based immunotherapy, because T cells, especially cytolytic T cells (CTL), are generally believed to play a major role in the control of tumor growth (8). Antigen-specific CTL recognize specific human leukocyte antigen class I (HLA1)-TAA–derived peptide complexes on the cell surface. These complexes are generated, transported to the cell membrane, and presented to CTL through a series of sequential steps including proteasomal cleavage of proteins in the cytoplasm (9), transport of peptides by the transporter associated with antigen-processing complex (TAP1-TAP2) to the endoplasmic reticulum (10), and loading of peptides on the b2-microglobulin (b2M)–HLA1 heavy chain complex (11,12). The peptide-b2M-HLA1 heavy chain complex then travels to the cell membrane and is presented to CTL. In the last decade, there has been renewed interest in the class I major histocompatibility complex (MHC1) antigens in tumors with the realization of the crucial role played by MHC1 antigens in the recognition of tumor cells by CTL (13) and with the emphasis on T cell–based immunotherapy for the treatment of human cancer (14,15). Most MHC1-presented peptides are derived from endogenous proteins such as tumor antigens and viral antigens. Approximately 40–90% of human tumors derived from various MHC1-positive tissues were reported to be MHC1 deficient. Furthermore, tumor cells with downregulated MHC1 antigen expression show enhanced growth and are frequently associated
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Translational Medicine Series 6 Can
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TRANSLATIONAL MEDICINE SERIES 1. Pr
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Informa Healthcare USA, Inc. 52 Van
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Preface Throughout the last 20 year
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Preface vii Table 1 A Diverse Techn
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Preface . . . . v Contributors . .
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Contributors Pedro Alves Ludwig Ins
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1 Factoring in Antigen Processing i
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Factoring in Antigen Processing in
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Preclinical Models and Clinical Sit
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56 Srinivasan disease agents. Garda
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58 Srinivasan expressing various kn
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60 Srinivasan The above-mentioned a
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62 Srinivasan (69). In another stud
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64 Srinivasan patients with prostat
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84 Luptrawan et al. Dendritic cells
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86 Luptrawan et al. of cancer cells
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88 Luptrawan et al. NK cells can ki
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90 Luptrawan et al. Figure 2 Repres
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92 Luptrawan et al. state (50). Pat
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94 Luptrawan et al. ability of TIL
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98 Luptrawan et al. Figure 6 Tumor
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104 Luptrawan et al. antigens (84,8
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106 Luptrawan et al. 30. Ranges GE,
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108 Luptrawan et al. 66. Dunn GP, B
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110 Schroter and Minev proteins (2,
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7 Multimodality Immunization Approa
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Multimodality Immunization Approach
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