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.

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 immu-notherapy (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 (HLAl)-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 ^-microglobulin (p2M)-HLA1 heavy chain complex (11,12). The peptide-p2M-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

Table 1 Benefits of Patient Stratification for Immunotherapy

Improve response rate

Obviate tumor variability

Maximize treatment efficacy

Minimize adverse side effects

Avoid unnecessary exposure to therapeutic agents

Save valuable time and health-care money with disease progression toward the invasive and metastatic tumor phenotype (16). Abnormalities in the expression and/or function of antigen-processing machinery components and/or HLA1 may lead to defects in the expression of HLAl-peptide complexes and defects in the recognition of targets by CTL. This seems to be used as an escape mechanism by tumor cells to escape from immune recognition and destruction (17). Additionally, production of factors that block effector cell functions locally would also enable the cancer cell to become resistant to the immune response induced by the therapy (18) and may account for the unexpected poor prognosis of the disease in patients with high expression of HLA1 in primary and/or metastatic lesions (19) and with recurrence of the disease in patients treated with T cell-based immunotherapy (20,21). Therefore, patient stratification or selection before prescribing immunotherapy is necessary for achieving the best efficacy and for minimizing undesirable side effects. From an economic point of view, it is also important to select the patient population most likely to benefit from the therapy so that health-care money is spent effectively (Table 1).

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