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Diagnostic Approaches to Maximize Therapeutic Effect 197 paper, markers useful for patient stratification should be identified and assays developed during preclinical development phase of the therapeutic product. Tests for stratifying patients suitable for use in a clinical lab should be available before the start of phase 1 trials. If an analytical platform change for testing (e.g., from RIA to EIA) is needed to make the diagnostics more easily adopted by the intended market, the change should be finalized before the start of phase 3 trials so that clinical validation of the test using the new platform can be completed in time. Different opinions exist for the optimal timing of various activities mentioned in FDA’s concept paper, but in general, strategies for satisfying FDA’s requirement of companion diagnostics should be formulated in the preclinical development phase and finalized during phase 2 trials, if not earlier. Negotiations with potential diagnostics partners should also begin as soon as the strategy is developed. The earlier an organization developing a promising immunotherapy starts the preparation for getting companion diagnostics ready, the more likely it would be able to navigate the approval process for the immunotherapy product without surprises and costly delays. CONCLUSIONS It is clear that we are evidencing a rapidly changing situation where more and more diagnostic information will be used before and throughout the treatment period to guide the therapy for cancer. Even for conventional chemotherapeutic agents, relevant biochemical characteristics of cancer cells can be used to select patients before therapy to improve response rates and outcome (55). This trend is also evident in other fields such as infectious diseases. For example, genotyping and phenotyping of HIV have been widely used to guide drug therapy for HIV infection since the 1990s (56). Relevant information of the virus makes rational and efficacious drug combinations possible for the control of HIV infection. Similar pictures are emerging for the treatment of HCV in terms of using genotype information to select the most appropriate drugs for each patient (57). As we learn more about the mechanisms of pathogenic processes of various diseases and develop more targeted therapies, relevant diagnostic information will be used more frequently to help stratify patients and guide therapy. For example, with the recent demonstration of potentially efficacious agents for ameliorating effects of nonsense mutations (58), use of genotype information (nature of mutation) of the affected gene in diseases such as cystic fibrosis may become essential in the treatment of certain genetic diseases. Therefore, in the next decade, we will probably see more extensive use of diagnostic information to help guide therapies in many diseases in addition to cancer. Targeted immunotherapies are specific for certain antigens expressed by tumors and hold great promises to improve treatment for many types of cancers where current modalities fall short. However, the exquisite specificity of immunotherapy requires that the targeted antigens be present in the tumor tissue.
198 Chiang et al. Because cancers are very variable, biochemical characteristics of a given type of cancer can differ significantly from patient to patient. Information on the characteristics of the tumor as well as the host will be important for the selection of patients most likely to benefit from immunotherapy. After initiation of immunotherapy, monitoring the host response would allow continuous adjustment of therapy to maximize desired outcome. The combined use of relevant diagnostic information obtained on the cancer tissue as well as that during the course of treatment from individual patients as guidance for therapy would be necessary for maximizing the therapeutic efficacy of immunotherapy (Figure 2). From a financial vantage point, the same reasoning applies that utilization of relevant diagnostic information will be critical for the most effective use of health-care dollars. Indiscriminate use of specific immunotherapy will increase the cost of health care and may generate undesirable side effects in some patients. From a regulatory point of view, the sooner an organization makes the needed diagnostic tests available, the more likely it would be successful at satisfying FDA requirements for timely approval of its immunotherapy product. Therefore, one should start formulating the strategies for utilizing and developing diagnostic and monitoring assays as early as possible in the development process of an immunotherapeutic agent. We can obviate tumor variability, maximize the treatment efficacy, minimize adverse side effects, and speed up the approval process of immunotherapeutic drugs if we develop needed tests early and utilize information obtained through testing intelligently. There is currently an increasingly growing emphasis on genetic testing and individualized therapy to improve drug efficacy and safety with large investments by major pharmaceutical firms in order to provide a competitive advantage. The future holds promise, with the growing availability of analytical capabilities, to perform genome wide association studies during clinical trials enabling the selection of disease susceptibility genes for prognosis, drug discovery, dosing, and selection of therapy and preventative medicine. There is a significant source of variability observed in the response to drugs, caused by genetic heterogeneity. We could continue to utilize the variability in interethnic and interindividual genetics to facilitate rational drug design and to avoid adverse effects in clinical trials. Thus, one could generate criteria for selecting patients most likely to benefit from a drug without incurring unnecessary risk. The future of theranostics approaches also holds promise for early or preventive therapy that could significantly enhance clinical outcome. Looking farther ahead, the efficacy of administered drugs may be improved, rather than avoiding toxicity as the main objective, by distinguishing good responders from poor responders prior to therapy, changing clinical trial design as we know it. Often, effective drug response is limited to a portion of treated patients, whereas the majority benefits little or not at all. Predicting which patients are most likely to respond best to a particular drug, or which drug will yield optimal effects for a given patient, would represent a significant advance in therapy even with current
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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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Preclinical Models and Clinical Sit
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56 Srinivasan disease agents. Garda
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60 Srinivasan The above-mentioned a
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62 Srinivasan (69). In another stud
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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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92 Luptrawan et al. state (50). Pat
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98 Luptrawan et al. Figure 6 Tumor
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102 Luptrawan et al. Table 1 Summar
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104 Luptrawan et al. antigens (84,8
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7 Multimodality Immunization Approa
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Multimodality Immunization Approach
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