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Development of Novel Immunotherapeutics 163 efficacy and vaccine-induced immune response. Thus, in essence, the induction of immune response would be aimed at eliciting central-memory (CM) T cells with a capability to further expand to peripheral memory (PM) and differentiate to peripheral effector (PE) cells, trafficking to the tumor site, and exerting antitumor cell activity inasmuch as there are T cells endowed with high functional avidity present. It is expected that host’s immune homeostatic mechanisms together with tumor’s environment result in exhaustion, apoptosis, and shrinkage of the self-tumor antigen–specific PE T-cell population. The subsequent immunization steps would be aimed to reelicit expansion and differentiation of PE cells from CM cells. Overall, repeat immunization would ensure reinduction of CM cells and differentiation of PE cells present in the system in an intermittent rather than continuous fashion. In addition, should there be induction of anticognate tumor antigen–specific T cells that promote a proinflammatory process, there is a possibility of “epitope spreading” that is mirrored by activation, expansion, and differentiation of T cells specific for other tumor antigens. Nevertheless, while the evidence in support of this phenomenon is quite limited (4), epitope spreading would be able to preempt—to a certain extent—immune escape mechanisms consisting in antigen loss. Despite the difficulties associated with the translation of observations from preclinical models to clinic, preclinical exploration is still important to optimize and advance complex active immunotherapeutic approaches to clinic. Exploration of “idealized” models encompassing dominant antigens and powerful methods of immunization in immune-competent organisms shed light on the limits of active immunotherapy and pinpoint the nature of indications associated with least chance of success in the clinic. Conversely, preclinical exploration provides hints regarding the type of indications to be explored in clinic and the end points to be evaluated (Fig. 9): 1. Minimal residual disease, postdebulking using surgery or other means that do not induce a persisting immune suppression (“adjuvant” approach); clinical end points may be overall survival, progression-free survival, and time to relapse. 2. Limited but measurable disease (metastatic or isolated lesions), in a setting that may or may not follow standard therapy that partially reduced the tumor burden without inducing persisting immune suppression; clinical end points may be progression-free survival, overall survival, tumor regression, and/or time to progression (TTP). 3. Bulky disease (metastatic or isolated lesions), refractory to standard therapy alone or rapidly relapsing, in a setting where immune competence is preserved. In that case, while active immunotherapy alone is not expected to impact disease progression, there is a potential that carefully selected combination approaches result in clinical benefit (increased response rate manifested through partial tumor regression, disease
164 Bot and Obrocea Figure 9 Defining the unmet clinical need vis-à-vis the potential of innovative immunotherapeutic approaches or cancer vaccines. stabilization, increased TTP, overall survival, and/or quality of life). There is still a significant amount of work that needs to be carried out both in preclinical models and in clinic to define combination approaches with impact on tumor progression; several candidates tested are: cyclophosphamide, fludarabine, doxorubicine, paclitaxel, or biological response modifiers such as anti-CTLA4, anti-CD25, or anti-CD4 monoclonal antibodies. BIOMARKER-GUIDED R&D In support of several components of the development process, the hallmarks of the new molecular targeted therapies are biomarkers. Unfortunately, there is a significant heterogeneity of biomarkers, somewhat hampering the communication in this area. We depicted three general categories of biomarkers in Figure 10, based on the scientific significance, utility, and implication to the drug development process. First, markers of disease, disease relapse, or progression are correlates of the pathologic process. Higher the disease burden, higher the level of such biomarkers or analytes. While there are very few sensitive and specific biomarkers in cancer, clusters of biomarkers as opposed to individual markers may be more reliable if they correlate with disease relapse or progression. In the context of cancer vaccines, such biomarkers may be key to identify individuals
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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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Table 1 Examples of Preclinical Act
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56 Srinivasan disease agents. Garda
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62 Srinivasan (69). In another stud
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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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104 Luptrawan et al. antigens (84,8
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Oncology and Immunology about the b
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