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Development of Novel Immunotherapeutics 161 be infused systemically and directly into the primary tumor. The relative removal of target cells can be assessed at various time points both within tumor and peripheral lymphoid or nonlymphoid organs containing metastatic tumor cells. An accumulating body of evidence supports the view that despite trafficking of tumor-specific T cells into the primary tumor, the specific activity within the tumor is limited in contrast to the optimal removal of antigenic target cells within peripheral lymphoid organs and blood (Fig. 6). Altogether, it appears that in a setting of immune competence, successful induction of tumor-specific immunity results in optimal systemic immune surveillance compatible with removal of M0/ M1-circulating cells and micrometastatic foci without effectively interfering with tumor-cell viability within bulky tumor lesions. Another key question related to optimal translation of investigational active immunotherapies is the duration and intensity of the immunization protocol; this question is relevant since only a minor fraction (1% or less) of the elicited tumor-specific T cells have the capability to produce proinflammatory or cytotoxic mediators upon contact with tumor cells. This supports the model in which most of the tumor-antigen-specific T cells elicited by active immunotherapy do not have an optimal functional avidity and indicate the need to improve on this parameter by deploying more advanced vaccination methods. Therefore, a key parameter to be followed—in addition to the magnitude of the immune response and its effector profile—is the functional avidity as expressed by the slope of the curve in Figure 7 (angle O, corresponding to the ratio between the variation of frequency of tumor-reactive cells and the variation of frequency of antigen-specific cells measured in condition of optimal restimulation of T cells with synthetic peptide). The relationship between the immune response to vaccine and the immune modulating activity of the tumor process can be modeled as well to a certain extent; there are at least two scenarios from the standpoint of whether vaccine-elicited Figure 7 Definition functional avidity of tumor antigen–specific T cells.
162 Bot and Obrocea immunity initiates or does not initiate a self-perpetuating response against the tumor. In the first scenario, tumor antigen–specific T cells induced or activated by the active immunotherapeutic regimen, traffic to the tumor site where they affect the viability of target tumor cells. Subsequently, antigens liberated by the tumor cells are internalized and processed by resident antigen-presenting cells (APCs) that migrate to regional lymph nodes where they successfully restimulate, amplify, or maintain the immune response to the immunizing antigen and even additional tumor-specific antigens. In this model, subsequent immunization to maintain a level of effector cells within tumor or lymphoid organs would not be necessary since the direct stimulating effect of the tumor is under the attack of vaccine-induced T cells. In the second model, while the vaccine is able to elicit a population of tumor antigen–specific T cells encompassing high-avidity T cells, tumor-derived antigen is not sufficient to maintain or amplify the immune response. This results in the model depicted in Figure 8, quite supported by experimental evidence. More specifically, repeat administration of antigen would be instrumental not only for eliciting a response with a maximum potential, but to maintain a subpopulation of high-avidity functional T cells with activity against tumor cells. In absence of continuing the immunization process, the tumor cells alone would be incapable to drive expansion and differentiation of memory T cells to effector cells, with serious consequences in terms of the Figure 8 A schematic depiction of the functional, immunologic relationship between tumor antigens–specific T cells and tumor cells, with impact on design-improved immunotherapeutic approaches.
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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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2 Outlining the Gap Between Preclin
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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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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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66 Srinivasan 33. Salgia R, Lynch T
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68 Srinivasan 67. Werness BA, Levin
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82 Teofilovici and Wentworth 17. Ba
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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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94 Luptrawan et al. ability of TIL
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98 Luptrawan et al. Figure 6 Tumor
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Table 1 Summary of results of phase
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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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108 Luptrawan et al. 66. Dunn GP, B
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112 Schroter and Minev tumor-challe
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212 Index Langerhans cells, 133, 13
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214 Index [Peptide vaccines] invest
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216 Index TCRL. See TCR-like immuno
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Oncology and Immunology about the b
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