Download File - JOHN J. HADDAD, Ph.D.

More documents

Recommendations

Info

Development of Novel Immunotherapeutics 177 Figure 16 Optimizing the development strategy of cancer vaccines coherent with challenges posed by this class of investigational drugs. information can be used to narrow down the development process to doses, regimens, and tumor types that are associated with higher likelihood of success. That is provided that preset success criteria were met for one or few of the regimens and/or tumor types. This approach is in line with what has been proposed by a cancer vaccine consortium panel recently (21) and would achieve a considerable amount of information in a shorter interval of time (in addition to safety/toxicity data)—the latter being the major aim of conventional phase 1 trials. The approaches are as follows: l Definition of dosage/regimens resulting in measurable immune responses; l Tumor types that have a lower likelihood of supporting immune responses against specific antigens due to various reasons; l Correlation between immunological response, biomarkers, and clinical outcome; more valuable in phase 2a when the homogeneity of the patient population is higher, after exclusion of less promising tumor types and dosing regimens. Beyond the phase 1/2a, a phase 2b program would focus on exploring the most promising dosing regimen in several indications associated with one or two tumor
178 Bot and Obrocea types at maximum, via a set of randomized trials carried out in parallel. This approach would achieve a faster evaluation, in an objective fashion, of the efficacy of the cancer vaccine as opposed to using historical controls (a usual source for bias in the case of first–in-class investigational drugs). If used properly, this approach may prevent transition to phase 3 if the drug is not likely to be effective; conversely, this strategy may offer significant information and even anticipate the optimal design of the phase 3 program. In addition, due to the fact that cancer vaccines can be applied as adjuvants in minimal residual disease post-standard therapy, they can be used as a companion to standard therapy (combination approach) or in late stages, in refractory setting as monotherapy. Ideally, all these indications should be explored in parallel in a randomized phase 2b program to provide a data set to make appropriate recommendations for one or multiple pivotal phase 3 trials necessary for defining the product profile and registration. CONCLUSIONS In conclusion, due to cancer vaccines’ intrinsic nature (targeted therapies with indirect MOA) and scarcity of benchmarks in terms of late-stage or approved products, a re-designed translational approach would be fully beneficial for the development of such therapies. The critical element of this approach is the stratified medicine concept—essentially encompassing biomarker-guided R&D. This approach can be done through an iterative translational strategy aimed to optimize the investigational drug and define the target population prior to randomized trials. In addition, innovative, flexible, and adaptive clinical trial designs will support early generation of relevant data in humans. While there are differences in between technology platforms explored as cancer vaccines, these principles apply irrespectively and should result in an increased likelihood of success. To extract the essence of R&D in the post–human genome project era of molecular targeted approaches, we no longer develop drugs alone but also therapeutic approaches, encompassing both the means to identify the patient and the appropriate medicament. REFERENCES 1. Gattinoni L, Powell DJ Jr., Rosenberg SA, Restifo NP. Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol 2006; 6(5):383–393. 2. Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002; 298:850–854. 3. Quezada SA, Peggs KS, Curran MA, et al. CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest 2006; 116(7):1935–1945. 4. Weber JS, Mulé JJ. How much help does a vaccine-induced T-cell response need? J Clin Invest 2001; 107(5):553–554.
Page 1 and 2:
Translational Medicine Series 6 Can
Page 3 and 4:
TRANSLATIONAL MEDICINE SERIES 1. Pr
Page 5 and 6:
Informa Healthcare USA, Inc. 52 Van
Page 8 and 9:
Preface Throughout the last 20 year
Page 10 and 11:
Preface vii Table 1 A Diverse Techn
Page 12 and 13:
Preface . . . . v Contributors . .
Page 14 and 15:
Contributors Pedro Alves Ludwig Ins
Page 16 and 17:
1 Factoring in Antigen Processing i
Page 18 and 19:
Factoring in Antigen Processing in
Page 20 and 21:
Page 22 and 23:
Page 24 and 25:
Page 26 and 27:
Page 28 and 29:
Page 30 and 31:
Page 32 and 33:
Page 34 and 35:
Page 36 and 37:
Page 38 and 39:
Page 40 and 41:
Page 42 and 43:
Page 44 and 45:
Page 46 and 47:
2 Outlining the Gap Between Preclin
Page 48 and 49:
Preclinical Models and Clinical Sit
Page 50 and 51:
Table 1 Examples of Preclinical Act
Page 52 and 53:
Page 54 and 55:
Page 56 and 57:
Page 58 and 59:
Page 60 and 61:
Page 62 and 63:
Page 64 and 65:
Page 66 and 67:
Page 68:
Page 71 and 72:
56 Srinivasan disease agents. Garda
Page 73 and 74:
58 Srinivasan expressing various kn
Page 75 and 76:
60 Srinivasan The above-mentioned a
Page 77 and 78:
62 Srinivasan (69). In another stud
Page 79 and 80:
64 Srinivasan patients with prostat
Page 81 and 82:
66 Srinivasan 33. Salgia R, Lynch T
Page 83 and 84:
68 Srinivasan 67. Werness BA, Levin
Page 85 and 86:
70 Teofilovici and Wentworth In 190
Page 87 and 88:
72 Teofilovici and Wentworth conduc
Page 89 and 90:
74 Teofilovici and Wentworth Lipono
Page 91 and 92:
76 Teofilovici and Wentworth (best
Page 93 and 94:
78 Teofilovici and Wentworth nature
Page 95 and 96:
80 Teofilovici and Wentworth In the
Page 97 and 98:
82 Teofilovici and Wentworth 17. Ba
Page 99 and 100:
84 Luptrawan et al. Dendritic cells
Page 101 and 102:
86 Luptrawan et al. of cancer cells
Page 103 and 104:
88 Luptrawan et al. NK cells can ki
Page 105 and 106:
90 Luptrawan et al. Figure 2 Repres
Page 107 and 108:
92 Luptrawan et al. state (50). Pat
Page 109 and 110:
94 Luptrawan et al. ability of TIL
Page 111 and 112:
96 Luptrawan et al. Figure 4 Drug s
Page 113 and 114:
98 Luptrawan et al. Figure 6 Tumor
Page 115 and 116:
Table 1 Summary of results of phase
Page 117 and 118:
102 Luptrawan et al. Table 1 Summar
Page 119 and 120:
104 Luptrawan et al. antigens (84,8
Page 121 and 122:
106 Luptrawan et al. 30. Ranges GE,
Page 123 and 124:
108 Luptrawan et al. 66. Dunn GP, B
Page 125 and 126:
110 Schroter and Minev proteins (2,
Page 127 and 128:
112 Schroter and Minev tumor-challe
Page 129 and 130:
114 Schroter and Minev Table 1 Inve
Page 131 and 132:
116 Schroter and Minev Table 1 Inve
Page 133 and 134:
118 Schroter and Minev demonstrated
Page 135 and 136:
120 Schroter and Minev loaded MART-
Page 137 and 138:
122 Schroter and Minev illustrate t
Page 139 and 140:
124 Schroter and Minev 4. Heemels M
Page 141 and 142:
126 Schroter and Minev 42. Minev BR
Page 143 and 144:
128 Schroter and Minev 74. Restifo
Page 146 and 147: 7 Multimodality Immunization Approa
Page 148 and 149: Multimodality Immunization Approach
Page 162 and 163: Figure 5.1 Immunohistochemical char
Page 164 and 165: Figure 8.5 A schematic representati
Page 170 and 171: 8 Bidirectional Bedside Lab Bench P
Page 172 and 173: Development of Novel Immunotherapeu
Page 200 and 201: 9 Diagnostic Approaches for Selecti
Page 202 and 203: Diagnostic Approaches to Maximize T
Page 222: Diagnostic Approaches to Maximize T
Page 225 and 226: 206 Index Antigenic peptides degrad
Page 227 and 228: 208 Index Chromogens, enzymatic act
Page 229 and 230: 210 Index Freund’s adjuvants. See
Page 231 and 232: 212 Index Langerhans cells, 133, 13
Page 233 and 234: 214 Index [Peptide vaccines] invest
Page 235 and 236: 216 Index TCRL. See TCR-like immuno
Page 238: Oncology and Immunology about the b
show all

Download File - JOHN J. HADDAD, Ph.D.

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?