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

More documents

Recommendations

Info

Preclinical Models and Clinical Situation 41 Chemotherapy Plus Active Immunotherapy Chemotherapeutic agents have been tested with cancer vaccines and have demonstrated synergy in several models. For instance, docetaxel administered two days prior to each of the three vaccinations of GM-CSF-secreting B16 melanoma cells results in 50% long-term survival of B16 tumor–bearing mice compared to 10% survival with either agent alone (76). While docetaxel was shown to induce neutropenia and lymphopenia, the expansion and survival of antigen-specific T cells (examined in OT-1 TCR transgenic mice using OVAtransfected B16 cells) was not impaired. In another study using neu transgenic mice, three different chemotherapeutic drugs (cyclophosphamide, doxorubicin, and paclitaxel) were tested in combination with a HER-2/neu expressing tumor vaccine and showed enhanced activity in a therapeutic setting (77). Whether drug was administered before or after vaccination affected the outcome and the optimal order of administration was found to vary from one drug to the next. Some recent clinical studies provide yet another somewhat surprising perspective on how active immunotherapy might synergize with chemotherapy. With the caveat associated with retrospective analysis, 25 patients with glioblastoma multiforme were vaccinated with DCs loaded with autologous tumor HLA-eluted peptides or tumor lysate (78). Thirteen of these patients went on to receive subsequent chemotherapy. An additional 13 nonvaccinated patients analyzed in this study also received chemotherapy. Of the vaccine plus chemotherapy-treated patients, 42% were two-year survivors while only 8% of patients treated with chemotherapy alone or vaccine alone survived this long. It is hypothesized that infiltrating CD8þ T cells may upregulate markers on the tumor (e.g., Fas), which render cells more susceptible to chemotherapeutic drugs that kill targets via induction of apoptosis. In another study, a striking response rate of 62% among 21 extensive-stage small cell lung cancer patients treated with second-line chemotherapy was observed after vaccination with DCs transduced with full-length p53 (79). Thirteen of the 21 patients were platinum-resistant and 61.5% of these were responders. In a third study of patients with various metastatic cancers treated with a DNA vaccine encoding a common tumor antigen, five of six immune responders who received subsequent salvage therapy experienced unexpected clinical benefit (80). Among those benefiting from the salvage therapy were four patients with progressive disease after vaccination. Among eight patients who did not demonstrate immunity to vaccination and who survived to receive additional therapy, only one derived clinical benefit. Clearly, determining the optimal mode of administration represents a challenge to clinical applications of vaccine/chemotherapy combinations, as the best regimen may only be understood through an extensive matrix of combination testing in clinical trials. Furthermore, as discussed by Lake and Robinson, delivery of more antigen by vaccination may not be necessary in cases where the chemotherapeutic agent alone results in sufficient antigen release via tumor cell
42 Levey apoptosis and secondary necrosis (81). In these situations, amplification of endogenous responses to cross-presented antigen using antibodies against, e.g., CD40, may be sufficient to realize clinical benefit (82). Nonspecific Immune Modulation Plus Active Immunotherapy Another trend emerging in the practice of active immunotherapy with personalized (and nonpersonalized) cancer vaccines is their use in combination with other nonspecific immunomodulatory agents. Again, these combination approaches are likely to be necessary in any setting more advanced than minimal residual disease (83). Moreover, if the nonspecific agents prove to be well tolerated with minimal toxicity, there may be incentive to employ them even in the setting of minimal disease burden to further decrease the likelihood of disease recurrence. The nonspecific agents include antibodies against CTLA-4 that are designed to prevent effector T cell downregulation and a large number of agents that address the problem of immune suppression in tumor-bearing hosts. With emphases on preclinical testing, these various agents are discussed in turn below. Striking synergy between anti-CTLA-4 antibody and autologous GM-CSFsecreting B16 melanoma and SM1 breast tumor vaccines against established disease in mice has been observed, and the antibody has also been tested in combination with an off-the-shelf GM-CSF-secreting prostate cancer vaccine, with promising results in preclinical studies (84–86). In a preliminary study in human cancer patients previously treated with either autologous or off-the-shelf cancer vaccines who went on to receive infusion with anti-CTLA-4 antibody, only those patients who received the autologous vaccine demonstrated signals of clinical activity (87). Many additional clinical trials are underway testing anti-CTLA-4 antibody either as monotherapy or in combination with off-the-shelf peptide vaccines, GM-CSF, and off-the-shelf whole cell vaccines (88,89 and http://www.clinicaltrials.gov/). Unfortunately, there are no clinical trials currently underway testing anti-CTLA-4 antibody with personalized cancer vaccines despite the suggestion that autologous vaccines may be a particularly potent partner for this antibody. Will the dose of antibody required vary depending on what vaccine type is employed? This later question is of interest given the autoimmune-like toxicities associated with the antibody (90). In the last 10 to 15 years, the issue of specific immune suppression in tumor-bearing hosts has moved from a concept with few tangible toe holds from which to direct therapeutic intervention to remarkable progress in identifying molecular structures and cell types that are ripe for targeting in preclinical and clinical settings. One can envision that just as different chemotherapeutics have been combined in the clinic based on unique mechanisms of action, multiple agents each working to address distinct pathways of immune suppression will be utilized in combination. A nonexhaustive list of agents, their biological targets and evidence, where available, for utility in combination with cancer vaccines are presented in Table 3. Two agents that address the problem posed by accumulation of regulatory T cells (Tregs) are discussed in some detail.
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 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 68: Preclinical Models and Clinical Sit
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 150 and 151:
Page 152 and 153:
Page 154 and 155:
Page 156 and 157:
Page 158 and 159:
Page 160 and 161:
Page 162 and 163:
Figure 5.1 Immunohistochemical char
Page 164 and 165:
Figure 8.5 A schematic representati
Page 166 and 167:
Page 168 and 169:
Page 170 and 171:
8 Bidirectional Bedside Lab Bench P
Page 172 and 173:
Development of Novel Immunotherapeu
Page 174 and 175:
Page 176 and 177:
Page 178 and 179:
Page 180 and 181:
Page 182 and 183:
Page 184 and 185:
Page 186 and 187:
Page 188 and 189:
Page 190 and 191:
Page 192 and 193:
Page 194 and 195:
Page 196 and 197:
Page 198 and 199:
Page 200 and 201:
9 Diagnostic Approaches for Selecti
Page 202 and 203:
Diagnostic Approaches to Maximize T
Page 204 and 205:
Page 206 and 207:
Page 208 and 209:
Page 210 and 211:
Page 212 and 213:
Page 214 and 215:
Page 216 and 217:
Page 218 and 219:
Page 220 and 221:
Page 222:
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.

Create successful ePaper yourself

Delete template?

Save as template?