372 Index. B Basic fibroblast growth factor receptor (bfgfr), 91 B7-H1/PD-1 pathway, monoclonal antibodies

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1 A Activation-induced cell death (AICD), 310 Adjuvant therapy, Adoptive cell therapy ACT, 234 advantages and disadvantages, biological and technical limitations long-term persistence, 245 technical issues, 242, telomere shortening and cellular senescence, terminal differentiation, CD8 + T Cells, capillary leak syndrome, 234 CARs, B-cell antigen recognition, 235, 256 CD4 + T-Helper 17/Th17 cells, 255 clinical-grade expansion adoptive therapy, erythromyeloid cell, 254 gas-permeable bag technology, 255 sleeping beauty system, 254 costimulatory pathways, negative and positive CTLA-4, 250 phase II/III testing, 250 TNF-R costimulatory pathways, 250 tumor eradication, 249 dacarbazine, 234 factors, melanoma patients, function and persistence, TIL, future perspective cytokines/synergistic immunomodulatory, pivotal multicenter clinical trial, TIL adoptive therapy, TKIs therapy, IL-2 therapy, 234 lymphodepleting, melanoma development cyclophosphamide and fludarabine, historical timeline and milestones, 236, 237 immunological competent cell, 236 NK cells, melanoma methods ACT and TIL, antigen-specific CD4 + T cells, 244 antigen-specific CD8 + T cells, TCR-transduced peripheral blood T cells, TIL expansion protocols, persistence and effector function, targeting TGF-., TIL methods and ACT, , 248 tumor migration, 252 Adoptive T cell therapy (ACT), 234 Agonist immune costimulatory agents anti-cd137/4-1bb cisplatin, 316 clinical experience, enhancement vs. suppression, 315 immune-enhancing effects, 314 osteosarcoma and lung cancer, 314 proliferation/survival, 314 tumor growth/regression, delays, 315 antitumor immune responses, CD40, clinical experience, anti-ox40, T.F. Gajewski and F.S. Hodi (eds.), Targeted Therapeutics in Melanoma, Current Clinical Oncology, DOI / , Springer Science+Business Media, LLC

2 372 Agonist immune costimulatory agents (cont.) endothelium, 322 human, host and tumor interaction, 309 IFN-a and interleukin-2, 308 licensing effect, 322 ligand receptor interactions, 308 OX40/CD134 AICD, 310 breast cancer model, 312 CD28/B7 interaction, 310 cyclophosphamide treatment, 312 proliferation and survival, sarcoma-bearing mice, 311 synergistic therapeutic effect, 312 transgenic mouse models, 311 OX40-specific nonhuman, Anti-angiogenesis therapy agents, completed trials, axitinib, 163 biologic/cytotoxic agents, chemotherapy theories, 171 clinical activity, 162 clinical trials, 169 combinations chemotherapy, 171 components, therapies, disease progression, EGFL7, 170 highly vascular malignancy, immunotherapy, 176 indirect effects, 169 inhibitors vs. combinations, 171, 175 integrins, 170 lymphangiogenesis, 171 mediators of angiogenesis immunohistochemical analysis, 158 soluble angiogenic factors, VEGF/VEGF-A, 158 monocyte maturation and activation, 175 prognostic significance, 162 sorafenib, 168 tumor-infiltrating myeloid cells, 170 vascular normalization, 171 VEGF ligand, VEGFR TKIs, Anti-CTLA-4 monoclonal antibodies blocking antibodies, 277 checkpoint immuno-inhibitory, 274 clinical trial testing adjuvant therapy, antibody responses, biomarkers, immune, adverse events, ipilimumab monotherapy, 278 ipilimumab plus chemotherapy, 282 peptide vaccines, 279 phase III, ipilimumab, 281 response criteria, tremelimumab, co-inhibitory molecule, 275 immune potentiation mechanism, immuno-inhibitory, 274 T cell-extrinsic suppression, T cell-intrinsic suppression, tumor immunotherapy, 277 Apoptotic pathways Bcl-2 protein cancer cells, 132 cell damage, BH3 domains, 128 family proteins, targeting, 132 gossypol, immunohistochemical, 129 loss expression, Mcl-1 expression, melanoma metastasis, MITF, 128 mitochondria, 127 neutralization model, 128 OMM interaction, PFS and ORR, 132 structure and role, BH3 mimetics, cancer therapy, smac mimetics, extrinsic pathway, 126 IAPs negative regulation, intrinsic/mitochondrial cell death, 126 melanoma proteins, micrornas, upregulation, BH3-only, 131 RAS/RAF/MEK/ERK blocks apoptosis, BRAF mutation, 134 carboplatin/paclitaxel effects, 136 CREB activation, 135 farnesyltransferase inhibitors, 135 G protein-coupled receptors, 134 GRP78, 135 SCCs toxicity and induction, 137 signal pathway inhibitors, tanespimycin, 137 TRAIL induction, tumorigenesis, tumor suppressors, Rb and P53, B Basic fibroblast growth factor receptor (bfgfr), 91 B7-H1/PD-1 pathway, monoclonal antibodies

3 APCs, 294 EAE, 293 hematopoietic cells, immune tolerance, 292 immunohistochemistry, 295, 296 immunotherapy, 293, 294, 297 interferon gamma observation, melanoma therapy application early clinical experience, future clinical development, preclinical considerations, 298 murine models, PD-1 expression, 293 phenotypes, deficient mice, 292 signaling and associated markers, 297 solid human tumors, T cell inhibition interaction, 294 BRAF, 5 7 B-Raf, targeted inhibition clinical trials broad-spectrum features, 70 GSK , resistance mechanism, sorafenib agent, 70 future perspective, MAPK pathway, MEK inhibition, melanoma mutations, 65 PLX4032/RO , clinical studies dose-response relationship and escalation, 68 immunohistochemistry, 69 keratoacanthoma (KA), 68 lesions, dose escalation cohorts, 68 phase II trial, 69 tumor cells inhibition, 67 untreated patients, phase III trial, preclinical studies mutated melanoma causes, cell death, wild-type cells, MAPK pathway activation, signaling pathway, MAPK, C Cancer Therapy Evaluation Program (CTEP), 81 Central nervous system (CNS), 50 Chimeric antigen receptors (CARs), 256 Chronic sun damage (CSD), 44 Comparative genome hybridization (CGH), 6 Cytotoxic T-lymphocyte antigen-4 (CTLA-4), 274 D Death-inducing signaling complexes (DISC), 126 Disease-specific survival (DSS), 21 Dose-limiting toxicities (DLTs), E Epidermal growth factor receptor (EGFR), 91 Epithelial-mesenchymal transition (EMT), 93 Experimental autoimmune encephalopathy (EAE), 293 F Fluorescent in situ hybridization (FISH), 46 G Gamma secretase inhibitors (GSIs), 30 Gangliosides, Gastrointestinal stromal tumors (GIST), 47 GNAQ, 11 Granulocytemacrophage colony stimulating factor (GM-CSF), 344 H Haemophilus infl uenza, 214 Hematopoietic cells, PD-1 expression, Herpes simplex virus type 1 (HSV-1), 346 I Indoleamine-2,3-dioxygenase (IDO), 32 Inhibitor of apoptosis protein (IAP), 126 Ipilimumab monotherapy, 278 Ipilimumab plus chemotherapy, 282 K c-kit, 9 10 KIT therapeutic target acral melanoma, 46, 47 amplification/mutation, 56 cancer role, dasatinib, 47, 52 imatinib, 48 inhibition, melanomas harboring activation, 44, 49 mucosal melanoma, nilotinib, 47 proto-oncogene

4 374 KIT therapeutic target (cont.) MAPK and PI3K, 44 signaling pathways, 44, 46 type III trans-membrane RTK, 44 sunitinib, 47 tyrosine kinase inhibitors CD117, immunohistochemistry, 48 chronic sun-damaged skin, 53 clinical trials, melanoma subtypes, CNS metastases, 50 first-line treatment, 52 immunohistochemistry, 48 masatinib, 56 mucosal and acral melanomas, multi-kinase inhibitor, 52 mutation/amplification, mutation analysis, nilotinib, 53 nodal and lung metastases, 50 overcoming resistance, 52, patient CT images, proliferation and progression, 44, 48 sunitinib, 52 M Malignant melanoma initiating cells (MMICs), 94 Mammalian target of rapamycin (mtor), 107 Melanoma genomics, gene expression profiling melanoma progression BRAF mutations, 18 nevi and primary melanoma, nevus and melanoma transition, 19 primary and metastatic melanoma transition, prognostic role, genes, 21 proliferation, SAM, 18 transcriptomic profiles, metastatic melanoma, primary melanoma biomarkers, 22 cdna microarrays, 20 custom array, 19 genomic signatures, 20 genomic signatures, 20 hierarchical clustering, 19 immunohistochemical gene analysis, 20 microarray analysis, 18, 21 SLN, RFS and DSS status, 21 Melanoma immunotherapy cytokine delivery, 333, 334 interleukin-12/il-12 antitumor activity, biological properties, clinical toxicities, 336 DLTs, 336 immunohistochemistry, 337 immunomodulatory cytokine, 338 intratumoral injection, 338 maximum tolerated dose, 336 metastatic melanoma patients, 338 mice and cynomologus monkey, PD and SD, 337 transfection, efficiency, 338 interleukin-15/il-15 biological properties, 344 GM-CSF, HSV-1, 346 p53-expressing tumor cells, therapeutic effect, 345 tumor microenvironment, 345 interleukin-21/il-21 biological properties, cancer immunotherapy, preclinical model, antitumor activity, novel cytokine, tumor microenvironment, 345 Melanoma vaccines cancer specific T Cell responses and correlation assessment, autologous tumor cells, 221 cytokine production, 219 disease protection, 218, 221 gene expression analysis, 220 phenotypic and functional analysis, 219 vaccination, cell based vaccines, 211 dendritic cell-based vaccines, 215 gangliosides, immunological tolerance, nucleic acid-based vaccines, peptide and recombinant protein autologous dendritic cells, 212 cancer testis antigens, 214 CD8 + T cells, DERMA, 214 GlaxoSmithKline Bio, 214 gp M, 213 intrinsic immunogenicity, 213

5 375 intrinsic poor immunogenicity, 212 long synthetic peptides, 214 metastatic melanoma, survival time, 213 recombinant vector-based vaccines, T cell vaccines antigen and adjuvant, 208 CD8 T cell responses, 209, 213 criteria, adjuvant, 208 current and future development, 209 immunological adjuvant, 208 therapeutic vaccination, 209 Microphthalmia-associated transcription factor (MITF), 128 Mixed lymphocyte-tumor cell cultures (MLTC), 189 Molecular targets and subtypes acral lentiginous melanomas, 4, 6 acral melanomas, 4 antihormonal therapy, 4 BRAF, 5 7 c-kit, 9 10 CML and RCC, 4 5 GNAQ, 11 HER2/neu oncogene, 4 KIT inhibitor imatinib, 10 lentigo melanoma, 4 mucosal melanomas, 4, 7 nevi, 7, 8, 12 nodular melanoma, 4, 8 NRAS, 7 8 PI3K-AKT pathway, 8 9 PLX4032, 11 skin cancer, 4 superficial spreading melanoma, 8 superficial spreading melanoma, 4 targeted therapy, 4 uveal melanoma, 4 mtor, PI3 K, and AKT pathways clinical results, combination chemotherapy, 114 downstream event, transcription control, everolimus and rapalogs temsirolimus, 113 genetic alteration -C1, C2, pleiotropic activity, 108 immunosuppression, molecular oncogenesis, 114 multi-kinase inhibitors, 115 mutations and gene alterations via. signaling AKT mutation, BRAF mutations, 112 clinicopathology, 112 MAPK pathway, 111 PTEN function loss, 112 rapalogs drugs, optimal therapeutic index, 114 patient history, 113 pharmacodynamics and biomarkers, rapalogs temsirolimus and everolimus, upstream effectors, PTEN, PI3K, and AKT, VEGFR2 blockade, 115 Myeloid-derived suppressor cells (MDSCs), 95 N National Cancer Institute (NCI), 234 Nonsteroidal antiinflammatory drugs (NSAIDs), 83 Notch and b-catenin pathways axin composition, cancer initiation and progression, malignant transformation, solid tumors, 80 Wnt signaling pathway., 81 cascade signaling, CK1 and GSK3b, 79, 82 clinical perspectives, 84 CTEP, 81 GSIs, 81 helix-loop-helix domains, 78 ligand-receptor interaction, 78 NSAIDs, 83 Parkinson s disease, 81 plasticity, 84 RO , 81 therapeutics, 84 Wnt/b-catenin and cancer, NRAS, 7 8 O O 6 -methylguanine methyltransferase (MGMT), 34

6 376 P Peripheral blood mononuclear cells (PBMCs), 94 PI3K-AKT pathway, 8 9 Platelet-derived growth factor receptor (PDGFR), 46 R Receptor tyrosine kinase (RTK), 44 Retinoblastoma Protein (Rb), 130 S Sentinel lymph node (SLN), 21 Signal Transducer and Activator of Transcription (STAT), 90 Solid human tumors, B7-H1 expression, Squamous cell carcinoma (SCC), 137 STAT3 and src signaling angiogenesis and metastasis, dephosphorylation, 90 EGFR and bfgfr, 91 immune evasion, 94 MDSCs, 95 melanoma tumor cells, 91 melanoma tumorigenesis, 92 melanoma via small-molecule inhibitors, metastasis, tumor, 93 MMICs and PBMCs, 94 oncogenesis interaction, 90 proliferation, 92 receptor-dependent and independent pathway, 90 survival, tumor cells, targeted therapy, melanoma, 96 treatment, 96 tumor-associated immune cells, tumor cell growth regulation, 92 Statistical analysis of microarrays (SAM), 18 T T cell-extrinsic suppression, Therapy biologic subsets, chemotherapy, 34 emerging molecular markers, 36 GSIs, 30 kinase mutations and clinical response B-Raf, c-kit, mechanism-based predictive biomarker, melanoma vaccines, clinical response anti-pd-1 mab, 33 chemokines, 31 immune inhibitory mechanisms, immunotherapeutic intervention, 31 MAGE3 protein-based vaccine, 32 MHC-binding epitopes, 32 tryptophan-catabolizing enzyme and IDO, 32 tumor biopsy, 31 tumor microenvironment, 33 OncotypeDx, breast cancer, 36 patient-specific therapy, PI3 kinase, 30 serum and germline DNA, 35 stabilized b-catenin, T lymphocytes, melanoma antigens CTL on human melanomas, HLA-loss, immunoaffinity purification, 189 immunogenic tumors, 188 immunotherapy, 199 melanocyte differentiation antigens, melanoma antigens resulting, melanoma cells, multiple HLA/peptide association, 198 reverse immunology, 189 shared tumor-specific antigens cancer-germline gene, gene families, 191 human tumor antigens, 195 MAGE-A genes, transcript NA17, 191, pseudogene, 191, 195 tumor antigens, main genes, TILs, 188 tumor-specific T cells, , 198 vaccination, Tremelimumab, Tumor-infiltrating lymphocytes (TIL), 235 ACT, short-term tumor control, 248 adoptive therapy, function and persistence, Tumor-infiltrating lymphocytes (TILs), 188 Tumor microenvironment modulation composition and development immune cells, stroma, tumor cells,

7 immune cell-mediated suppression, immune escape mechanism stroma-mediated suppression, tumor cell-mediated suppression, immunotherapy local immune system, stroma, tumor, melanoma antigens, milieu, cellular and noncellular components, 354 tumor and immune system interaction, 354 Tumor necrosis factor receptor (TNF), 317 Tyrosine kinase inhibitors (TKIs), 44, 168 V Vascular disrupting agents (VDAs), 169 Vascular endothelial growth factor (VEGF), 158, 354