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Chapter 5 melanoma cells; MC2 pos /A2 neg EVSA-T breast carcinoma cells, both pre-treated with IFNg; or BSM B cells loaded with gp100 or MC2 peptide. Effector T cells were MC2/A2 TCR or Mock T cells (as in Figure S1A). T cells only were included as an additional control. Supernatants were harvested after 20 h co-culture between effector T cells and target cells, and analyzed for the presence of IFNg by ELISA. Data are from representative experiments out of 15 experiments from 5 donors with similar results. 160 B IFNγ production (pg/ml) 15000 12000 9000 6000 3000 MA3/DP4 opt TCR T cells Mock T cells 0 Medium EBV- EBV- MZ2- MZ2- TE-4 MA3 MAGJ MEL43 MEL43 + MA3 peptide Target cells figure S2. Codon-optimized Ma3 TCR genes are functionally expressed in T cells. a. Surface expression of codon-optimized MA3 TCR genes in PBMC. PBMCs were activated by anti-CD3 mAb and transduced with pMP71:opt MA3/DP4 TCRb-2A-a or control genes (i.e., pMP71:opt MC2/ A2 TCRb-2A-a, termed Mock T cells). CD3 and CD3, CD4-positive T cells were analyzed for TCRVb22 expression and MA3/DP4 pMHC binding by flow cytometry. B. MA3/DP4-specific IFNg production by PBMC transduced with codon-optimized MA3 TCR genes. Target cells were: MA3-positive B cells (EBV- MA3); MA3-negative B cells (EBV-MAGJ); MZ2-MEL43 melanoma cells loaded with MA3 peptide or not (all HLA-DP4-positive cells) and MA3 pos /DP4 neg TE-4 esophagus carcinoma cells. Effector T cells were MA3/DP4 TCR or Mock T cells (as in Figure S2A). T cells only were included as an additional control. Supernatants were harvested after a 20 h co-culture between effector T cells and target cells, and analyzed for the presence of IFNg by ELISA. Data are from representative experiments out of 6 experiments from 2 donors with similar results. REfEREnCES 1. Lamers CH, Sleijfer S, Vulto AG, Kruit WH, Kliffen M, Debets R, Gratama JW, Stoter G & Oosterwijk E (2006) Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. J Clin Oncol 24(13):e20-22.
Chapter 6 General Discussion
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Towa r d s c l i n i c a l Tc r g e
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Studies described in this thesis we
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PROMOTIECOMMISSIE Promotor: Prof.dr
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6.2.3 Tumor relapse 168 6.2.3.1 Pot
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1.1 IMMunE ThERaPy fOR ThE TREaTMEn
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1. Isolation and activation of peri
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General Introduction synovial carci
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Table 3. Challenges of TCR gene the
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General Introduction Table 4. Stren
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1.3.2 Environmentally induced tumor
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General Introduction adoptive T cel
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General Introduction would require
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General Introduction different plat
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REfEREnCES General Introduction 1.
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General Introduction metastatic syn
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General Introduction 51. Schambach
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General Introduction 80. Leach DR,
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General Introduction 112. Umansky V
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General Introduction 142. Hanson HL
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General Introduction 172. Liu W, Ch
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Chapter 2 aBSTRaCT Importance of th
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Chapter 2 receptors, CARs) to treat
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Chapter 2 Table 2. advantages of Ma
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Chapter 2 within a vector is of imp
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Chapter 2 expression and pMHC multi
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Chapter 2 potential in eradicating
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Chapter 2 differentiation state and
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Chapter 2 recognize such a self-ant
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Chapter 2 Table 3. Strategies to im
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Chapter 2 60 3. Lymphodepletion Iso
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Chapter 2 CC, Rudy SF, VanWaes C, D
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Chapter 2 42. Schultz ES, Schuler-T
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Chapter 2 73. Sadelain M, Brentjens
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Chapter 2 105. Moroz A, Eppolito C,
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Chapter 2 134. Willemsen RA, Sebest
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Chapter 3 T cell receptor gene ther
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InTRODuCTIOn TCR-engineered T cells
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OV-CAR3 (MUC-CD) cells OC SCID Beig
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TCR-engineered T cells in SCID and
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AT models TCR-engineered T cells in
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A tumor volume (mm 3 ) 800 700 600
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DISCuSSIOn TCR-engineered T cells i
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REfEREnCES TCR-engineered T cells i
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REfEREnCES: TCR-engineered T cells
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Chapter 4 aBSTRaCT Clinical therapy
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Chapter 4 transferred and the occur
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Chapter 4 bind gp100/A2 pMHC, which
Page 112 and 113: Chapter 4 RESulTS TCR T cells preve
Page 114 and 115: Chapter 4 figure 1. Treatment with
Page 116 and 117: Chapter 4 114 day Bu 0 ….. 10 tum
Page 118 and 119: Chapter 4 116 B genomic DNA (arbitr
Page 120 and 121: Chapter 4 cells in the viable gate
Page 122 and 123: Chapter 4 that relapsed tumors func
Page 124 and 125: Chapter 4 are in line with previous
Page 126 and 127: Chapter 4 124 tumor growth Treatmen
Page 128 and 129: Chapter 4 11. Mackensen A, Meidenba
Page 130 and 131: Chapter 4 42. Zou W (2005) Immunosu
Page 132 and 133: Chapter 4 Assessment of promoter me
Page 134 and 135: Chapter 4 132 lymphocytes (number /
Page 136 and 137: Chapter 4 HLA-A2 transgenic mice be
Page 138 and 139: Chapter 5 aBSTRaCT Adoptive therapy
Page 140 and 141: Chapter 5 in up to 50% of non-small
Page 142 and 143: Chapter 5 140 MC2/A2 peptide MHC (p
Page 144 and 145: Chapter 5 duction procedure was des
Page 146 and 147: Chapter 5 figure 2. Primary human T
Page 148 and 149: Chapter 5 figure 4. Surface express
Page 150 and 151: Chapter 5 figure 7. Ma3/DP4 TCR CD4
Page 152 and 153: Chapter 5 extent of lysis, a typica
Page 154 and 155: Chapter 5 may provide a preclinical
Page 156 and 157: Chapter 5 12. Parkhurst MR, Yang JC
Page 158 and 159: Chapter 5 40. Carrasco J, Van Pel A
Page 160 and 161: Chapter 5 68. Kuball J, Schmitz FW,
Page 164 and 165: Chapter 6 Currently, TCR gene thera
Page 166 and 167: Chapter 6 murine T cells with solub
Page 168 and 169: Chapter 6 6.2.1 Major findings of t
Page 170 and 171: Chapter 6 mouse antibody sequences
Page 172 and 173: Chapter 6 (IDO) and arginase that d
Page 174 and 175: Chapter 6 enhance T cell accumulati
Page 176 and 177: Chapter 6 MAGE surface expression l
Page 178 and 179: Chapter 6 1. Isolation and activati
Page 180 and 181: Chapter 6 REfEREnCES 1. Powell DJ,
Page 182 and 183: Chapter 6 F, Bordignon C & Bonini C
Page 184 and 185: Chapter 6 58. Spiotto MT, Rowley DA
Page 186 and 187: Chapter 6 CD8+ T cells expressing i
Page 188 and 189: Chapter 6 118. Kantarjian HM, O’B
Page 191 and 192: SuMMaRy Summary To date, adoptive T
Page 193 and 194: Summary 20% of mice durable remissi
Page 195 and 196: SaMEnVaTTIng Samenvatting Momenteel
Page 197 and 198: Samenvatting experimenten laten wij
Page 199: Curriculum Vitae List of publicatio
Page 203: lIST Of PuBlICaTIOnS List of public
Page 206 and 207: PhD portfolio 1.4b Poster presentat
Page 208: Samenvatting In het bijzonder wil i
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