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PROMOTIECOMMISSIE Promotor: Prof.dr. J. Verweij Overige leden: Prof.dr. S. Sleijfer Prof.dr. R. Hendriks Prof.dr. C. Melief Copromotor: Dr. R. Debets
COnTEnTS Chapter 1 General Introduction 7 1.1. Immune therapy for the treatment of tumors 9 1.2. Challenges of TCR gene therapy 14 1.3 Mouse tumor models for TCR gene therapy 14 1.3.1 Genetically engineered mouse tumor models 16 1.3.2 Environmentally induced tumor models 19 1.3.3 Transplantable tumor models 19 1.4. Target antigens and TCR transgenes: topics of this thesis 21 1.4.1 Safe target antigens 21 1.4.2 T cell receptors 23 1.5 Aims and scope of this thesis 25 Chapter 2 TCR gene therapy to treat melanoma: lessons from clinical and preclinical studies. Expert Opinion Biological Therapies 2010; 10(4):547-62 Chapter 3 T cell receptor gene therapy in human melanoma-bearing immunedeficient mice: human but not mouse T cells recapitulate outcome of clinical studies Human Gene Therapy 2011; 23(2):187-201 Chapter 4 Tumor relapse following T cell receptor gene therapy is not due to loss of immunogenicity Manuscript submitted Chapter 5 TCR gene transfer: MAGE-C2/HLA-A2 and MAGE-A3/HLA-DP4 epitopes as Melanoma-Specific Immune targets Clinical and Developmental Immunology 2012 (2012); ID 586314 Chapter 6 General discussion 161 6.1 Immune deficient mouse models for TCR gene therapy 162 6.1.2 Human TCR T cells in immune-deficient mice 162 6.1.3 Mouse TCR T cells in immune-deficient mice 164 6.2 Immune-competent mouse melanoma model for TCR gene therapy 165 6.2.1 Major findings of the HLA-A2tg melanoma mouse model 166 6.2.2 Characteristics of the HLA-A2tg melanoma mouse model 166 41 73 103 135
Page 1: Towa r d s c l i n i c a l Tc r g e
Page 4 and 5: Studies described in this thesis we
Page 8 and 9: 6.2.3 Tumor relapse 168 6.2.3.1 Pot
Page 11 and 12: 1.1 IMMunE ThERaPy fOR ThE TREaTMEn
Page 13 and 14: 1. Isolation and activation of peri
Page 15 and 16: General Introduction synovial carci
Page 17 and 18: Table 3. Challenges of TCR gene the
Page 19 and 20: General Introduction Table 4. Stren
Page 21 and 22: 1.3.2 Environmentally induced tumor
Page 23 and 24: General Introduction adoptive T cel
Page 25 and 26: General Introduction would require
Page 27 and 28: General Introduction different plat
Page 29 and 30: REfEREnCES General Introduction 1.
Page 31 and 32: General Introduction metastatic syn
Page 33 and 34: General Introduction 51. Schambach
Page 35 and 36: General Introduction 80. Leach DR,
Page 37 and 38: General Introduction 112. Umansky V
Page 39 and 40: General Introduction 142. Hanson HL
Page 41: General Introduction 172. Liu W, Ch
Page 44 and 45: Chapter 2 aBSTRaCT Importance of th
Page 46 and 47: Chapter 2 receptors, CARs) to treat
Page 48 and 49: Chapter 2 Table 2. advantages of Ma
Page 50 and 51: Chapter 2 within a vector is of imp
Page 52 and 53: Chapter 2 expression and pMHC multi
Page 54 and 55: 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
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Chapter 4 RESulTS TCR T cells preve
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Chapter 4 figure 1. Treatment with
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Chapter 4 114 day Bu 0 ….. 10 tum
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Chapter 4 116 B genomic DNA (arbitr
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Chapter 4 cells in the viable gate
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Chapter 4 that relapsed tumors func
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Chapter 4 are in line with previous
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Chapter 4 124 tumor growth Treatmen
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Chapter 4 11. Mackensen A, Meidenba
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Chapter 4 42. Zou W (2005) Immunosu
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Chapter 4 Assessment of promoter me
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Chapter 4 132 lymphocytes (number /
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Chapter 4 HLA-A2 transgenic mice be
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Chapter 5 aBSTRaCT Adoptive therapy
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Chapter 5 in up to 50% of non-small
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Chapter 5 140 MC2/A2 peptide MHC (p
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Chapter 5 duction procedure was des
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Chapter 5 figure 2. Primary human T
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Chapter 5 figure 4. Surface express
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Chapter 5 figure 7. Ma3/DP4 TCR CD4
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Chapter 5 extent of lysis, a typica
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Chapter 5 may provide a preclinical
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Chapter 5 12. Parkhurst MR, Yang JC
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Chapter 5 40. Carrasco J, Van Pel A
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Chapter 5 68. Kuball J, Schmitz FW,
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Chapter 5 melanoma cells; MC2 pos /
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Chapter 6 Currently, TCR gene thera
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Chapter 6 murine T cells with solub
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Chapter 6 6.2.1 Major findings of t
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Chapter 6 mouse antibody sequences
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Chapter 6 (IDO) and arginase that d
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Chapter 6 enhance T cell accumulati
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Chapter 6 MAGE surface expression l
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Chapter 6 1. Isolation and activati
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Chapter 6 REfEREnCES 1. Powell DJ,
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Chapter 6 F, Bordignon C & Bonini C
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Chapter 6 58. Spiotto MT, Rowley DA
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Chapter 6 CD8+ T cells expressing i
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Chapter 6 118. Kantarjian HM, O’B
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SuMMaRy Summary To date, adoptive T
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Summary 20% of mice durable remissi
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SaMEnVaTTIng Samenvatting Momenteel
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Samenvatting experimenten laten wij
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Curriculum Vitae List of publicatio
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lIST Of PuBlICaTIOnS List of public
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PhD portfolio 1.4b Poster presentat
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Samenvatting In het bijzonder wil i
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