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Tandem Minigene (TMG): String of Minigenes Encoding the Mutated AA Flanked by 12 AA on Each Side

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Tandem Minigene (TMG): String of Minigenes Encoding the Mutated AA Flanked by 12 AA on Each Side Presenter Disclosure Information Eric Tran The following relationships exist related to this presentation: No Relationships to Disclose 1 Identification of Antigens Targeted by Tumor Infiltrating Lymphocytes to Enhance Adoptive Immunotherapy SITC Workshop Nov. 5, 2015, National Harbor, MD Eric Tran, PhD Rosenberg Lab, Surgery Branch, NCI, NIH 2 Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) 3 Rosenberg and Restifo, Science , Apr 3 2015, 348 (6230): 62-68 Adoptive transfer of TIL can cure some patients with metastatic melanoma What antigens are recognized by TIL and are contributing to tumor regression? 4 T cells recognizing mutated antigens likely play a major role in the effectiveness of T-cell based therapies against melanoma Lu et al. Robbins et al. Van Rooij et al. Lu et al. Snyder et al. Van Allen et al. Can TIL therapy be effective in epithelial cancers such as gastrointestinal cancers with lower mutation burdens? 5 Conventional TIL therapy is largely ineffective against metastatic GI cancers Patient ID Tumor type Response PD : progressive disease SD : stable disease 3454 Colorectal PD PR : partial response 3596 Colon PD 3610 Rectal PD 3671 Colon PD 3674 Colorectal PD 3690 Colon PD 3717 Gastric PD 3737 Cholangio PD (13 mo SD ) Did T cells contribute to this response? 3788 GE junction PD If so, what do they recognize? Mutations? 3812 Cholangio PD 3894 Colon PD 3942 Rectal PD 3948 Esophageal PD 3970 Colon (Lynch) PD 3971 Colon PD 3978 Cholangio PD 6 Mutation-reactive T cells can be found in a patient with cholangiocarcinoma and appear capable of mediating tumor regression Rx2 Gated on CD4 (97%) Rx1 Gated on CD4 (55%) wt ERBB2IP mut ERBB2IP 0 0 3 93 wt ERBB2IP mut ERBB2IP 1 0 10 47 TNF 2 98 1 3 Vβ22 IL-2 43 56 38 5 Retreated with ~ 120 billion mutation- 1 0 10 50 ACT of > 10 billion mutation- reactive Vβ22+ Th1 cells (~ 95% of Rx2) reactive Th1 cells (~25% of Rx1) Cell Infusion TNF 43 56 37 3 200 Lung 0 0 8 47 Liver Total 150 γ Cell Infusion IFN- 44 56 40 6 100 Vβ22 Tumor burden Tumor Oct. 21, 2015 50 (% of pre-treatment baseline) (% of pre-treatment 0 -6 0 6 12 18 24 30 36 42 7 Tran et al., 2014, Science , May 9;344(6184):641-5 (updated). Months relative to cell transfer Tumor regression after ACT with ERBB2IP-mutation-reactive Th1 cells Lung CT Main Questions 1. Are mutation-reactive T cells frequently found in other patients with metastatic GI cancers? 2. Can we effectively harness the mutation-specific T-cell response to treat other patients with GI cancers? 9 Assessing T-cell reactivity against mutated antigens GI Isolate genomic Tumor DNA and RNA Whole exome and transcriptome sequencing to Expand TIL (IL-2) identify mutations Synthesize mutated tandem minigenes (TMGs), and/or long peptides (LPs) LPs Introduce TMGs + and/or LPs into APCs I TMG II Co-culture 1) IFN-γγγ ELISPOT 2) 4-1BB/OX40 upregulation Autologous APC 10 Tandem minigene (TMG): String of minigenes encoding the mutated AA flanked by 12 AA on each side Mutation 12 AA 12 AA QNAADSYSWVPE QAESRAMENQYSP Variable number Minigene of minigenes Clone TMG into exp’n plasmid Tandem minigene (variable # of minigenes) In vitro transcribe (IVT) RNA Transfect into APC Co-culture with T cells 11 Patient LS (4007) - 52-year old male with primary colon cancer metastatic to the liver and lung - Hepatic wedge resection for GI-TIL and whole exome sequencing - 134 mutations (PGDx, stringent), 264 mutations (in-house, relaxed) - 17 TMGs constructed TMG # minigenes IL-2 expanded TIL 1 16 2 16 3 16 4 16 5 16 23/24 TIL fragments grown 6 16 TIL and evaluated 7 16 8 12 9 16 10 15 + 11 16 I 12 14 TMG 13 16 II Co-culture 14 16 1) IFN-γγγ ELISPOT 15 16 2) 4-1BB/OX40 upregulation 16 16 17 15 Autologous APC 12 LS-4007: Several TIL cultures display reactivity ag Co-culture: TIL fragments with TMG RNA transfected IFN- γ ELISPOT (top); 4-1BB upregulation by flow cytometry 1000 500 250 spots/2e4 cells* γ 125 IFN- 0 1 60 2 20 15 3 10 4 % 4-1BB+ (of CD8) 5 5 DCs 0 6 1 7 (bottom) ainst TMG-7 and TMG-14 2 8 *above 500 spots not accurate 3 Tran et al., 2015, 9 4 10 5 11 6 12 Science 7 13 8 14 , October 29, 2015 9 15 10 16 11 17 TIL culture12 18 13 19 14 20 15 21 Irrelevant 16 TMG-1 22 TMG-2 17 23 TMG-3 18 TMG-4 TMG-5 19 TMG-6 20 TMG-7 TMG-8 21 TMG-9 22 TMG-10 TMG-11 23 TMG-12 TMG-13 TMG-14 TMG-15 TMG-16 TMG-17 13 TIL#8 Irrelevant TMG TMG-14 LS-4007: What do TIL from culture #8 recognize? 4-1BB CD8 TMG-14 Mutated gene Long peptide AA sequence GRK6 CRGGSAREVKEHRLFKKLNFKRLGA MGAT1 PGRPPSVSALDGAPASLTREVIRLA CDH10 TTVNITLTDVNDKPPRFPQNTIHLR LIFR VIVGVVTSILCYQKREWIKETFYPD MROH2B LWDPNPKIGVACHDVLMVCIPFLGL SNX18 YSTGEEASRDVDTWVFSLECKLDCS SV2C MEYDNGRFIGVKLKSVTFKDSVFKS TCP10(1) AFGKISHLSADEETTPKYAGRKSQS TCP10(2) TLALEPAFGKISPLSADEETTPKYAGRKSQS Sort, expand, co-culture with peptide pulsed DCs TCP10(3) LLALEPAFGKISPLSADEDTTPKYA HGC6.3 VFSSPHTAGGMTSTVFSSPHTAGGM FAM65B MSDLAPSNLLAQHEVLRTLALLLTR ABHD16A NEIDTMFVDRRGAAEPQGQKLVICC 1000 SKIV2L PILKEIVEMLFSHGLVKVLFATETF TNXB(1) RETSAKVNWMPPRSRADSFKVSYQL 750 TNXB(2) QFIPTASPLLCSSSPHSPAKAEAEI 500 250 IFN-γ spots/2e4* ELISPOT 0 Flow GRK6 MGAT1 CDH10 LIFR MutatedMR peptidesOH2B from TMG-14 RNA SNX18 SV2C TCP10(1) SKIV2L: putative RNA helicase involvedTCP10 (with2) *above 500 spots not accurate TCP10(3) HGC6.3 FAM65B altering RNA secondary structure ABHD16A SKIV2L TNXB(1) 100 % TNXB(2) 75(CD8) 4-1BB+ % 4 50 - 1 TMG-7 B 25 B ( TMG-14 0 C D 8 ) 14 TIL#23 Irrelevant TMG TMG-7 LS-4007: What do TIL from culture #23 recognize? 4-1BB CD8 TMG-7 Mutated gene Long peptide AA sequence KRTAP5-3 CGSCGGCKGGCGACGGSKGGCGSSC VAT1L IDNPPKTPLVPGYECSGIVEALGDS INPP5K PAWTDRILWRLKQQPCAGPDTPIPP PLD6 DCDYMALNGSQIRLLRKAGIQVRHD C17orf97(1) RLDRRGGAGTMGDKDNDGEEEEREG C17orf97(2) FHIDPEALKGFHTDPKALKGFHPDP EVI2B TSTVKNSPRSTPPRSTPGFILDTTSNKQTP HSD17B1-005 RRGSGRVLVTGSLGGLMA HSD17B1 RRGSGRVLVTGSLGGLMGLPFNDVY CDC27 LNTDSSVSYIDSA Sort, expand, co-culture with peptide pulsed DCs HOXB8 PSSGGSFQHPSQTQEFYHGPSSLST WFIKKN2 DRENVVMRPNHVCGNVVVTNIAQLV COIL NKATCGTVGDDNKEAKRKSPKKKEK WSCD1 TICVKTHESGRRGIEMFDSAILLIR 750 KCNH6 VAAIPFDLLIFRNGSDETTTLIGLL H3F3B VKKPHRYRPGTVTLREIRRYQKSTE 500 250 IFN-γ spots/2e4* ELISPOT 0 Flow KRTAP5-3 VAT1L INPP5K PLD6 C17orf97(1) Mutated peptidesC17orf97(2) from TMG-7 RNA EVI2B HSD17B1-005 HSD17B1 *above 500 spots not accurateH3F3B: histone protein of the H3 familyCDC27 HOXB8 WFIKKN2 COIL WSCD1 KCNH6 15 H3F3B (CD8) 4-1BB+ % 10 TMG-7 5 TMG-14 0 15 Evidence for mutation-reactive TIL in 20 out of 22 patients with metastatic GI cancers Patient ID Tumor type # of mutations assessed Mutated gene recognized T cell Notes 3737 Cholangio 25 ERBB2IP CD4 Multiple clonotypes 3812 Cholangio 179 ------- ------- Highbackground in TIL NUP98 CD8 3942 Rectal 140 KARS CD8 GPD2 CD4 PLEC CD4 3948 Esophageal 210 XPO7 CD4 AKAP2 CD4 3971 Colon 119 CASP8 CD8 3978 Cholangio 37 ITGB4 CD4 SortedPD-1+ T-cell subset TUBGCP2 CD8 3995 Colon 154 RNF213 CD8 KRAS-G12D KRAS CD8 SKIV2L CD8 4007 Colon 264 Two clonotypes for SKIV2L H3F3B CD8 API5 CD8 4032 Colon 222 RNF10 CD8 Two clonotypes for API5 PHLPP1 CD8 4060 Colon 315 SMC1A CD4 4069 Pancreatic 97 ZFYVE27 CD8 QSOX2 CD8 4071 Colon 285 POR CD8 MRPS28 CD8 HIST1H2BE CD8 4077 Cholangio 127 FLII CD8 2xCD4 4078 Gastroesophageal 79 In progress Sorted PD-1+ T-cell subset 2xCD8 ALDOC CD8 4081 Colon 191 RPL12 CD8 USP8 CD8 4090 Colon 201 RPS15 CD8 MRLPL39 CD4 KRAS CD8 KRAS-G12D; at least 2 4095 Colon 61 In progress CD4/8? clonotypes 4107 Cholangio 161 ------- ------- 4108 Colon 146 Inprogress 2xCD8 In progress CD8 4110 Cholangio 151 In progress CD4 4xCD8 4112 Cholangio 215 In progress CD4 In progress CD4 4115 Colon 123 16 In progress CD8 Can we effectively harness the mutation-reactive T-cell response? 17 LS-4007: ACT with SKIV2L-mutation specific CD8+ T cells Irrelevant TMG-1 60 TMG-14 TMG-2 20 (SKIV2L) TMG-3 15 TMG-4 TMG-5 10 TMG-6 5 TMG-7 0 TMG-8 TMG-9 % 4-1BB+ (of CD8) (of 4-1BB+ % 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 TMG-10 TMG-11 TMG-12 TIL #8 selected for rapid expansion and treatment TMG-13 • TMG-14 TMG-15 • Infusion bag: ~94% Vβ5.1+ SKIV2L mutation-reactive CD8 T cells TMG-16 TMG-17 Infusion bag 94 Vβ5.1 CD8 – Infusion of 2.8e10 total cells (~2.6e10 mutation-reactive) • Third month follow up (05-18-15): Progressive disease (↑ ~22%) • NB: Cells expanded poorly during REP 18 Patients treated with selected populations of mutation-reactive T cells Patient ID Tumor type Cell % T cell Mutated gene Treatment Response Persistence, number mutation targeted date TRBV deep seq infused reactive (~ 1 month) 3737/3941 Cholangio 126e9 94.4 CD4+ ERBB2IP 10/25/13 PR 23.5% (ongoing 24+ mo) 4032 Colon 37e9 74 CD8+ PHLPP1 (49%) 12/18/14 PD 0.0033% API5 (22%) Not detected RNF10 (3%) 0.014% 4007 Colon 28e9 64.4 CD8+ SKIV2L 02/19/15 PD (3 mo) 0.93% 4069 Pancreatic 90e9 91.9 CD8+ ZFYVE27 03/06/15 PD (2 ½ mo) Not detected (mixed response?) 4071 Colon 95.1e9 32.3 CD8+ QSOX2 03/26/15 PD 0.0014% 4077 Cholangio 65.8e9 38.3 CD8+ HIST1H2BE 05/08/15 PD (2 mo) 0.49% (1 month, ↓ ~40%) 4081 Colon 152.4e9 72.1 CD8+ ALDOC 05/15/15 PD (2 mo) 1.40% Why are we not observing a higher response rate? 19 Potential reasons for lack of clinical efficacy with T-cell targeting of somatic mutations • T-cell properties: • Dose • Type • Function/fitness/age • Number of antigens targeted • T-cell affinity/avidity toward antigen • Tumor-intrinsic properties: • Lack/heterogeneous expression of targeted mutation in metastases • Impaired MHC processing and presentation pathway • Other host (regulatory) factors • Can we improve the efficacy of ACT against somatic mutations
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