Clinical Translation of Immunotherapy using WT1 and CMV specific TCR Gene Transfer
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1 Clinical Translation of Immunotherapy using WT1 and CMV specific Gene Transfer Dr Emma C Morris Reader, Dept of Immunology, UCL Consultant Haematologist (BMT), UCLH and RFH ISCT, 2/5/211
2 Gene Transfer Designer T cells with re-directed antigen specificity. Adoptively transfer T cells with known antigen specificity and known (high) functional avidity. Potential to manipulate homing ability, etc.
3 CD8 Retroviral gene transfer Antigen-specific CD8 T cell Insert into retro-viral vector CD3 CD3 CD3 Clone DNA of antigen-specific Before After Antigen-specific multimer
4 CMV Gene Transfer Shao-An Xue, Liquan Gao, Emma Nicholson
5 CMV Disease Post Allogeneic Haematopoietic Stem Cell Transplantation CMV Retinitis CMV Pneumonitis CMV Colitis CMV Inclusion Body
6 CMV Reactivation Post Allogeneic HSCT Recipient CMV seropositive HSC Donor CMV seropositive Infuse CMV-specific CTL Donor engraftment and T cell expansion Potential for expansion of CMV-specific T cells CMV reactivation conditioning Time Pre- and post transplant immune suppression Day Day 28 Recipient CMV seropositive HSC Donor CMV seronegative Donor engraftment and T cell expansion NO CMV-Specific T Cells conditioning CMV reactivation Pre- and post transplant immune suppression Time Day Day 28
7 mc CD8 pnlv-tetramer Generation of Cys1-hybrid CMV construct LTR hv 18 mc p2a hv 13 mc LTR SS Mock Td CMV- Td Wild-type Cys-1 Hybrid Cys-1 Hybrid % 41% ss ss ss ss ss ss pnlv-tetramer Mock Td CMV- Td.1% 18% 14%
8 Classical CD4+ T cell Class I restricted CD4+ T cell CD4 T cell CD4 T cell CD4 Class II restricted CD4 Class I restricted Class II MHC Class I MHC APC Virally infected cell or tumour cell Are MHC class I restricted CMV-specific CD4+ T cells functional? Do they function in the same way as a classical class II restricted CD4+ T cells?
9 IL2 TNF TNF Ag-specific function of CMV -Td T cells IL2 TNF TNF CD4+ CMV- Td CD8+ CMV- Td Irrelevant Peptide (CLG) Relevant Peptide (NLV) Irrelevant Peptide (CLG) Relevant Peptide (NLV) 5.8%.2% 14% 14.7%.6%.3% 2.7% 11.8% IFN IFN 5.7%.3% 15.4% 13.2%.9%.2% 7.6% 7.3% IL2 IL2.4%.1% 5.4% 7.5%.1%.4% 1.9% 7.7%.4% 8.4% 1.8% 19.9% IFN IFN
10 % Killing % Killing CMV -Td T cells recognise endogenously processed antigen A Bead sorted CD4+ CMV -Td T cells B Bead sorted CD8+ CMV -Td T cells E:T Ratio E:T Ratio Target cells T2+NLV T2+CLG K562/A2/pp65 K562/A2/LMP2
11 % IFN producing T cells Functional avidity of CMV- Td CD8+ and CD4+ T cells % of INFg+ T cells % of IFNg+ T cells % Killing % Killing % IL-2 producing T cells % of IL2+ T cells 5 of IL2+ T cells IFN secretion 6 IL-2 secretion CLG nm 1nM 1nM 1pM 1pM 1pM KA2 [peptide] nm 1nM 1nM 1pM 1pM 1pM KA2 [peptide] CLG NLV CLG NLV nM 1nM 1nM 1pM 1pM 1pM KA2 [peptide] nM 1nM 1nM 1pM 1pM 1pM KA2 [peptide] NLV CLG NLV CMV- Td CD8 + T cells CMV- Td CD4 + T cells CMV- Td CD4+ T cells CMV- Td CD8+ T cells T2+CLG T2+NLV KA2LMP2 KA2pp65 E:T from 4:1 E:T from 4:1
12 CMV- Td CD8+ and CD4+ T cells reject CMV pp65- expressing tumours in vivo CMV- Td CD8+ T cells CMV- Td CD4+ T cells EBV- Td CD8+ T cells d1 d5 d1 d15 d2 d25 2x1 6 K562A2-pp65-Luc tumor cells
13 Clinical GMP Grade CMV- Td CD8+ T cells SSC NLV-Tetramer CD3 FSC CD8 Mock transduction 1 round transduction 2 round transduction Anti Murine C
14 A Phase I Safety, Toxicity and Feasibility Study of Adoptive Immunotherapy with CMV -td donor-derived T cells for Recipients of Sibling Allo HSCT (CMV -1) TCD Myeloablative HSCT or Reduced Intensity HSCT Start anti-viral Rx if: Copy number at 1 wk CMV PCR pos at + 2 wks CMV disease Conditioning Weekly CMV PCR Follow Up D Exclusion criteria: agvhd grades II-IV Neuts <.5 x 1 9 /l CMV -td bulk donor-derived T cells /kg recipient weight 1 st positive PCR (Pre-emptive Rx) Immunology Ix: V 13, tetramer staining Ag-specific proliferation Intracellular CK secretion Cytotoxicity repertoire PCR for V 13/ fragments Clinical Assessment for GVHD T cell subsets & phenotype
15 Class I restricted CD4+ T cell Class I restricted CD4+ T cell + additional CD8 CD4 T cell CD4 T cell CD4 Class I restricted CD4 Class I restricted Class I MHC CD8 Class I MHC Virally infected cell or tumour cell Virally infected cell or tumour cell
16 means of OD45 means of OD45 means of OD45 means of OD45 Co-transfer of CD8 co-receptor into CMV -Td CD4 + T cells improves function 3 CMV-CD4-INFg CLG NLV.5 CMV-CD4-IL2 CLG NLV nM 1nM 1nM 1pM 1pM 1pM KA2 1nM 1nM 1nM 1pM 1pM 1pM KA2 [peptide] 3 CMV-CD8-INFg CLG NLV 2.5 CMV-CD8-IL2 CLG NLV nM 1nM 1nM 1pM 1pM 1pM KA2 1nM 1nM 1nM 1pM 1pM 1pM KA2 [peptide] CMV8-CD4-INFg 1nM 1nM 1nM 1pM 1pM 1pM KA2 CLG NLV CMV8-CD4-IL2 CLG NLV 1nM 1nM 1nM 1pM 1pM 1pM KA2
17 Co-transduction with additional CD8 co-receptor into CMV- Td CD4+ T cells may improve in vivo function CMV- Td CD4+ T cells CMV- Td CD8+ T cells CMV- and CD8 Td CD4+ T cells d5 d1 d15 d2 d25
18 Improving function of -td T cells Maryam Ahmadi, Judy King
19 Co-transduction of and CD3 into T cells Increased surface expression of leads to increased functional avidity of the δ α β Υ CD3 rate limiting for expression of introduced ζ ζ Can surface expression of be increased by introduction of additional CD3? Does this lead to increased functional avidity of the T cell expressing a class I restricted? 5 LTR CD3 2A CD3 2A CD3 2A CD3 IRES GFP 3 LTR
20 CD3 is rate limiting for expression WT1 F5 CD3 Vβ2.1 Tet Vβ11 Tet Mock x1 x1 x1 x1 x1 +GFP + CD3-GFP x26 x16 x2 x5 x4 GFP BW cells
21 CD3 is rate limiting in primary T cells F5- WT1- CD3 Vβ11 Tet CD3 Vβ2.1 Tet x1 x1 x1 x1 x1 +GFP + CD3-GFP x3 x4 x1 x3 x5 GFP Murine splenocytes
22 CPM IL-2 (pg/ml) Vβ11 CD3 improves antigen-specific IL2 production F5- F5-+CD3 F5 F5+CD3 GFP 1 1pM 1-6 1pM 1nM 1nM pnp (μm) nM 1-3 1uM 1uM [NP conc, um] 1 1 pwt SV9 Sorted CD8+ murine T cells
23 IFNg CPM pg/ml CPM CPM/1 Vβ11 CD3 improves antigen-specific proliferation F5 F5- F5+CD3 F5-+CD3 F5+CD3 GFP [NP conc, um] [NP conc, um] [NP conc, um] 1 1 pwt1 1 1 pwt1 1 1 pwt1 pnp peptide conc (um)
24 In vivo function of +CD3 transduced T cells d d1 > 8 weeks EL4-NP tumour cells (luciferase) + CD3 td CD8 + T cells (luciferase) Monitor tumour clearance and T cell memory
25 CD3 limits tumour growth in vivo Tumour volume Mock +CD3 D5 D8 D11 D13 D17 D2 D33 D Days post tumor injection Photons./sec x 1 1 Mock Mock Mock Mock CD3 +CD3 +CD CD Days post tumor injection
26 +CD3 enhances T cell accumulation in tumours +CD3 D 3 D 5 D 6 D 8 D 11 D 16
27 +CD3 enhances T cell accumulation in tumours Photon flux x Mock 75. Mock Mock F5 6. +CD3 F5+CD3 6. +CD3 F5+CD3 +CD3 45. F5+CD Days post tumor injection T cell no x Days post tumor injection
28 Vβ11 +CD3 T cell persist in larger numbers than -only T cells Spleen Lymph nodes Pre-injection Day 35 Post-injection Absolute no/ * * Absolute no/ *.. +CD3. +CD3 +CD3 GFP +CD3 +CD3 F5- F5-+CD3
29 % Transduced % cells Cells % Transduced Cells % cells +CD3 T cells dominate central and effector memory development ns Spleen 1 ns *** *** Lymph nodes *** *** *** *** CD3 CD44 + /CD62L + CD F5+CD3 CD62L+ F5 +CD3 CD44 + /CD62L - F5+CD3 F5 F5+CD3 F5 CD62L- F5+CD3 CD62L- +CD3 +CD3 CD44 + /CD62L + CD44 + /CD62L -
30 +CD3 T cell mount an effective memory recall response D F5- F5-+CD3 6 months Absolute no x TDLN LND Non-TDLN non-lnd
31 WT1 Gene Transfer Shao-An Xue, Liquan Gao, Sharyn Thomas, Irma Martinez-Davila
32 IFN-g (ng/ml) CD19 % of survival WT1 -td T cells display in vitro function and eliminate A autologous 1 leukaemia cells in NOD/SCID mice T2+pWT235 T2+pWT126 BV Cys1 WT1 -td T cells Control -td T cells 15 B Weeks 1 Control 1 Control 2 Control 3 Control 4 Control 5 5 Cys1 WT1 1 Cys1 WT1 2 Cys1 WT1 3 Cys1 WT1 4 Cys1 WT1 5 Normal AML CML T cells T cells T cells Human Class I Xue SA, et al. Blood. 25; 16(9):362-7 Xue SA, et al. Haematologica. 21;95(1):
33 V 2 Ladder PBMC C(-) Clinical Scale Production of GMP grade WT1 -td T cells Lymphocyte Gate Isotype Control.56% qrt-pcr of PBMC to determine persistence of GMP grade WT1 -td T cells Diluted in 1 6 PBMC V 2 Mock-Transduced Post 1 Round.4x1 6 4x1 4 4x % 26.13%
34 Trial Outline UK Multi Centre, non-randomised, dose-escalation, Phase I/II pilot study Infusion of WT1 -td Autologous T cells into HLA-A2 + adult AML or CML patients Ex-vivo Transduction (5-7 days) QC on transduced cells: expression i.c. CK secretion Microbiology Leucapheresis D-14 Start infection Prophylaxis *Provision to escalate conditioning intensity if required Lymphodepleting Conditioning* Flu/MP or Flu/Cy D-7 to D-2 Cryopreserved D Re-infusion of WT1 -td Bulk T cells Cohort 1 (n=6): Cohort 2 (n=12): + Low dose IL2 (D to D+5) 2 x 1 7 /kg 1 x 1 8 /kg Monitoring & Follow Up Immunology Ix: V 2.1, tetramer staining Ag-specific proliferation Intracellular CK secretion Cytotoxicity repertoire PCR for V 2.1/ fragments Clinical Assessment for toxicity T cell subsets & phenotype Integration site analysis & archives
35 WT1 Gene Therapy: Time Lines Pre-clinical development: Ongoing Including vector development 1 st expression in murine model Vector development (ongoing) In vitro expts with Td-T cells NOD/SCID In vivo expts (ongoing) CRUK/LRF funding LRF funding GTAC applic Vector production commenced DOH funding Clin scale tests EU ATMP Regs MHRA CTA/EAG Legal issues Stauss/Morris In vivo data Blood/PNAS Prov GTAC approval Rosenberg et al Science Phase 1 Trial Full GTAC approval? Opening End 21
36 Acknowledgments UCL Immunology Hans Stauss Shao-an Xue Liquan Gao Sharyn Thomas Emma Nicholson Judy King Irma Martinez-Davila GOSH/ICH Adrian Thrasher, Waseem Qasim, Sue Swift, Kate Parsley, Hong Zhan
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