Slide 1: Targeting Innate Immunity in Cancer - Eric Vivier
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Slide 2: Disclosures
Disclosures • Innate-Pharma, co-founder + CSO
Slide 3: The Immuno-Oncology Revolution
The Immuno-Oncology Revolution Immune Checkpoints Inhibitors Anti-CTLA4 • Ipilimumab (IgG1, YERVOY, BMS) • Tremelimumab (IgG2, ASTRAZENECA) Proportion alive Anti-PD-1 Immunotherapy (combination) • Nivolumab (IgG4, OPDIVO, BMS) • Pembrolizumab (IgG4, KEYTRUDA, MERCK) • Cemiplimab (IgG4, LIBTAYO, SANO
Slide 4: The Immuno-Oncology Revolution
The Immuno-Oncology Revolution • Understand the resistance to Immune Checkpoint Inhibitors • Increase the fraction of patients sensitive to ? Proportion alive IO treatments Immunotherapy (combination) • Decrease toxicity Immunotherapy (monotherapy) Chemotherapy/TKI Control Time from treatment
Slide 5: The Immuno-Oncology Revolution
The Immuno-Oncology Revolution • Understand the resistance to Immune Checkpoint Inhibitors • Increase the fraction of patients sensitive to ? Proportion alive IO treatments Immunotherapy (combination) • Decrease toxicity Immunotherapy (monotherapy) • Identify new targets (cells and molecules) • Iden
Slide 6: A pivotal role of T cells in tumor immunity
A pivotal role of T cells in tumor immunity KILLING Tumor-specific CD8 T cell Tumor cell
Slide 7: T cells are not autonomous in their anti-tumor functions
T cells are not autonomous in their anti-tumor functions Tumor cell Tumor-specific CD8 T cell
Slide 8: A pivotal role of innate immunity to mount anti-tumor T cell responses
A pivotal role of innate immunity to mount anti-tumor T cell responses DC / Macrophage / Endothelial cell Tumor Microenvironment cGAS STING DNA cGAMP TYPE I IFNs cGAS STING NK cell RLR XCL1/CCL5/FLT3L cDC1 Tumor cell CXCL9/CXCL10 Tumor-specific CD8 T cell
Slide 9: Innate Lymphoid cells
Innate Lymphoid cells Tumor NK Vivier et al., Nature Immunol. 2008 Vivier et al., Science 2011 Vivier et al., Cell 2018
Slide 10: Targeting Innate Immunity in Cancer
Targeting Innate Immunity in Cancer • Targeting NK cells – Targeting inhibitory NK cell surface receptors – Targeting activating NK cell surface receptors
Slide 11: Targeting Innate Immunity in Cancer
Targeting Innate Immunity in Cancer • Targeting NK cells – Targeting inhibitory NK cell surface receptors: NKG2A – Targeting activating NK cell surface receptors
Slide 12: Blocking anti-NKG2A mAb: a novel immune checkpoint inhibitor in cancer immunotherapy
Blocking anti-NKG2A mAb: a novel immune checkpoint inhibitor in cancer immunotherapy + Tumor NK cell Target T cell cell cell SHP-1 _ CD94/NKG2A HLA-E MONALIZUMAB (IPH2201) IS A FIRST-IN-CLASS ANTI-NKG2A HUMANIZED IGG4 BLOCKING MAB
Slide 13: NKG2A targeting with monalizumab
NKG2A targeting with monalizumab Monalizumab is a novel checkpoint inhibitor promoting anti- tumor immunity by enhancing the activity of both T and NK cells, which may complement the activity of the first generation of active immunotherapies against cancer André et al., Cell 2018
Slide 14: Monalizumab: a large spectrum immune checkpoint inhibitor
Monalizumab: a large spectrum immune checkpoint inhibitor
Slide 15: Monalizumab: a large spectrum immune checkpoint inhibitor
Monalizumab: a large spectrum immune checkpoint inhibitor
Slide 16: Targeting Innate Immunity in Cancer
Targeting Innate Immunity in Cancer • Targeting NK cells – Targeting inhibitory NK cell surface receptors: NKG2A – Targeting activating NK cell surface receptors
Slide 17: NKp46 is a conserved activating cell surface receptor
NKp46 is a conserved activating cell surface receptor NKp46 NK cell + Alessandro Moretta Comparing mouse and human data (65-75 Mya differences between mice and humans)
Slide 18: Multifunctional antibody technology engaging NK cells in oncology
Multifunctional antibody technology engaging NK cells in oncology Innovative multifunctional antibody technology for engaging NK cells to kill tumor cells through activating receptors expressed on Multifunctional NKCE NK cells CD16 NK Tumor cell • Co-engaging CD16 and NKp46 on NK cells NKp46 • Stimu
Slide 19: NKp46 is expressed at the tumor bed
NKp46 is expressed at the tumor bed + Density of NKp46 cells CD8 / Hematoxylin NKp46 / Hematoxylin 26.2% 57.4% 72% 24.5% 44.4% 49.4% 53.9% 1,000 100 Cells / mm2 10 1 0 n=103 n=68 n=75 n=106 n=45 n=77 n=76 50 µm
Slide 20: NKp46 NK cell engagers in oncology
NKp46 NK cell engagers in oncology • Correct chain pairing driven by affinity Fc-Silent TA NKCE-1 • 100% antibody sequences TA • Binding to Protein-A and FcRn Fc-Silent NKp46 CH1 VH • Monovalent binding to NKp46 Ck Vk NKp46 TA NKCE-2 CD16 TA • FcγR binding options CD16 NKp46 NKp46 only : NKCE-1 CH
Slide 21: NKp46 NK cell engagers in oncology
NKp46 NK cell engagers in oncology NKp46-1 NKp46-1 VH domain Vk domain NKp46 D1/N-term D2/C-term
Slide 22: Bispecific NKCEs promote tumor control in vivo
Bispecific NKCEs promote tumor control in vivo IC/(Fc)/CD20-F6 IC (6.25 /(F c )/C D 2 0 -F mg/kg) 6 (6 .2 5 m g /k g ) NNKp46/(Fc)/CD20-F6 K p 4 6 /(F c )/C D 2 0(6.25 -F 6 mg/kg) (6 .2 5 m g /k g ) F6 NNKp46/(Fc)/CD20-F6 K p 4 6 /(F c )/C D 2 0(0.25 -F 6 mg/kg) (0 .2 5 m g /k g ) Randomization ~ 10
Slide 23: Bispecific NKCEs promote tumor control in vivo
Bispecific NKCEs promote tumor control in vivo NKp46/(Fc)/CD20-F6 NCR1+ cell count Randomization Sacrifice ~ 100 mm3 RNAscope ** Treatment start analysis 400 Injection 5x106 Raji cells 300 Treatment Cells / mm2 S.C. 200 100 0 IC/(Fc)/CD20-F6 Day 0 Day 11 Day 18 Day 20 Bispecific NKCE treatment promo
Slide 24: Trifunctional NKCEs promoting ADCC are more efficient than bispecific mAbs
Trifunctional NKCEs promoting ADCC are more efficient than bispecific mAbs CD16 CD16* NKp46 TA NKp46 TA NKp46 TA NKp46/(Fc)/TA-F6 NKp46/Fc/TA-F5 NKp46/Fc*/TA-F5* 80 80 80 80 CD20 40 40 40 40 obinutuzumab o b in u tu z u m a b 0 0 0 0 10-6 10-4 10-2 100 10-6 10-4 10-2 100 10-6 10-4 10-2 100 10-6 10-4
Slide 25: Trifunctional NKCEs are more potent than the combination of molecules activating NKp46 and CD16 separately
Trifunctional NKCEs are more potent than the combination of molecules activating NKp46 and CD16 separately D1 D2 100 100 NNKp46/Fc/CD20-F5 K p46-1/F c/C D 20-F 5 Specific lysis (%) NNKp46/(Fc)/CD20-F6 K p46-1/(F c)/C D 20-F 6 50 50 NNKp46/(Fc)/CD20-F6 K p46-1/(F c)/C D 20-F 6 + IC+/FIC/Fc/CD20-F5 c/
Slide 26: Trifunctional NKCEs do not mediate off-target killing nor NK-vs-NK toxicity
Trifunctional NKCEs do not mediate off-target killing nor NK-vs-NK toxicity HUT78 Daudi 100 CD19- KIR3DL2+ 100 CD19+ KIR3DL2- Specific lysis (%) NNKp46/Fc/CD19-F5 K p 4 6 /F c /C D 1 9 - F 5 50 50 KKIR3DL2-IgG1 IR 3 D L 2 -Ig G 1 * IC/Fc/CD19-F5 IC /F c /C D 1 9 - F 5 0 0 NNo o Ab Ab 10-6 10-4 10-2
Slide 27: NKp46 NK cell engagers
NKp46 NK cell engagers Innovative multifunctional antibody technology for engaging NK Multifunctional NKCE cells to kill tumor cells through activating receptors expressed on CD16 NK cells NK Tumor cell • Co-engaging CD16 and NKp46 on NK cells NKp46 • Stimulates NK cells instead of T cells Killing +
Slide 28: Next generation IO: strategic key pillars to harness the potential of immunity
Next generation IO: 3 strategic key pillars to harness the potential of immunity 1 2 Immune Tumor Checkpoints Targeting MONALIZUMAB NK CELL ENGAGERS
Slide 29: Next generation IO: strategic key pillars to harness the potential of immunity
Next generation IO: 3 strategic key pillars to harness the potential of immunity 1 2 3 Immune Tumor Tumor Checkpoints Targeting microenvironment MONALIZUMAB NK CELL ENGAGERS ADENOSINE
Slide 30: The adenosine pathway is immunosuppressive
The adenosine pathway is immunosuppressive ATP: Adenosine Triphosphate AMP: Adenosine Monophosphate
Slide 31: CD39 is upregulated on TILs
CD39 is upregulated on TILs A NK cells CD8+ T cells CD4+ T cells CD4+ Treg B lo o d * * * * * * * * * * * * * * * * * * * * * * * T u m o r - a d ja c e n t t is s u e 1 0 0 * * 1 0 0 1 0 0 1 0 0 CD39+ (%) T u m o r 8 0 8 0 8 0 8 0 6 0 6 0 6 0 6 0 4 0 4 0 4 0 4 0 2 0 2 0 2 0 2 0 0 0 0 0 B Tumor tiss
Slide 32: IPH52 (anti-CD39) enhances ATP-mediated DC activation
IPH52 (anti-CD39) enhances ATP-mediated DC activation A D C A c tiv a tio n 2 0 0 0 o f F lu o r e s e n c e 1 5 0 0 H L A -D R 1 0 0 0 M e d ia n 5 0 0 IPH52 0 0 0 .1 2 5 0 .2 5 0 .5 IPH53 A T P (m M ) B T c e ll p r o life r a tio n No Ab (% ) 4 0 C e lls 3 0 T P r o life r a tin g 2 0 1 0 0 b 2 3
Slide 33: IPH5201 (anti-CD39) restores T cell proliferation
IPH5201 (anti-CD39) restores T cell proliferation + C D 4 T c e lls 8 0 P r o lif e r a t in g T C e lls ( % ) A c t. 7 0 6 0 5 0 4 0 3 0 A c t.+ A T P 2 0 -2 -1 0 1 2 3 0 1 0 1 0 1 0 1 0 1 0 1 0 m A b (n M )
Slide 34: IPH52 (CD39) enhances tumor control in human CD39 KI mice
IPH52 (CD39) enhances tumor control in human CD39 KI mice IPH52/Control Ab IPH52/Control Ab 400 µg, IV 200 µg, IV MCA205 cells 1x106 D4 D7 D11 D14 D19 D22 D26 D29 Tumor growth D5 D12 or D14 Survival Oxaliplatin Oxaliplatin 10 mg/kg, IP 10 mg/kg, IP P B S + c o n tro l A b P B S + IP H 5 2 ) 2 0 0 0
Slide 35: The adenosine pathway
The adenosine pathway Ferretti et al., Immunol. Letters 2019
Slide 36: The adenosine pathway
The adenosine pathway Ferretti et al., Immunol. Letters 2019
Slide 37: The adenosine pathway
The adenosine pathway Ferretti et al., Immunol. Letters 2019
Slide 38: High efficacy of IPH53, a blocking anti-CD73 mAb
High efficacy of IPH53, a blocking anti-CD73 mAb Cell-associated CD73 Soluble CD73 * * * * ) ) (% ) 1 .8 1 0 0 A M P + S N + A P C P 6 1 2 6 A M P ( L u m . u n its x 1 0 ( L u m . u n its x 1 0 1 .5 1 0 in h ib itio n 8 0 8 1 .2 6 0 6 0 .9 4 0 E n z y m e 4 0 .6 2 0 A M P A M P 2 A M P + c e lls A
Slide 39: High efficacy of IPH53, a blocking anti-CD73 mAb
High efficacy of IPH53, a blocking anti-CD73 mAb + + + + C D 4 T c e lls C D 4 T c e lls C D 8 T c e lls C D 8 T c e lls P r o life r a tin g T C e lls ( % ) ( n o r m a liz e d t o c o n tr o l) 1 0 0 1 0 0 A c t. * * * P r o life r a tio n r a te 9 0 1 0 0 * * * * 1 0 0 * * * 8 0 8 0 8 0 8 0 7 0 6
Slide 40: IPH53 blocks enzyme activity by constraining CD73 in an intermediate conformation
IPH53 blocks enzyme activity by constraining CD73 in an intermediate conformation CD73 dimer • The negative staining of the CD73-IPH53 complex analyzed by electron microscopy revealed that IPH53 IPH53 F(ab) mAb interacts with CD73 mainly in a 1:1 stoichiometry IPH53 Fc (upper panel) • As shown on th
Slide 41: The combination of IPH52 and IPH53 releases ATP-mediated suppression of T cells
The combination of IPH52 and IPH53 releases ATP-mediated suppression of T cells from healthy donors and cancer patients + + CD4 T c e lls CD8 T c e lls P r o life r a t in g T C e lls ( % ) 90 100 A ct A ct • When used in combination at inefficient 80 80 70 suboptimal doses, the anti-CD39/CD73 mAbs
Slide 42: The adenosine pathway is immunosuppressive
The adenosine pathway is immunosuppressive ATP: Adenosine Triphosphate AMP: Adenosine Monophosphate
Slide 43: The adenosine pathway can be controlled
The adenosine pathway can be controlled ATP: Adenosine Triphosphate AMP: Adenosine Monophosphate Perrot et al., in press
Slide 44: Next generation IO: strategic key pillars to harness the potential of immunity
Next generation IO: 3 strategic key pillars to harness the potential of immunity 1 2 3 Immune Tumor Tumor Checkpoints Targeting microenvironment MONALIZUMAB NK CELL ENGAGERS ADENOSINE
Slide 45: Thanks to patients and their families
Anaïs BALSAMO Pascale ANDRE Carole BERRUYER Agnès BOYER-CHAMMARD Adeline CRINIER Mathieu BLERY Bertrand ESCALIERE Cécile BONNAFOUS et al. Marion ETIENNOT Caroline DENIS et al. Marion FABRE Pierre DODION Justine GALLUSO Laurent GAUTHIER Sophie GUIA Ariane MOREL et al. Yann KERDILES Yannis MOREL Guill
Slide 46: Slide 46
Slide 47: Co-expression of NKG2A and PD-1 in TILs
Co-expression of NKG2A and PD-1 in TILs CD8+ T cells Spleen Tumor 3.3 0.2 26.1 33.8 96.0 0.5 39.0 1.1 André et al., Cell 2018
Slide 48: HLA-E expression in human solid tumors
HLA-E expression in human solid tumors André et al., Cell 2018
Slide 49: Combination of monalizumab and durvalumab
Combination of monalizumab and durvalumab • Tumor infiltrating NK and CD8+ T cells expressing NKG2A and/or PD-1 are present in several cancer types • HLA-E is expressed by tumor cells in the large majority of solid tumors • Blocking both NKG2A/HLA-E and PD-1/PD-L1 pathways can enhance responses of N
Slide 50: Anti-NKG2A as a novel immune checkpoint inhibitor in cancer
Anti-NKG2A as a novel immune checkpoint inhibitor in cancer In vitro data support the rationale for ongoing clinical trial investigating the combination monalizumab/durvalumab NK cell and T cell inhibition by NKG2A & PD-1 Activation by NKG2A & PD-L1 blockade
Slide 51: Monalizumab potentiates cetuximab-induced ADCC
Monalizumab potentiates cetuximab-induced ADCC CAL27 (SCCHN) 40 **** % o f C D 1 3 7 c e lls * *** 30 + 20 10 ADCC enhancement by NKG2A blockade 0 C tx - - + + M ona - + - + Cetuximab (Ctx): anti-EGFR Monalizumab (Mona): anti-NKG2A
Slide 52: Phase II clinical trial in recurrent or metastatic SCCHN
Phase II clinical trial in recurrent or metastatic SCCHN KEY RESULTS n (%) CI Complete Response (CR) 1 (2.5%) Partial response (PR)* 10 (25%) Stable disease 22 (55%) Overall Response Rate (ORR) 27.5% [16.1-42.8] Median PFS 5.0 months [3.7-6.9] Median OS 10.3 months [7.3.-NR] Safety data: - Good safe
Slide 53: IPH52 blocks CD39 in human CD39 preclinical mouse model
IPH52 blocks CD39 in human CD39 preclinical mouse model Splenocytes • We generated a human CD39 knock-in mice by 2.0× 10 07 WT KO KI Ab-treated KI replacing the mouse CD39 by human CD39 protein using a knock-out/knock-in (KI) molecular biology ATP (Lum. Units) strategy Cont. Ab moIPH52 1.5× 10 07 1.
Slide 54: Trifunctional NKCEs more efficient than bispecific mAbs in vivo
Trifunctional NKCEs promoting ADCC are more efficient than bispecific mAbs in vivo NKp46/(Fc)/CD20-F6 (6.25 mg/kg) G A 1 0 1 - F 6 -2 9 A 1 .4 F6 (Fc-silent) F5 (Normal Fc) NKp46/Fc/CD20-F5 G A 1 0 1 - F 5 - 2(6.25 9 A mg/kg) 1 .4 IC/(Fc)/CD20-F6 G A 1 0 1 - F 6(6.25 - I Cmg/kg) b Obinutuzumab O b i
Slide 55: Trifunctional NKCEs more efficient than bispecific mAbs in vivo
Trifunctional NKCEs promoting ADCC are more efficient than bispecific mAbs in vivo 0.8 µg/kg 4 µg/kg 20 µg/kg Treatment 100 100 100 Injection **** 5x106 Raji ** * Survival (%) cells I.V. * 50 50 50 **** Day 0 Day 1 ** 0 0 0 0 20 40 60 0 20 40 60 0 20 40 60 Days (post cell injection)
Slide 56: NKp46 expression is not downregulated in cancer
NKp46 expression is not downregulated in cancer A Density plots Heatmaps NKp46 CD16 NKp44 Cluster 1 Cluster # 1 Blood Cluster # 2 100 79 % among NK cells Cluster 2 80 -377 3995 -454 38,854 -395 2192 53 60 47 40 21 20 0 Tumor -430 3995 -474 37,413 -398 2192
Slide 57: Qa-1b expression blocks the anti-tumor efficacy of NK and CD8+ T cells
Qa-1b expression blocks the anti-tumor efficacy of NK and CD8+ T cells Control NK cell depleted ) A20 3 T u m o r v o lu m e ( m m 2000 2000 100 2 /1 1 S u r v iv a l ( % ) 0 /1 1 1500 1500 80 Control Control NK cell depleted 60 1000 1000 40 500 500 20 0 0 0 ** 0 10 20 30 40 50 0 10 20 30 40 50 0 10
Slide 58: Co-expression of NKG2A and PD-1
Co-expression of NKG2A and PD-1 A20 tumor-bearing BALB/c mice NK cells CD8+ T cells Spleen Tumor Spleen Tumor 0.4 0.2 0.3 0.3 3.3 0.2 26.1 33.8 PD1 38.7 60.8 37.9 61.5 96.0 0.5 39.0 1.1 NKG2A NKG2A+PD1- 60 ± 0.4 61.9 ± 2.9 0.7 ± 0.5 2.2 ± 0.9 NKG2A-PD1+ 0.5 ± 0.3 0.5 ± 0.7 3.9 ± 2.1 23.4 ± 12.1 NKG2
Slide 59: The combined blockade of NKG2A and PD-1/PD-L1 promotes anti-tumor immunity
The combined blockade of NKG2A and PD-1/PD-L1 promotes anti- tumor immunity 100 S u r v iv a l ( % ) a-NKG2A+ a-PD-L1 80 a-PD-L1 60 *** 40 a-NKG2A **** ** 20 Control 0 0 10 20 30 40 50 D ays A20 tumor-bearing BALB/c mice
Slide 60: Combined blockade promotes anti-tumor immunity in RMA Rae-1β tumor-bearing mice
Combined blockade of NKG2A and PD-1/PD-L1 promotes anti-tumor immunity in RMA Rae-1β tumor-bearing mice RMA Rae-1β tumor-bearing C57BL/6 mice treated with anti-PD-L1 and anti-NKG2A mAbs
Slide 61: Combined blockade promotes anti-tumor immunity in RMA Rae-1β tumor-bearing mice
Combined blockade of NKG2A and PD-1/PD-L1 promotes anti-tumor immunity in RMA Rae-1β tumor-bearing mice RMA Rae-1β tumor-bearing C57BL/6 mice treated with anti-PD-L1 and anti-NKG2A mAbs
Slide 62: Combined blockade promotes anti-tumor immunity in RMA Rae-1β tumor-bearing mice
Combined blockade of NKG2A and PD-1/PD-L1 promotes anti-tumor immunity in RMA Rae-1β tumor-bearing mice RMA Rae-1β tumor-bearing C57BL/6 mice treated with anti-PD-L1 and anti-NKG2A mAbs
Slide 63: NKG2A expression by TILs in humans
NKG2A expression by TILs in humans
Slide 64: Monalizumab unleashes human CD8+ T cell function in vitro alone and with durvalumab
Monalizumab unleashes human CD8+ T cell function in vitro alone and with durvalumab CD8 Flu-tetramer PD1 NKG2a CD8+ T cells cultured in vitro with monocytes, flu peptide and IL-15 (day 10) Flu-specific CD8+ T cells challenged with flu peptide-pulsed K562 cells expressing PD-L1, HLA-E and HLA-A2
Slide 65: Monalizumab unleashes human NK cell function in vitro alone and with durvalumab
Monalizumab unleashes human NK cell function in vitro alone and with durvalumab NKG2A+ PD1- NKG2A+ PD1+ *** *** *** *** *** 60 60 *** *** *** c e lls + K562 40 40 % of C D 107 HLA-E 20 20 0 0 l l a a a a bo bo ro ro rv rv on on nt nt m m du du m m co co co co **** **** ** 60 **** * ** 60 % of CD107+
Slide 66: Trifunctional NKCEs promoting ADCC are more efficient than bispecific mAbs
Trifunctional NKCEs promoting ADCC are more efficient than bispecific mAbs D5 D6 NK cells alone NK cells + Daudi NK cells alone NK cells + Daudi 60 60 80 80 NNKp46/Fc*/CD20-F5* K p 4 6 /F c * /C D 2 0 -F 5 CD107+ 60 60 40 40 cells (%) 40 40 20 20 NNKp46/Fc/CD20-F5 20 20 K p 4 6 /F c /C D 2 0 -F 5 0
Slide 67: NKp46 NK cell engagers in oncology: solid tumor model
NKp46 NK cell engagers in oncology Solid tumor model F6 IC/(Fc)/CD20-F6 IC /(F c )/C D 2 0 -F 6(6.25 (6 .2 5mg/kg) m g /k g ) Randomization NNKp46/(Fc)/CD20-F6 K p 4 6 /(F c )/C D 2 0 -F 6(6.25 (6 .2mg/kg) 5 m g /k g ) ~ 100 mm3 Treatment start NNKp46/(Fc)/CD20-F6 K p 4 6 /(F c )/C D 2 0 -F 6(0.25 (
Slide 68: NKp46 NK cell engagers in oncology: solid tumor model
NKp46 NK cell engagers in oncology Solid tumor model NKp46/(Fc)/CD20-F6 G A 1 0 1 - F 6 -2 9 A 1(6.25 .4 mg/kg) F6 (Fc-silent) F5 (Normal Fc) NKp46/Fc/CD20-F5 G A 1 0 1 - F 5 -2 9 A(6.25 1 .4 mg/kg) IC/(Fc)/CD20-F6 G A 1 0 1 - F 6 -IC(6.25 b mg/kg) Obinutuzumab O b in u tu z u m(6.25 a b mg/kg) 1,50
Slide 69: NKp46 NK cell engagers in oncology: invasive tumor model
NKp46 NK cell engagers in oncology Invasive tumor model Treatment 0.8 µg/kg 4 µg/kg 20 µg/kg Injection 100 100 100 5x106 Raji **** cells I.V. ** * Survival (%) * 50 50 50 **** Day 0 Day 1 ** 0 0 0 0 20 40 60 0 20 40 60 0 20 40 60 Days (post cell injection) Gauthier et al.