Transplant and immunotherapy in CML - Agnes Yong

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Transplant and immunotherapy in CML :

Transplant and immunotherapy in CML Agnes Yong August 2014

Overview:

Overview There are known knowns There are things we know that we know There are known unknowns That is to say, there are things that we know we don ’ t know But there are also unknown unknowns There are things we don ’ t know we don ’ t know Donald Rumsfeld US Secretary of Defense Jan 2001-Dec 2006 Allogeneic stem cell transplantation cures CML Can immune responses be enhanced in non-alloSCT CML Can CML really be cured without alloSCT

Allogeneic stem cell transplantation: The most successful immunotherapy in CML:

Allogeneic stem cell transplantation: The most successful immunotherapy in CML

AlloSCT cures CML-CP :

AlloSCT cures CML-CP

Probability of Survival after HLA-identical Sibling Donor Transplants for CML, 1998-2010 - By Disease Status and Transplant Year -:

Probability of Survival after HLA-identical Sibling Donor Transplants for CML, 1998-2010 - By Disease Status and Transplant Year - Slide 34 Years 0 2 6 1 3 4 5 0 20 40 60 80 100 10 30 50 70 90 0 20 40 60 80 100 10 30 50 70 90 Probability of Survival, % P < 0.0001 CP, 1998-2000 (N=2,239) AP, 1998-2000 (N=291) CP, 2001-2009 (N=2,498) AP, 2001-2009 (N=360) SUM12_11.ppt

Indications for Hematopoietic Stem Cell Transplants in the US, 2011:

Indications for Hematopoietic Stem Cell Transplants in the US, 2011

Slide7:

Chronic Myelogenous Leukemia Overall Survival Unrelated Transplantation for Adult Patients, by Year of Transplant (1991-2012) Log-rank p-value < 0.001 SOURCE: Data and analysis on NMDP-facilitated transplants through CIBMTR ® , the research arm of the NMDP.

Slide8:

SOURCE: Data and analysis on NMDP-facilitated transplants through CIBMTR ® , the research arm of the NMDP. Chronic Myelogenous Leukemia Overall Survival Unrelated Transplantation with Bone Marrow for Adult Patients, by Disease Status at Transplant (2002-2011) Log-rank p-value < 0.001

Slide9:

Chronic Myelogenous Leukemia Overall Survival Unrelated Transplantation with PBSC for Adult Patients, by Disease Status at Transplant (2002-2011) Log-rank p-value < 0.001 SOURCE: Data and analysis on NMDP-facilitated transplants through CIBMTR ® , the research arm of the NMDP.

Donor relationship for allogeneic transplants Australia and New Zealand 1992-2011:

Donor relationship for allogeneic transplants Australia and New Zealand 1992-2011 Recipients aged 0-15 Recipients aged 16+ ABMTRR 2012, courtesy of L Wilcox

EBMT score for alloSCT in CML:

EBMT score for alloSCT in CML HLA match (sib/other) Disease stage (CP1/AP/other) Age (<20/20-40/>40) Donor/recipient (Other/F M) Time from diagnosis (≤12m/>12m) n=3142 (1989-97) Gratwohl, et al, Lancet 1998

Which CML patient needs transplant?:

Which CML patient needs transplant? Blast crisis TKI-resistant chronic phase/accelerated phase Failure to achieve early molecular response? Economic reasons? Children? Adolescents?

Slide13:

OS all T315I pts 1999-2010 EBMT registry (n=222) Pre-ponatinib n=64 alloSCT (67 grafts; 6MRD, 41MUD, 5MMRD,13MMUD,2UNK )

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OS T315I pts with alloSCT 1999-2010 EBMT registry (n=222) Pre-ponatinib n=64 alloSCT (67 grafts; 6MRD, 41MUD, 5MMRD,13MMUD,2UNK )

Slide15:

1 yr TRM 18.2% CP 11.2% AP 2yr OS 59% CP 67% AP 30% BP 1999-2010 EBMT registry (n=222) Pre-ponatinib n=64 alloSCT (67 grafts; 6MRD, 41MUD, 5MMRD,13MMUD,2UNK )

Which CML patient needs transplant?:

Which CML patient needs transplant? Blast crisis TKI-resistant chronic phase/accelerated phase Failure to achieve early molecular response? Economic reasons? Children? Adolescents?

Economics and alloSCT in CML:

Economics and alloSCT in CML Cost of alloSCT = cost of TKI in middle income countries Gratwohl & Heim, Best Prac Res Clin Haem 2009

Which CML patient needs transplant?:

Which CML patient needs transplant? Blast crisis TKI-resistant chronic phase/accelerated phase Failure to achieve early molecular response? Economic reasons? Children? Adolescents?

Which conditioning regime for alloSCT?:

Which conditioning regime for alloSCT? 2. Cy/TBI or BuCy myeloablative 1. RIC better than NMA in older pts (Warlick, CIBMTR Blood 2012) 4. Scheduled DLI? 3. Prophylactic TKI post-SCT?

Slide20:

AlloSCT results in the TKI era German CML IV study, Saussele, Blood 2010 59% AdP-CML (n=28) 88% CP-CML elective (n=20) 94% CP-CML IM-NR (n=36) Matched pair analysis (1:2) Non-inferior OS alloSCT vs IM 8% TRM (GVHD, infection) Median FU 30mo

Slide21:

AlloSCT in AdP-CML CIBMTR, Khoury, BMT 2012 n=449 1999-2004 AP(185), CP2(184),BC(80) Cond MA 78% vs 78% vs 84% AP and CP2 similar OS and DFS Aim: Achieve more CP2 (2GTKI) to improve outcome Median FU 3y AP CP2 BC Pre-alloSCT IM not prognostic

Slide22:

AlloSCT in patients >40y CIBMTR, Warlick, Blood 2012 3y OS 41-54% (age gp NS) 1 y TRM 13-20% (age gp NS) NMA inferior DFS cf RIC Age 40-75, Median FU >3y n=306, RIC/NMA 2001-2007 Pre-alloSCT IM better OS >60y (n=70, 23%) 3y relapse 66%, DFS 16% (69% AdP, 56%AP/CP2,13% BC) 40-49y (n=117, 38%) 3y relapse 36%, DFS 35% (29% AdP,26% AP/CP2, 3%BC)

Slide23:

AlloSCT in patients >40y CIBMTR, Warlick, Blood 2012 3y OS 41-54% (age gp NS) 1 y TRM 13-20% (age gp NS) NMA inferior DFS cf RIC Age 40-75, Median FU >3y n=306, RIC/NMA 2001-2007 Pre-alloSCT IM better OS >60y (n=70, 23%) 3y relapse 66%, DFS 16% (69% AdP, 56%AP/CP2,13% BC) 40-49y (n=117, 38%) 3y relapse 36%, DFS 35% (29% AdP,26% AP/CP2, 3%BC) DFS similar for CP1-CML

Role of TKIs after transplant:

Role of TKIs after transplant 2. Treat GVHD 1. Pre-emptively to reduce MRD; Dasatinib crosses blood-brain barrier (LBC) 4. Combination with DLI? 3. Treat relapse

Longterm follow-up after transplant for CML:

Longterm follow-up after transplant for CML 2. Late TRM – 5%@10y organ failure, inf, GVHD, relapse, 2nd CA 1. Post-alloSCT 5y survivors have same life expectancy/QoL as general population by 15y post-SCT 3. Late relapse 4%@10y n= 2444 alloSCT 1978-1998 CML-CP1 Sib 1692, VUD 639, other related donor 113 Median FU 11y (5-25) OS 10y 94%, 15y 87%

How to improve alloSCT results for AdP-CML? Future directions (immunotherapy):

How to improve alloSCT results for AdP-CML? Future directions (immunotherapy) 2. Enhance NK cell function 1. Target leukaemia-associated antigens (WT1, PR1, others) 3. Enhance T cell function

What is targeted on leukaemia cells ? (1) (by donor CTLs in GVL):

What is targeted on leukaemia cells ? (1) (by donor CTLs in GVL)

What is targeted on leukaemia cells ? (2) (by donor CTLs in GVL):

What is targeted on leukaemia cells ? (2) (by donor CTLs in GVL) PR1-CTL: IFN responders 11/12 vs IFN non-responders 0/7 alloSCT responders 6/8 vs non-responders 0/1 chemotherapy responders 0/1 vs non-responders 0/9

Are these CTL responses relevant in the TKI era?:

Are these CTL responses relevant in the TKI era? Burchert, JCO 2010 German CML IV trial: n=20 IM + IFN > 2y stopped IM median 2.4y (0.5-4) 15/20 ≥ MMR PR1-CTLs in IFN responders

What is a good leukaemia-associated antigen?:

What is a good leukaemia-associated antigen? Therapeutic function Immunogenicity Role in oncogenicity Specificity for tumour Expression level and percent Ag+ cells Stem cell expression Number of patients with Ag+ cells Number of antigenic epitopes Cellular location of Ag expression Translational Research Working Group, NCI Cheever, et al, Clin Can Res 2009

Slide31:

Therapeutic function Immunogenicity Specificity Oncogenicity Expression level Stem cell expression Proportion of +ve patients # epitopes Cellular location of expression The Prioritization of Cancer Antigens: NCI Pilot Project for the Acceleration of Translational Research Cheever, et al, Clin Cancer Res 2009 Which antigen? 1 18

Wilms tumor 1 (WT1):

Wilms tumor 1 (WT1) Zinc finger transcription factor Function: regulates genes  cell development and survival , essential in urogenital development; mutated in 20% nephroblastoma (Wilms ’ tumor) Tissue specificity: glomeruli, ovaries, testis, CD34+ Cancer and leukaemia cells  increased expression WT1-CTLs selectively kill leukaemia cells Gao, et al, Blood 2000; Oka, et al, PNAS 2004; van Tendeloo, et al, PNAS 2010

Elastase (ELA2) and Proteinase 3 (PR3):

Elastase (ELA2) and Proteinase 3 (PR3) Primary granular proteins and serine proteases (azurophilic granules) ELA2 has 55% homology with PR3 Function: bactericidal (Gram neg), inflammation (ELA2 degrades extra-cellular matrix), etc Tissue specificity: granulocytic lineage ELA2 pathological role in chronic lung disease – e.g. alpha-1 anti-trypsin deficiency Congenital neutropenia and SCN – mutations in ELA2 PR3 antibodies in Wegener ’ s granulomatosis

Role of ELA2 and PR3 in CML (immunological effects) :

Role of ELA2 and PR3 in CML (immunological effects) PR3 and ELA2 in CML > normal Molldrem, et al, Blood 1997; Fujiwara, et al, Blood 2004 PR1 (VLQELNVTV) pulsed APCs induce CTLs  selectively kills leukaemia cells Degree of cytotoxicity correlates with PR3 amount in leukaemia cells Molldrem, et al, Blood 1996 PR1 responses correlate with disease response to IFN and alloSCT Molldrem, et al, Can Res 1999; Nat Med 2000 PR1-CTLs in CML patients and healthy people Rezvani, et al, Blood 2003

PRAME Preferentially expressed antigen of melanoma:

PRAME Preferentially expressed antigen of melanoma Cancer testis antigen Tissue expression: testis, adrenals, endometrium, brain Overexpressed in leukaemias and cancers Function: inhibit myeloid cell differentiation through blockage of RAR a signalling pathway Immune responses to PRAME epitopes detected in AML, CML, ALL and healthy donors PRAME-CTLs can selectively kill leukaemia cells Rezvani, Yong, et al, Blood 2008 Quintarelli, et al, Blood 2008, Blood 2011

BMI-1:

BMI-1 BMI-1 ( B -cell lymphoma m urine i nsertion site 1 ) = PCGF4 ( P oly c omb g roup ring f inger 4 ) Component of PRC1 (polycomb repressive complex 1) Important in self-renewal of hematopoietic stem cells Overexpressed in many cancers  aggressive phenotype/poor prognosis Lessard & Sauvageau, Nature 2003; Park, et al, Nature 2003; Rizo, et al, Blood 2008, Blood 2009 In CML-CP, high expression of BMI-1 in CD34+ cells at diagnosis  poor survival in non- transplanted patients, BUT high BMI-1 pre-SCT  improved survival post-allo-SCT Mohty, Yong, et al, Blood 2007, Blood 2008

Polycomb group proteins as leukemia associated antigens:

Polycomb group proteins as leukemia associated antigens Peptides derived from BMI-1 (PRC1) and EZH2 (PRC2) induce cytotoxic T-cell responses in 20-25% patients with solid tumors and healthy controls (Steele, et al, Br J Cancer 2006) Cytotoxic T-cell lines specific for HLA-A*0201 restricted BMI-1 peptides CLPSPSTPV and TLQDIVYKL expanded from healthy donors can lyse leukemia cells from AML and CML patients (Fujii, et al, ASH 2008)

Slide38:

0.10% 0.13% 0.12% 0.12% 0.22% 0.26% CD8 CD107a 0.01% NEG 0.03% BMI-T 0.1 m M 0.24% CMV 0.12% BMI-T 10 m M EZH-Y 0.1 m M 0.03% EZH-Y 10 m M 0.06% CD8 IFN- g 0.04% 0.14% 0.08% 0.10% 0.04% 0.06% CD8 TNF- a 0.01% 0.00% 0.01% 0.00% 0.00% 0.01% CD8 IL-2 BMI-1 elicits polyfunctional CTLs

Leukaemia-associated antigens:

Leukaemia-associated antigens Which proteins are immunogenic? What is the expression pattern on normal vs. leukaemia stem/progenitor cells? Can these leukaemia-associated antigens be used clinically?

Slide40:

Comparing LAAs in primitive progenitors WT1 useful to differentiate AdP-CML from normal in all groups (including most primitive HSC) PRAME useful to differentiate AdP-CML from normal in more mature progenitors PR3 useful to differentiate CP-CML from normal in HSCs Normal CP AdP Yong, et al, Leukemia 2008

Leukaemia-associated antigens:

Leukaemia-associated antigens Which proteins are immunogenic? What is the expression pattern on normal vs. leukaemia stem/progenitor cells? Can these leukaemia-associated antigens be used clinically? Autologous Allogeneic

Immunotherapy targeting single protein:

Immunotherapy targeting single protein WT1 Short peptides: (Keiholz, Scheibenbogen, Oka, Sugiyama) HLA-A*0201 ( RMFPNAPYL) WT1-126 HLA-A*2402 (C M TWNQ MNL) WT1-235 Long peptides: (Scheinberg) Electroporation mRNA (Van Tendeloo, Berneman) DNA vaccine (Stevenson) PR1 Short peptide: HLA-A*0201 ( VLQELNVTV) (Molldrem)

Slide43:

n= 26 2 breast cancer, 10 lung cancer, 12 AML in CR, 1 tAML, 1 MDS Phase I trial WT1-235 (HLA-A*2402) CMTWNQMNL, C Y TWNQMNL WT1 vaccine (Montanide adjuvant) every 2 weeks x 3 doses  Every 2 weeks after 4 weeks per patient response Toxicity: severe leukopaenia in 2 (MDS and tAML) Efficacy: WT1 i Blasts ii (7) SD(1) PD (6)

Slide44:

n= 26 2 breast cancer, 10 lung cancer, 12 AML in CR, 1 tAML, 1 MDS Phase I trial WT1-235 (HLA-A*2402) CMTWNQMNL, C Y TWNQMNL WT1 vaccine (Montanide adjuvant) every 2 weeks x 3 doses  Every 2 weeks after 4 weeks per patient response Toxicity: severe leukopaenia in 2 (MDS and tAML) Efficacy: WT1 i Blasts ii (7) SD(1) PD (6)

Slide45:

WT1-126 (HLA-A*0201) RMFPNAPYL n=19 17 AML, 2 RAEB (5-85% BM blasts) WT1 vaccine (D1-4 GM-CSF and D3 WT1+KLH adjuvant) Cohort 1 (n=9) every 2 weeks x 4, then monthly Cohort 2 (n=10) every 2 weeks 4-27 vaccinations per patient (median 11) Toxicity: transient local; erythema nodosum (3)  cough(2) Efficacy: (a) 8 AML no prior Rx (BM blasts 40-85%)  SD ~ 4mo (6) (b) 9 AML prior Rx (BM blasts 5-60%) PFS~50 d (c) 2 RAEB neut response 10mo and 2 mo (no cytopaenia)

Slide46:

WT1-126 (HLA-A*0201) RMFPNAPYL n=19 17 AML, 2 RAEB (5-85% BM blasts) WT1 vaccine (D1-4 GM-CSF and D3 WT1+KLH adjuvant) Cohort 1 (n=9) every 2 weeks x 4, then monthly Cohort 2 (n=10) every 2 weeks 4-27 vaccinations per patient (median 11) Toxicity: transient local; erythema nodosum (3)  cough(2) Efficacy: (a) 8 AML no prior Rx (BM blasts 40-85%)  SD ~ 4mo (6) (b) 9 AML prior Rx (BM blasts 5-60%) PFS~50 d (c) 2 RAEB neut response 10mo and 2 mo (no cytopaenia)

Slide47:

Phase I/II trial Full length WT1-mRNA electroporated into autologous DC n=10 AML (8CR, 2PR[6,9% blasts]) WT1 vaccine (KLH-exposed mRNAe-DC) every 2 weeks x 4 doses  every 2 months per patient response Toxicity: Local; ax LN pain (1); transient i platelets (1) Efficacy: Clinical response (5)  3 >3y CR

Slide48:

Phase I/II trial Full length WT1-mRNA electroporated into autologous DC n=10 AML (8CR, 2PR[6,9% blasts]) WT1 vaccine (KLH-exposed mRNAe-DC) every 2 weeks x 4 doses  every 2 months per patient response Toxicity: Local; ax LN pain (1); transient i platelets (1) Efficacy: Clinical response (5)  3 >3y CR

Slide49:

PR1 Peptide Vaccine-Induced Immune Response Is Associated with Better Event-Free Survival in Patients with Myeloid Leukemia. Qazilbash, et al Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 283 Phase I/II trial PR1 (HLA-A*0201) VLQELNVTV n=66 AML (42), CML (13), MDS (11) [13CR, 53 “ measurable disease ” ] PR1 vaccine (Montanide adjuvant) + GMCSF Cohort 1: every 3 weeks x 3 doses (54) Cohort 2: every 3 weeks x 6 doses (12) Toxicity: local Efficacy: “ PR1 immune response ” 25/53 with measurable disease Clinical response in 9/25 IR vs 3/28 no-IR

Slide50:

PR1 Peptide Vaccine-Induced Immune Response Is Associated with Better Event-Free Survival in Patients with Myeloid Leukemia. Qazilbash, et al Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 283 Phase I/II trial PR1 (HLA-A*0201) VLQELNVTV n=66 AML (42), CML (13), MDS (11) [13CR, 53 “ measurable disease ” ] PR1 vaccine (Montanide adjuvant) + GMCSF Cohort 1: every 3 weeks x 3 doses (54) Cohort 2: every 3 weeks x 6 doses (12) Toxicity: local Efficacy: “ PR1 immune response ” 25/53 with measurable disease Clinical response in 9/25 IR vs 3/28 no-IR

PR1 / WT1 vaccine safety study (n=8) :

PR1 / WT1 vaccine safety study ( n=8) Inclusion Criteria: Low risk MDS, AML and CML-CP HLA-*A201 positive at one allele Exclusion Criteria: Hypoplastic MDS History of Wegener ’ s granulomatosis/ ANCA positive 1 injection of PR1 0.3mg 1 injection of WT1 0.3mg Vaccine Follow up visits WK1D1 Day 7 Day 14 Day 21 Day 28 Off Study + GMCSF + montanide adjuvant Rezvani, Yong, et al, Blood 2008

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Rezvani, Yong, et al, Blood 2008 Single vaccination with WT-1 PR-1 peptide + adjuvant: induces transient peptide-specific CTL (immunogenic) temporarily lowers WT1 expression 700 350 250 2 1 0 500 1200 4500 6000 PR1 WT1 WT1 mRNA BCR/ABL CMV

Phase 2 efficacy study design (n=8) multiple vaccinations to boost T cell response:

Phase 2 efficacy study design (n=8) multiple vaccinations to boost T cell response Inclusion Criteria: Low risk MDS, AML and CML-CP HLA-*A201 positive at one allele 6 injection of PR1 Q 2wk 6 injection of WT1 Q 2wk + 3 monthly boost Wk0 Wk2 Wk4 Wk6 Wk8 Wk10 Wk22 V1 Off Study + GMCSF + montanide adjuvant V2 V3 V4 V5 B1 V6 Rezvani , Yong, et al, Haematologica 2011

Repeated vaccination with PR1 and WT1 peptides in Montanide does not induce high avidity CD8+ T cells:

Repeated vaccination with PR1 and WT1 peptides in Montanide does not induce high avidity CD8+ T cells Patient 1- Wk 22 post-vaccine Neg CMV PR1 Pre- stimulation Post- 3x stimulation CD8 IFN- g WT1

CD8+ CTL Priming by Exact Peptide Epitopes in Incomplete Freund’s Adjuvant Induces a Vanishing CTL Response, whereas Long Peptides Induce Sustained CTL Reactivity Bijker et al J. Immunol 2007:

CD8+ CTL Priming by Exact Peptide Epitopes in Incomplete Freund ’ s Adjuvant Induces a Vanishing CTL Response, whereas Long Peptides Induce Sustained CTL Reactivity Bijker et al J. Immunol 2007 Mice were vaccinated s.c. with minimal OVA CTL peptide mixed in IFA or in PBS + IFA Tolerance induced by sustained and systemic presentation of the CTL peptides gradually leaking out of the IFA depot without systemic danger signals

Slide56:

Identified 41 new WT1 epitopes (15mer peptide library) 36 Class I (HLA-A*0101, 0201, 0203, 2402, 3101, 6901, HLA-B*0702, 3501, 3503, 3508, 3801, 3802, 3901, 4001, 4402, 4701, 5701, HLA-C*0401, 1701) 5 Class II (DRB1*0101, 0401, 0402, 1104) Generate high avidity PRAME-CTLs from HLA-A*0201 donors and pts PRAME-CTLs kill leukaemia progenitor cells (CFUs)

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23 75 138 123 78 49 41 132 7 day HARPY050314 Wash 21/07/14 34 74 56 62 41 68 108 34 133 63 102 50 142 105 72 Media only WT37 WT126 WT187 WT235 PR1169-177 BMI C BMI T 258 75 67 126 86 69 60 17 113 49 48 63 61 70 89 21 45 55 125 63 36 91 14 64 101 PRA100 PRA142 PRA300 PRA425 PRA435 CMVpp65 PHA SEB

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n=16 (min Rx 12m IM [10], 24m IFN [6]) b3a2 (e14a2)+ CML “ stable response ” (med 10m IM, 17m IFN) HLA-A3, A11, B8, DR1, DR4, DR11 Phase II CMLVAX100 (5 peptides; 4 Class I, 1 Class II) with QS-1 GMCSF 50 m g/m 2 D-1, D0 6 x 2wkly S/C Toxicity: local redness, oedema; fever 7/16 after GMCSF Efficacy: immunology: 14/16 class II+, 13 CD4 responses after vaccines MRD ↓ but patients still on IM or IFN

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n=16 (min Rx 12m IM [10], 24m IFN [6]) b3a2 (e14a2)+ CML “ stable response ” (med 10m IM, 17m IFN) HLA-A3, A11, B8, DR1, DR4, DR11 Phase II CMLVAX100 (5 peptides; 4 Class I, 1 Class II) with QS-1 GMCSF 50 m g/m 2 D-1, D0 6 x 2wkly S/C Toxicity: local redness, oedema; fever 7/16 after GMCSF Efficacy: immunology: 14/16 class II+, 13 CD4 responses after vaccines MRD ↓ but patients still on IM or IFN

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n=19 (min Rx 6m IM) b3a2(e14a2)+ CML, “ any ” HLA type Phase I/II 3/5 peptides; HLA-A2, A3, A11, B8; consensus peptide + 15mer PADRE GMCSF 40 m g/m 2 15min prior 6 doses intradermal D1,8,15,22,36,64 4 cohorts 100 m g, 300 m g, 600 m g, 1000 m g peptides Toxicity: local DTH type skin after 2 nd dose; GMCSF Rxn one pt 3 rd dose Efficacy: immunology: responses peak D64-92, gone D148 11-13/19 BCR-ABL responses post-vaccine; PADRE response all; 6 NR, 13 MRD ↓ but patients still on IM

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n=19 (min Rx 6m IM) b3a2(e14a2)+ CML, “ any ” HLA type Phase I/II 3/5 peptides; HLA-A2, A3, A11, B8; consensus peptide + 15mer PADRE GMCSF 40 m g/m 2 15min prior 6 doses intradermal D1,8,15,22,36,64 4 cohorts 100 m g, 300 m g, 600 m g, 1000 m g peptides Toxicity: local DTH type skin after 2 nd dose; GMCSF Rxn one pt 3 rd dose Efficacy: immunology: responses peak D64-92, gone D148 11-13/19 BCR-ABL responses post-vaccine; PADRE response all; 6 NR, 13 MRD ↓ but patients still on IM

Slide62:

NK cells and KIR genotypes predict response in CML

Slide63:

Parham et al J Clin Invest. 2010 Nov;120(11):3801-4 Adelaide Marin: IM. ↓PFS/OS/CCR Multivariate with Sokal Kreutzman: DAS. ↓BCR-ABL; no multivariate La Nasa: 3 TKIs ↓CMR

Targeting of CML leukaemia stem cells :

Targeting of CML leukaemia stem cells CD123 CD123 CAR

Slide65:

NK cells and sensitisation with bortezomib IL1RAP development LAA-CTLs post-alloSCT Clinical trials in anti-PD1 (nivolumab, etc)

Slide66:

Acknowledgement Carine Tang Ljiljana Vidovic David Ross David Yeung Deb White LB To Tim Hughes Contributing Haematologists Committee

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