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Koehne ebmt-2017-wt1-mm
1. www.ebmt.org#EBMT17
WT1 heteroclitic epitope immunization following autologous
SCT induces WT1-specific immune responses and improves
survival in patients with high-risk multiple myeloma
G. Koehne, MD, PhD1,2, S. Devlin, PhD3, N. Korde2, S. Mailankody2, H. Landau, MD1,2, H.
Hassoun, MD2, A. Lesokhin, MD2, N. Lendvai, MD, PhD2, D. Chung, MD, PhD1,2, S. Giralt, MD1,2
and O. Landgren2
Adult Bone Marrow Transplantation Service1, Myeloma/Lymphoma Service2, Dept. of Epidemiology – Biostatistics3,
Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Marseille, 28/03/2017
2. 2
• G. Koehne is a consultant to Sellas Life Sciences Group, Ltd.
• Support for this study was provided by Leo A. Guthart and Kathryn
Medina Research Fund in Multiple Myeloma and Sellas Life Sciences
Group, Ltd.
Disclosures
Koehne G. et al.; EBMT 2017
3. 3
Wilms Tumor-1 (WT1) gene product in
multiple myeloma (MM)
• The Wilms tumor 1 (WT1) protein is a zinc finger transcription factor
— Roles in cell proliferation, differentiation, apoptosis and organ development
— Initially described as a tumor suppressor gene but later identified as a true oncogene
— Tumor associated antigen (TAA) that is an established -and indeed optimal- target for anticancer
immunotherapy
• Our group had previously demonstrated overexpression of WT1 in multiple myeloma (MM)
cells by IHC, as well as formation of a WT1 peptide fragment (RMFPNAPYL) complex on
malignant plasma cells*
• We also described the development of WT1-specific immune responses following donor
lymphocyte infusion post CD34+-selected allografts**
• We now report initial results from MM pts immunized with galinpepimut-S (GPS), a first-in-
class WT1 heteroclitic peptide mixture, following autologous stem cell transplantation
(autoSCT)
*Koehne G, et al. ASH Ann Mtg; Abst. #98, 2015.
** Tyler EM, et al. Blood. 2013;121:308-317
Koehne G. et al.; EBMT 2017
4. 4
IHC With WT1 mAb 6F-H2 in MM
CD138 (brown)/ WT1 (red) co-staining of BM biopsy
WT1 (red) co-staining of kidney biopsy CD138 (brown) staining of BM biopsy
BM, bone marrow; IHC,
immunohistochemistry.
Tyler EM, et al. Blood.
2013;121:308-17.
Koehne G. et al.; EBMT 2017
5. 5
TCR-like mAbs allow to target intracellular tumor
antigens by binding to MHC/ Peptide Complex (ESK1)
T-Cell
Receptor
(TCR)
MHC Class I
(HLA-A, -B, -C)
Cytotoxic
CD8+
T Cell Malignant
Plasma
Cell
TCR-like
anti-WT1
mAb
(ESK1)
WT1 Peptide
Dao & Scheinberg, MSKCC, Data on file
Koehne G. et al.; EBMT 2017
6. 6
Binding of anti-WT1 mAb ESK1 to PBMCs
from healthy donors
Gated cells are listed on y-axis;
left column is HLA-A02(+) and
right column is HLA-A02(-)
(Single representative of 16
samples)
Red line = ESK1;
Blue line = isotype control mAb
Dao & Scheinberg, MSKCC
Data on file
Koehne G. et al.; EBMT 2017
8. 8
Galinpepimut-S (GPS): Immunogenicity and Decreased
Tolerization Improved by Creating Synthetic Heteroclitic
Peptides
• A heteroclitic epitope describes an altered peptide that is a better agonist for inducing T-cell responses than the
native, unaltered peptide
• This is particularly important for “self” cancer antigens, like WT1, to elicit and maintain an effective immune response
• Previous immune response and clinical efficacy data with galinpepimut-S (GPS) in AML and mesothelioma (in the
setting of CR1/ minimal residual disease) supports this increased antigenicity and breach in tolerance^
*: Denotes mutated sequences,
whereby Tyr (Y) replaces Arg (R); R
being in the native sequence; CTL:
cytotoxic lymphocytes
^: Maslak PG, et al. Blood. 2010;116:171-9;
Maslak PG, et al. ASCO Ann Mtg, Abst.
#7005, 2016;
Krug LM, et al. CA Immunol Immunother.
2010;59:1467-79;
Zauderer MG, et al. ASCO Ann Mtg, Abst.
#8519, 2016.
Koehne G. et al.; EBMT 2017
9. 9
Heteroclitic Technology-Based
Cancer Immunogens/ Vaccines
• GPS is a mixture of 2 native and 2
synthetic WT1 peptide sequences:
The heteroclitic peptides - bearing
point mutations (*) - were created to
stimulate both CD4+ and CD8+ T cell
responses.
• Heteroclitic peptides:
A. have higher affinity for HLA
B. are prone to break tolerance
and
C. generate a response to the
native peptide sequence (of
the cognate target antigen)
expressed by cancer cells
Koehne G. et al.; EBMT 2017
Pinilla-Ibarz J, et al. Leukemia. 2006;20:2025-33;
May RJ, et al. Clin Cancer Res. 2007;13:4547-55;
Krug LM, et al. CA Immunol Immunother. 2010;59:1467-79.
TCR: T-cell receptor
10. 10
Phase 1/2 Study (MSK #12-288)
A Pilot Trial of Vaccination with a WT1 Analog Peptide Mixture in
Patients with Multiple Myeloma (MM) following Autologous Stem
Cell Transplantation
Principal Investigator: Guenther Koehne, MD, PhD
Koehne G. et al.; EBMT 2017
11. 11
Study Objectives
Primary:
• Assessment of T-cell responses 12-14 weeks after the initial administration of
galinpepimut-S (GPS) in MM following autologous stem cell transplantation
(N.B.: GPS is first administered within 22 days from the auto-transplant)
Secondary:
• Definition of toxicity profile
• Study of WT1 expression on malignant plasma cells by IHC
• Estimation of the proportion of patients with minimal residual disease (MRD) as
measured by flow cytometry of marrow specimen (per IWM criteria)
• Estimation of Progression-(Disease-) Free and Overall Survival (PFS and OS)
Koehne G. et al.; EBMT 2017
12. 12
Key Eligibility Criteria
• Age ≥ 18y
• KPS ≥ to 50%
• Symptomatic multiple myeloma, ISS stage 1-3
• Patients must be eligible to undergo autologous stem cell
transplantation
• Patients must have documented WT1 positive disease
• Absolute neutrophil count (ANC) > 1K/μl & platelets > 50K/μl
• Adequate renal and liver function
• Absence of intercurrent infections, serious medical conditions,
secondary malignancies
Koehne G. et al.; EBMT 2017
13. 13
Patient and Disease Characteristics
Variable n
Age — yr
Mean (range) 61.3 (46-72)
Female/ Male— no. of patients (%) 11/ 8 (58/ 42)
Type of myeloma — no. (%)
IgG 12 (63)
IgA 4 (21)
Light-chain 3 (16)
Number of prior Therapies, median (range) 2 ( 1-13)
Type of induction therapy — no. of patients (%) (not mutually exclusive)
RVD 10 (53)
CyBorD 7 (37)
Lenalidomide and dexamethasone (Rd) 4 (21)
VDT-PACE 3 (16)
Other regimens 6 (32)
Post-SCT therapy (%)
Lenalidomide alone or in combination 18 (95)
Other 1 (5)
None 0
N/A* 0
Prior ASCT — no. (%)
1 17 (89)
2 2 (11)
Sellas & MSKCC; Data on file; Analysis dated: JAN17 – Preliminary report
N.B.: Full repeat QA/QC for all values pending subsequent DB Lock and re-analysis
Koehne G. et al.; EBMT 2017
14. 14
Risk Stratification based on Cytogenetics at
Diagnosis
Koehne G. et al.; EBMT 2017
Abnormalities - No. of patients
(Not mutually exclusive)
Pre-SCT
N (%)
Post-SCT (Day 91;
post-completion of 6
GPS administrations)
Post-ASCT
(EOS, 1 yr or relapse;
whichever occurred earlier)
-13/del(13q)
11 (58) 4 (16) 6 (10)
t(4;14) translocation
3 (16) 1 (16) 2 (10)
17/del(17p) (TP53 loss)
5 (26) 3 (16) 3 (10)
1q21/1q25 gain 8/1 (42/5) 4/0 (16) 3/0 (10)
*: -13/del(13q), -17/del(17p), t(4;14), t(14;16), t(14;20), hypodiploidy (<45 chromosomes, excluding -Y), Chr 1 aberration [+1, -1, t(1;x)]
(as per: Sonneveld P, et al. Blood. 2016;127:2955-62).
GPS: Galinpepimut-S; EOS: End of Study; ASCT: Autologous Stem Cell Transplantation
15 out of 19 total enrolled (or 18 evaluable) pts had high-risk* cytogenetics
Sellas & MSKCC; Data on file; Analysis dated: JAN17 – Preliminary report
N.B.: Full repeat QA/QC for all values pending subsequent DB Lock and re-analysis
15. 15
Therapeutic Response◊ to Galinpepimut-S
Administration (after successful ASCT) Over
Time (N = variable over time*)
Koehne G. et al.; EBMT 2017
◊: Response criteria as per: Kumar S, et al. Lancet Oncol. 2016;17:e328-46.
GPS: Galinpepimut-S; SD: Standard Deviation; ASCT: Autologous Stem Cell Transplantation
MM Therapeutic
Response◊
(vs. baseline)
Post-Induction;
Pre-ASCT
Total N = 19*
Post ASCT and
Post-completion of 6 GPS
Administrations
(N=18)
6 mo Post-ASCT or EOS
(N=18)
1 Year Post ASCT
N* = 12
18 mo Post ASCT
N* = 8
Categories N (%) N (%) N (%) N (%) N (%)
CR 1 (5.3) 3 (16.7) 5 (27.7) 5 (41.7) 1 (12.5)
VGPR 5 (26.3) 6 (33.3) 3 (16.7) 0 0
PR 10 (52.6) 4 (22.2) 4 (22.2) 1 (8.3) 2 (25.0)
SD 3 (15.8) 2 (11.1) 1 (5.5) 2 (16.7) 1 (12.5)
PD 0 1 (5.5) 2 (11.1) 2 (16.7) 2 (25.0)
N/A 0 2 (11.1)^ 2 (16.7)^ 2 (16.7) 2 (25.0)
*: One patient had not received GPS by the time of this analysis; hence maximum N evaluable for this analysis is 18 pts
16. 16
Time to Event Variables (N=19)
Time from Diagnosis to ASCT (mo*)
Missing 1
Average ± SD 18.5 ± 27.9
Median 7.4
Min 3.6
Max 103.8
Time from ASCT to 1st GPS^
administration (days)
Missing 1
Average ± SD 17.8 ± 4.6
Median 17.5
Min 12
Max 29
*: Months are derived as Days/30.5
^: Galinpepimut-S
SD: Standard Deviation; ASCT: Autologous Stem Cell Transplantation
Koehne G. et al.; EBMT 2017
17. 17
Efficacy Endpoints: Overall and
Progression-Free Survival
Koehne G. et al.; EBMT 2017
Median follow-up among survivors: 18 mo
(range: 5 -31 months)
EventProbability
Time (months) from ASCT
• Current median PFS: 23.6 mo (15.2-NR)
• Median OS has not been reached (NR) to-date
Landmark Values:
OS (95% CI):
@18 mo: 88%
(73%-99%)
PFS (95% CI)
@18 mo: 62%
(42%-92%)
18. 18
Progression-Free Survival
Koehne G. et al.; EBMT 2017
PATIENTS WITH HIGH-RISK CYTOGENETICS1, 2 (with MRD+ disease; after frontline Rx, ASCT & maintenance Rx)
Comparison vs. comparable historical controls (Best Standard Therapy; BST) from the MRC MM-IX study 3,*
ü Median PFS: GPS: 23.6 mo
(currently) vs. BST: ~9.3 mo
(2.5-fold ↑)
ü PFS @ 12 mo: GPS: 81% vs.
BST: ~35% (landmark)
(2.3-fold ↑)
ü PFS @ 18 mo: GPS: 62% vs.
BST: ~24% (landmark)
(2.6-fold ↑)
• (1): Any of the abnormalities below alone or in combination: -13/del(13q), -17/del(17p), t(4;14), t(14;16), t(14;20), hypodiploidy (<45 chr’s, excluding -Y), Chr 1 aberration [+1, -1, t(1;x)]
• (as per: Sonneveld P, et al. Blood. 2016;127:2955-62).
• (2): 3 out of 18 patients had aberrations not classified as high-risk (adverse)
• (3): Non-matched controls from cohort of comparable patients (all of whom had high-risk/ adverse cytogenetics) treated in the MRC myeloma IX trial*; median follow-up: 71 mo.
Maintenance treatment after auto-HSCT was provided to 100% of pts with thalidomide. In this graph, the population shown consist only of those who did not achieve minimal residual
disease (MRD) by cytoflow after auto-HSCT (i.e., pts who were MRD+)
Median follow-up:
71 mo
*Rawstron A, et al. J Clin Oncol. 2013;31:2540-7
EventProbability
Time (months) from ASCT
19. 19Koehne G. et al.; EBMT 2017
^: Patients withdrew consent; ◊: Response criteria as per: Kumar S, et al. Lancet Oncol. 2016;17:e328-46.
GPS: Galinpepimut-S; SD: Standard Deviation; ASCT: Autologous Stem Cell Transplantation
*: One patient had not received GPS by the time of this analysis; hence maximum N evaluable for this analysis is 18 pts
Therapeutic Response◊ to Galinpepimut-S
Administration (after successful ASCT) Over
Time (N = variable over time*)
ResponseCategory(%)
20. 20
WT1-specific T-cell responses pre- and
post-WT1 active immunization with GPS
Koehne G. et al.; EBMT 2017
A. Pre-transplant (05/14) B. Post 1st 6 GPS doses (10/14) C. Post 2nd
set of GPS doses (#7-12) (04/15)
21. 21
WT1-Specific Immune Response Patterns
(Representative Results)
0
200
400
600
800
1000
1200
1400
Pre Auto-SCT After 6 Doses
of GPS
Cells/mL blood
CD8+ Responses
CD8 T-cell pool reacting against any epitope of WT1
WT1 A-reacting CD8 T-cells
WT1A1-reactive CD8 T-cells
After 12 Doses
of GPS
CD4 T-cell pool reacting against any epitope of WT1
WT1 A-reacting CD4 T-cells
WT1A1-reactive CD4 T-cells
CD4+ Responses
Cells/mL blood
Pre Auto-SCT After 6 Doses
of GPS
After 12 Doses
of GPS
200
Patient #19
Patient #19
Koehne G. et al.; EBMT 2017
22. 22
WT1-Specific Immune Response Patterns
(Representative Results)
Koehne G. et al.; EBMT 2017
0
10
20
30
40
50
60
70
80
90
100
WT1 A – reacting CD8 T-cells
WT1A1 – reacting CD8 T-cells
122A1 peptide-reacting CD8 T-cells
122A peptide-reacting CD8 T-cells
CD8+ Responses
Patient #16
CD8 T-cell pool reacting against any epitope of WT1
Pre Auto-SCT After 6 Doses
of GPS
After 12 Doses
of GPS
Cells/mL blood
CD4+ Responses
Patient #16
WT1 A – reacting CD4 T-cells
WT1A1 – reacting CD4 T-cells
122A1 peptide-reacting CD4 T-cells
122A peptide-reacting CD4 T-cells
CD8 T-cell pool reacting against any epitope of WT1
Cells/mL blood
Pre Auto-SCT After 6 Doses
of GPS
After 12 Doses
of GPS
23. 23
Conclusions
• Administration of the novel WT1 heteroclitic peptide mixture immunizer galinpepimut-S
(GPS) in multiple myeloma patients following auto-SCT demonstrates remarkable
safety
• This ‘off-the-shelf’ immunotherapeutic is easy to administer and has been specifically
designed to elicit responses across most common HLA Class I and II alleles
• Multifunctional cross-epitope T-cell reactivity was observed in select patients across
epitopes against which hosts were not specifically immunized
• Impressive WT1-specific CD8+ and CD4+ immune responses were seen, along with a
notable median PFS of 23.6 mo post-treatment in a population at extremely high risk for
progression and poor long-term outcomes (based on high-risk cytogenetics and MRD
positivity post-ASCT)
• Based on these results, a larger phase II trial is being planned to optimally integrate
post-transplant immunotherapeutic strategies to meaningfully delay or reduce risk of
relapse in this extremely challenging clinical setting
Koehne G. et al.; EBMT 2017
