Koehne, G., et al. Galinpepimut-S in multiple myeloma data – clinical updates. ASCO 2017 Poster

1. Figure 5. Representative Immune Responses From 2 Patients
CD8+ Responses
CD4+ Responses
CD8+ Responses
Patient #19 Patient #16
CD4+ Responses
1400
1200
1000
800
600
400
200
0
Cells/mLBlood
After 6 GPS
Doses
After 12 GPS
Doses
Pre-ASCT
400
200
0
Cells/mLBlood
After 6 GPS
Doses
After 12 GPS
Doses
Pre-ASCT
CD8 T-cell pool reacting
against any WT1 epitope
WT1 A-reacting CD8 T cells
WT1A1-reacting CD8 T cells
CD4 T-cell pool reacting
against any WT1 epitope
WT1 A-reacting CD4 T cells
WT1A1-reacting CD4 T cells
100
90
80
70
60
50
40
30
20
10
0
Cells/mLBlood
After 12 GPS
Doses
After 6 GPS
Doses
Pre-ASCT
2000
1500
500
1000
0
Cells/mLBlood
CD8 T-cell pool reacting against any WT1 epitope
WT1 A-reacting CD8 T cells
122A1 peptide-reacting CD8 T cells
122A peptide-reacting CD8 T cells
After 12 GPS
Doses
Pre-ASCT
CD4 T-cell pool reacting against any WT1 epitope
WT1 A-reacting CD4 T cells
122A1 peptide-reacting CD4 T cells
122A peptide-reacting CD4 T cells
After 6 GPS
Doses
ASCT, autologous stem cell transplantation; CD, cluster of differentiation; GPS, galinpepimut-S; WT1, Wilms’ tumor 1.
Safety
■■ Other than disease-related laboratory abnormalities, all patients tolerated GPS administration
without any grade >2 systemic side effects observed; patients developed local nodularity at
the site of injections, which resolved over 2–6 weeks
■■ Two patients died during the study; both had extramedullary disease prior to ASCT and
developed rapid progression afterward, which was uncontrollable by additional combination
therapy
CONCLUSIONS
■■ Administration of the novel WT1 heteroclitic peptide immunizer GPS in MM patients
post-ASCT demonstrates encouraging median PFS (currently 23.6 months), therapeutic
responses, and a favorable safety profile in this high-risk MM population with historically
poor long-term outcomes (eg, 9.3-month PFS for patients with adverse cytogenetics
and MRD after best standard induction therapy and ASCT, in Medical Research Council
Myeloma IX study12
)
■■ 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
■■ WT1-specific CD8+ and CD4+ immune responses were seen in 16 of 18 patients, and
multifunctional cross-epitope T-cell reactivity was observed in select patients
■■ A larger phase 2 trial is being planned to optimally integrate posttransplant
immunotherapeutic strategies to meaningfully delay or reduce risk of relapse in this
challenging clinical setting
REFERENCES
1. Call KM, et al. Cell. 1990;60:509-520.
2. Nakahara Y, et al. Brain Tumor Pathol. 2004;21:113-116.
3. Cheever MA, et al. Clin Cancer Res. 2009;15:5323-5337.
4. Koehne G, et al. Blood. 2015;126: abstract 98.
5. Tyler EM, et al. Blood. 2013;121:308-317.
6. Pinilla-Ibarz J, et al. Leukemia. 2006;20:2025-2033.
7. Maslak PG, et al. Blood. 2010;116:171-179.
8. Maslak PG, et al. J Clin Oncol. 2016;34(suppl): abstract 7005.
9. Zauderer MG, et al. J Clin Oncol. 2016;34(suppl): abstract 8519.
10. Kumar S, et al. Lancet Oncol. 2016;17:e328-e346.
11. Sonneveld P, et al. Blood. 2016;127:2955-2962.
12. Rawstron AC, et al. J Clin Oncol. 2013;31:2540-2547.
DISCLOSURES
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. All other authors have nothing to disclose.
ACKNOWLEDGMENTS
Medical writing assistance was provided by Sandra Mendes, PhD, CMPP, from TRM Oncology, The Hague, The Netherlands, and funded by Sellas Life
Sciences Group.
WT1 heteroclitic epitope immunization following autologous stem cell transplantation in patients with high-risk
multiple myeloma (MM)
Guenther Koehne, MD, PhD1,2
, Sean Devlin, PhD3
, David J. Chung, MD, PhD1,2
, Heather J. Landau, MD1,2
, Neha Korde, MD2
, Sham Mailankody, MBBS2
, Hani Hassoun, MD2
, Alexander M. Lesokhin, MD2
, Nikoletta Lendvai, MD, PhD2
, Sergio Giralt, MD1,2
,
and Carl O. Landgren, MD, PhD2
1
Adult Bone Marrow Transplantation Service, Memorial Sloan-Kettering Cancer Center, New York, NY; 2
Myeloma/Lymphoma Service, Memorial Sloan-Kettering Cancer Center, New York, NY; 3
Department of Epidemiology, Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY
8016
INTRODUCTION
■■ The Wilms’ tumor 1 (WT1) protein is a zinc finger transcription factor that has been implicated
in cell proliferation, differentiation, apoptosis, and organ development1
–– It was initially described as a tumor suppressor gene but later identified as a true oncogene2
■■ WT1 is a tumor-associated antigen well established as a target for anticancer immunotherapy3
■■ Our group has previously demonstrated overexpression of WT1 in MM cells and the formation
of a WT1 peptide fragment (RMFPNAPYL) complex on the engagement interface between
malignant plasma cells and T cells in MM patients4
■■ We have also described the development of WT1-specific immune responses in MM patients
following donor lymphocyte infusion postallogeneic T-cell–depleted stem cell transplantation
(SCT), which were associated with a graft-vs-myeloma effect5
■■ Galinpepimut-S (GPS) is a first-in-class WT1 heteroclitic peptide mixture of 2 native and 2
synthetic WT1 peptide sequences (Table 1). The synthetic heteroclitic peptides, which bear
point mutations, were created to stimulate both cluster of differentiation 4-positive (CD4+) and
CD8+ T-cell responses (Figure 1)
–– Synthetic heteroclitic peptides have higher affinity for human leukocyte antigen (HLA), are
prone to break tolerance to “self” cancer antigens, like WT1, and generate a response to
the native peptide sequence expressed by cancer cells6
–– Immune response and clinical efficacy data with GPS in acute myeloid leukemia and
mesothelioma support increased antigenicity and breach in tolerance7-9
Table 1. Peptide Sequences of GPS Elicit Both CD4+ and CD8+ T-Cell Activation
Peptide Sequences (position)
Peptide
Length
Computationally
Predicted Binding to HLA
Immune
Response
WT1-A1:
*YMFPNAPYL (126–134)
9 aa
A0201, A0301, A2402,
B1501, B3901
CD8+ CTLs
427 long:
RSDELVRHHNMHQRNMTKL
(427–445)
19 aa
A0201, A0301, A2402,
B1501, B3901, B0702,
B08, B2705, B4001,
B5801, and numerous
HLA-DRB1-XX
CD4+ T cells
331 long:
PGCNKRYFKLSHLQMHSRKHTG
(331–352)
22 aa CD4+ T cells
122A1 long:
*SGQAYMFPNAPYLPSCLES
(122–140)
19 aa
CD4+ and
CD8+ T cells
aa, amino acids; CD, cluster of differentiation; CTLs, cytotoxic T lymphocytes; GPS, galinpepimut-S; HLA, human leukocyte antigen; WT1, Wilms’
tumor protein 1.
*Mutated peptide.
Figure 1. Heteroclitic Technology-Based Cancer Immunogens/Vaccines
Heteroclitic peptide (WT1 fragment)
Naive CD8+ cell
Cytotoxic
T-lymphocyte
(CTL)
Native peptide
(WT1 fragment)
Cancer cell
Antigen-presenting cell (APC)
TCR in T cells:
Recognizes and kills cancer cells expressing WT1
Activation
CD, cluster of differentiation; TCR, T-cell receptor; WT1, Wilms’ tumor protein 1.
*Mutated peptide.
■■ Herein, we report the results of a phase 1/2 study in which MM patients with high-risk disease
were immunized with GPS, following autologous SCT (ASCT)
OBJECTIVES
■■ The primary objective of the study was to assess T-cell responses 12‒14 weeks after the initial
administration of GPS and 1‒4 weeks following a second cycle of monthly × 6 doses of GPS in
MM patients, post-ASCT
■■ Secondary objectives were to determine the toxicity profile of GPS in MM patients, to study
WT1 expression on malignant plasma cells, to estimate the proportion of patients with minimal
residual disease (MRD), and to estimate progression-free survival (PFS) and overall survival
(OS)
METHODS
Study Design and Treatment
■■ Phase 1/2 open-label trial (NCT01827137) of GPS treatment in patients with MM after ASCT
with melphalan conditioning (200 mg/m2
)
■■ GPS dosing schedule is shown in Figure 2. GPS was administered subcutaneously with
Montanide adjuvant, with first dose within 22 days of ASCT and biweekly administration
thereafter, for a total of 6 initial doses. Subsequently, patients continued to receive booster
GPS administrations every 4 weeks, for an additional set of 6 doses
–– TheGPSmixtureconsistedof4peptidesatadoseof200µgeach:WT1-A1(Y*MFPNAPYL),
427 long (RSDELVRHHNMHQRNMTKL), 331 long (PGCNKRYFKLSHLQMHSRKHTG),
and 122A1 long (SGQAY*MFPNAPYLPSCLES)
●● Two of the 4 peptides were mutated at a single residue (*) (R to Y)
–– Granulocyte macrophage colony-stimulating factor (70 µg) was administered on day –2
and day 0 of each GPS administration
■■ Lenalidomide maintenance (10 mg daily) started 3 months post-ASCT in all patients, except
1 who was maintained with bortezomib instead
Figure 2. GPS Dosing Schedule
ASCT
Pre-ASCT Pre-GPS
0 2 4 6 8 10
GPS
Week
Assessments Assessments
2–4 weeks after last
GPS administration
Lenalidomide maintenance (10 mg daily) was started 3 months post-ASCT
Assessments
2–4 weeks after last
GPS administration
Baseline
assessments
GPS
• GPS biweekly sc administration (dose of 200 μg
for each of the 4 peptides)
• First GPS administration within 22 days of ASCT
• 6 doses over 10 weeks
• GPS monthly sc administration (dose of
200 μg for each of the 4 peptides)
• 6 doses
ASCT, autologous stem cell transplantation; GPS, galinpepimut-S; sc, subcutaneous.
Key Eligibility Criteria
■■ Age ≥18 years, eligible to undergo ASCT, and documented WT1+ disease
■■ Karnofsky Performance Status ≥50%
■■ Symptomatic MM, International Staging System stage 1‒3
■■ Absolute neutrophil count 1K/μL; platelets 50K/μL
■■ Adequate renal and liver function
■■ Absence of intercurrent infections, serious medical conditions, and secondary malignancies
Study Assessments
■■ MRD and therapeutic response were measured by flow cytometry of marrow specimens, using
International Myeloma Working Group criteria10
■■ PFS and OS were evaluated using Kaplan-Meier estimates
■■ Protein expression for WT antigens was assessed by immunohistochemistry
■■ WT1-specific immune responses were assessed by intracellular interferon-Ɣ analyses upon
stimulation with peripheral blood mononuclear cells pulsed with a “total pool” of overlapping
15mers along the entire WT1 protein, or each of the 4 WT1 peptides in GPS, or the nonmutated
(native) WT1 peptides corresponding to the 2 heteroclitic sequences within GPS (WT1-A and
122A-L)
■■ Adverse events (AEs) were graded in accordance with Common Terminology Criteria for
Adverse Events version 4.0. The only toxicities captured outside of the serious AEs reported
were all grade AEs deemed definitely, probably, or possibly related to GPS administration
RESULTS
■■ Nineteen patients were enrolled in this study. Demographics and baseline characteristics are
shown in Table 2
–– Median age was 61.3 years (46–72), most patients (53%) received an induction regimen of
RVD (lenalidomide, bortezomib, dexamethasone), and lenalidomide maintenance therapy
was administered in 95% of all patients
–– Fifteen of 19 (79%) patients had high-risk cytogenetics at diagnosis (–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)])
Table 2. Patient Demographics and Baseline Characteristics (N = 19)
Median age (range), years 61.3 (46‒72)
Female, n (%) 11 (58)
Type of myeloma, n (%)
IgG
IgA
Light chain
12 (63)
4 (21)
3 (16)
Prior therapies, median (range) 2 (1‒3)
Type of induction therapy*, n (%)
RVD
CyBorD
Rd
VDT-PACE
Other regimens
10 (53)
7 (37)
4 (21)
3 (16)
6 (32)
Post-ASCT therapy, n (%)
Lenalidomide alone or in combination
Other
18 (95)
1 (5)
Prior ASCT, n (%)
1
2
17 (89)
2 (11)
High-risk cytogenetics at diagnosis**, n (%) 15 (79)
ASCT, autologous stem cell transplantation; CyBorD, cyclophosphamide, bortezomib, dexamethasone; Rd, lenalidomide and dexamethasone; Ig,
immunoglobulin; RVD, lenalidomide, bortezomib, dexamethasone; VDT-PACE, bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin,
cyclophosphamide, and etoposide.
Analysis dated: JAN17 – Preliminary report.
*Not mutually exclusive. **Stratification as per Sonneveld P, et al.11
Therapeutic Response
■■ Therapeutic responses to GPS over time are depicted in Figure 3. By the time of this analysis,
1 patient had not yet received GPS treatment
Figure 3. Therapeutic Response* to GPS Over Time
100
80
60
40
20
ResponseCategory,%
0
Postinduction;
Pre-ASCT
Post-ASCT;
Post-GPS 6×
6 Months
Post-ASCT
12 Months
Post-ASCT
18 Months
Post-ASCT
N = 19** N = 16†
N = 15‡
N = 10§
N = 6¶
68.4
31.6
37.5
6.2
56.3
33.3
13.3
53.3
30
20
50
50
33.3
16.7
CR + VGPR PR + SD PD
ASCT, autologous stem cell transplantation; CR, complete response; GPS, galinpepimut-S; MRD, minimal residual disease; PD, progressive
disease; PR, partial response; SD, stable disease; VGPR, very good partial response.
*Response criteria as per Kumar S, et al.10
**Eighteen of 19 patients had MRD or worse postinduction and pre-ASCT.
†
Response data not available (n = 2); had not received GPS by the time of analysis (n = 1).
‡
Progressed at previous assessment (n = 1).
§
Progressed at previous assessment (n = 2); withdrew consent (n = 3).
¶
Progressed at previous assessment (n = 2); withdrew consent (n = 2).
Survival
■■ Median OS in this population has not been reached to date; median PFS is currently 23.6
months (Figure 4)
■■ At 18 months, OS and PFS rates were 88% (95% confidence interval [CI]: 73‒99) and 62%
(95% CI: 42‒92), respectively
■■ Median follow-up for survivors was 18 months (5‒31)
Figure 4. Survival Outcomes
OS, N = 18
PFS, N = 18
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0
0 3
Median OS has not been reached to date
Current median PFS: 23.6 months (15.2–NR)
6 9 12 15 18 21 24
Time From ASCT (months)
EventProbability
ASCT, autologous stem cell transplantation; NR, not reached; OS, overall survival; PFS, progression-free survival.
Immune Response
■■ CD8+ and CD4+ immune responses could be detected at various levels in all but 2 patients
following GPS administration
■■ These immune responses were induced not only against the heteroclitic peptides (within GPS),
but also were detected against the corresponding native WT1 peptide sequences that are
expressed on malignant plasma cells, as well as the “total pool” of WT1-derived overlapping
peptides
■■ Representative immune responses from 2 patients are shown in Figure 5
Please contact the corresponding
author for any questions:
koehneg@mskcc.org
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Presented at the American Society of Clinical Oncology Annual Meeting, June 2–6, 2017, Chicago, IL