Download Single-Agent LV305 Induces Anti

Single-Agent LV305 Induces Anti-tumor Immune And Clinical Responses In Patients With Advanced Or
Metastatic Sarcoma And Other Cancers Expressing NY-ESO-1
Abstract #3093
[email protected]
Neeta Somaiah1, Matthew S. Block2, Joseph W. Kim3, Geoffrey Shapiro4, Khanh T. Do4, Patrick Hwu1, Joseph P. Eder,3 Robin L. Jones5, Sacha Gnjatic6, Hailing Lu7, Jan ter Meulen7, Frank J. Hsu7, Seth M. Pollack8
Anderson Cancer Center, Houston, TX; 2Mayo Clinic, Rochester, MN; 3Yale School of Medicine, New Haven, CT; 4Dana-Farber Cancer Institute, Boston, MA; 5Seattle Cancer Care Alliance, Seattle, WA; 6Icahn School of Medicine at Mount Sinai, New York, NY; 7Immune Design, Seattle, WA; 8Fred Hutchinson Cancer Research Center, Seattle, WA.
All
24
39
47.6 (25 - 76)
56.1 (25 – 76)
13F/11M (54/46%)
24/15 (62/38%)
Synovial Sarcoma
13 (54%)
13 (33%)
Myxoid Liposarcoma
6 (25%)
6 (15%)
Other Sarcoma*
5 (21%)
5 (13%)
6 (15%)
NSLCL
1 (3%)
III
0
2 (5%)
IV
20 (83%)
29 (74%)
Missing
4 (17%)
8 (21%)
NY-ESO-1 Expression
Other tumor type
18 (75%)
Ovarian: 0 (0%) ; Mel: 3 (50%);
Lung: 1 (100%)
≥ 1% and < 50%
6 (25%)
Ovarian: 4 (50%); Mel: 0 (0%)
<1%
0 (0%)
Ovarian: 4 (50%); Mel: 3 (50%)
*Included: leiomyosarcoma (2), spindle cell sarcoma (1), rhabdomyosarcoma (1), Ewing's sarcoma (1)
Sarcoma Patients: Pretreatment Characteristics
LV305 STS (n=24)
III. LV305 TRIAL DESIGN AND RESULTS
Day: 0 7 14 21 28 35 42 49 63 182 20 If no DLT within 28d,
continue LV305
*NY-ESO-1 expression determined by central lab using IHC
**No minimum tumor size; Maximum tumor size: 8cm for single mass
and 10cm total for all lesions (3cm and 9cm for melanoma)
***Cohort 1 pts received 3 doses
CD8
≥ 3 lines
8
4
3.4 yrs (0.5 to 13.4)
0.6 yrs (±0.8)
Median 0.42 (0.08 to 4)
SD (5 with minimal disease3)
13
PD
11
Excludes 5 with NED and 6 with non-target lesions only
Excludes 1 with NED and 1 with non-target lesions only
3 All patients had locally advanced, relapsed, and/or metastaGc cancer at high risk for recurrence.
5 patients entered the study with minimal disease/NED following their last treatment 1
CD4
2
IVS
CD4
Sarcoma Patients:
Treatment Emergent AEs Occurring in >2 Patients
Grade 1
Grade 2
Grade 3
and higher
Total
(N=24)
Patients with Events
13 (54.2%)
8 (33.3%)
0
21 (87.5%)
Fatigue
Injection site reaction
Myalgia
Arthralgia
Bilirubin conjugated
incr.
Nasal congestion
Nausea
Paraesthesia
5 (20.8%)
12 (50.0%)
4 (16.7%)
2 (8.3%)
7 (29.2%)
0
2 (8.3%)
0
0
0
0
0
12 (50.0%)
12 (50.0%)
6 (25.0%)
2 (8.3%)
2 (8.3%)
0
0
2 (8.3%)
2 (8.3%)
2 (8.3%)
2 (8.3%)
0
0
0
0
0
0
2 (8.3%)
2 (8.3%)
2 (8.3%)
•  Table includes all AEs considered at least possibly related to LV305. There were no DLTs or treatment related SAEs reported.
•  An Independent DSMB determined that the highest dose level 1010 vg was the maximum safe dose examined in the study.
•  Similar safety profile was found in other cancer indications. Overall there was 1 grade 3 AE which consisted of transient
asymptomatic hyponatremia
CD8
CD8
7 Day IVS
CD4
11 Day IVS
21 42 63 84
*All pts had a planned treatment of 4 LV305 doses and restaging on Day 84,
with the exception of cohort 1 who received 3 doses and restaging on Day 63
12.5*
20.5
41.7
8.8
PD
PD
PD
PD
PD
PD
PD
PD
573
438
217
141
139
85
74
64
-10.7
10.3
39.3
-17.1
4.9
-34.3
1.2
-5
**
• 
• 
• 
• 
Days Post First LV305 Dose
N=24 patients with sarcoma: synovial (13), MRCL (6), other (5)
20/24 completed all planned therapy.
Best Response: 1 PR (4%); 13 SD (54%); 10 PD (42%, includes 1 symptomatic deterioration).
7/11 pts with pretreatment PD had SD or PR following LV305. Of SD/PR pts with responses lasting >6+
mths, the majority had anti-NY-ESO-1 responses: 6 CD4; 7 CD8; 8 CD4 and/or CD8 with 1 pt not evaluable.
LV305 Sarcoma: PFS & OS
Kaplan-­‐Meier Plot of Progression Free Survival All Sarcomas
N= 24 (progressed= 18)
95% CL: 2.6, 14.4
Median PFS= 4.6 months
CD8
Last dose
(Cohort 1)
PFS And OS Subgroup Analysis: No Impact From
Pretreatment Growing Tumor or Target/Non-Target Disease
N=
PFS
(months)
1 yr
survival
# Survived /
# Evaluable
at 1 year
All Sarcomas
24
4.6
81%
17/21
Sarcomas with growing tumor prior to
start of LV305
11
4.6
80%
8/10
Sarcomas with Disease (RECIST Target
or Non-Target tumor) prior to LV305
19
4.7
82%
14/17
Sarcomas NED prior to LV305
5
19
80%
4/5
Patient Population
•  The impact of pre-treatment disease status was assessed by examining subgroups: pre-treatment
measureable tumor growth, RECIST identified tumor, or minimal disease state (5 pts).
•  Subgroup analyses demonstrated similar results regardless if the study population was limited to those with
tumor progression prior to LV305 or the presence of Target/non-Target disease at the time of study initiation.
IV. SUMMARY
•  LV305 is the first product candidate from the ZVex platform. It induces DCs to generate
potent T cell responses against NY-ESO-1 following a skin injection.
CD4
0
0
5
5
10
10
Months
Months
15
15
20
20
•  The trial has demonstrated significant evidence of immunologic activity which was broad,
tumor-specific, and durable, with measureable responses ongoing at ~2 years.
•  The highest dose level was well-tolerated with no grade 3 or 4 AE in sarcoma patients,
which supports its selection for a pivotal trial.
CD8
•  Patient had disease stabilization following LV305 and then a slow tumor regression over time
resulting in a PR beginning around 1.5 years after treatment (Figure below shows % tumor size
change over time). The slow regression is consistent with immune based responses, the patient's
long-lasting immune response, and a tumor which is fibrotic and may not shrink until remodeling
occurs.
-30
710
577
537
264
NED
CD4/CD8
•  Preliminary evidence of clinical benefit has been demonstrated with 1 PR and 13 SD, of
which 6 patients remain progression-free (median 474 days, range: 264 to 710 days).
•  Median PFS for sarcomas is 4.6 months and compares favorably with that of recently
approved chemotherapy agents.
•  The median OS has not been reached. The 1 year survival is 81%.
•  Delayed response (PR) was observed consistent with immune-based mechanisms, which
represents a potential change in standard treatment paradigms.
•  LV305 appears to be a clinically active agent with an overall favorable risk/benefit profile.
RECIST PR
0.2
0.2
After EOS visit (d182) pts enter
LT follow-up for up to 2 years
CD4
Median OS not yet reached
1 year survival= 81%
All Sarcomas
N= 24 (deaths= 4)
0.0
0.0
*** Anti-NY-ESO-1
Ab
•  LV305 can induce broad and durable immunity associated with clinical response.
•  Tetramer Staining: Increased p157-specific CD8 T cells (0.06  0.12%) in unstimulated blood
•  Anti-NY-ESO-1 reactive T cells in response to stimulation with peptides [10 fold increase of
specific CD8 T cells by ELISPOT post-LV305 (CD4 T cells positive at baseline by ELISPOT);
activated CD4 T cells by ICS; intra-epitope NY-ESO-1 spreading post LV305 by ELISPOT].
•  TCR sequencing of pre- and post-PBMC demonstrated increased clonality of T cells post LV305
treatment and increased T cell frequency in PBMC of TIL and NY-ESO-1 reactive/expanded cells.
•  Specific anti-NY-ESO-1 CD4 and CD8 T cells were detected ~2 years post-LV305 treatment by
intracellular cytokine staining for IFNg.
ICS after IVS culture
Ex-vivo ICS
Tumor Status at Study Entry
Treatment/Study Measurements:
−  Part 1, Dose Escalation: 4 cohorts, 3 dose levels
Cohorts 1 (108 vg x 3 doses), 1A (108 vg x 4), 2 (109 vg x 4), and 3 (1010 vg x 4)
−  Part 2, Patient expansion: the dose determined in Part 1 to be safe was used to
treat additional cancer patients
−  LV305 administered q21d intradermally; 28d DLT observation period
−  Blood samples collected for safety and immunologic testing at multiple time points
including leukapheresis pre- and post- LV305.
−  Disease status measured by irRC criteria modified to use RECIST.
−  Follow-up: 2 yrs monitoring safety, disease status and LV305 persistence in blood
0 0.2
0.2
3
Time Since Last Treatment
{Expression data derived from CT Database (http://www.cta.lncc.br/index.php) or from Jungbluth, Int J Ca 2001; Nicholaou, Imm Cell Bio 2006;
Hudolin, J Trans Med 2013; Gjerstorff, BMC Can 2013; Demirovic, Path Res Prac 2010}
• 
10 0.0
0.0
2 lines
Time Since Diagnosis (median)
•  Vpx prevents degradation within DCs
Indication: Locally advanced, recurrent or metastatic melanoma, sarcoma, ovarian, or
lung cancers (breast cancer allowed in Part 1 dose escalation) expressing NY-ESO-1* s/p
at least one prior cancer therapy (2 for lung) with low tumor burden**
20 Patient 1-1: LV305 Stimulated A Broad Anti-NY-ESO-1
Response With Long-lasting Memory And Late PR
9
Surgery/Radiation alone
Specificity:
• 
30 1.0
1.0
DC
Rationale: In this first-in-human study, we examined the safety, immunologic activity, and
preliminary efficacy of LV305 in patients whose cancers expressed NY-ESO-1
40 % of IFNγ+ CD4 T cells
1 line
Safety:
• 
50 •  Anti-NY-ESO-1 Abs detected by ELISA against either the whole NY-ESO-1 protein or to peptides.
A 4-fold rise or newly positive response was scored as positive
•  Anti-NY-ESO-1 CD4 and CD8 responses were determined to be positive by the following assays:
− IFNg production detected by ELISPOT in separated T cell fractions
− Intracellular cytokine staining for IFNg or TNFa after stimulation with NY-ESO-1 peptides
− ELISPOT >50 spots & >2-fold rise and/or ICS >2-fold over baseline were considered positive
20
PR
SD
SD
SD
•  Increased clonality is thought to represent a refinement of T cell
populations to those with TCR having a greater affinity and
reactivity
•  Data indicate a trend where prolonged PR/SD are correlated
with an increase in clonality
60 % of IFNγ+ CD8 T cells
Genome:
generation lentiviral vector backbone
•  Modified to be replication incompetent and
integration deficient
70 % of IFNγ+ CD4 T cells
Chemotherapy and kinase inhibitors
% of
Change in
Clonality
80 Prior Systemic Therapies
DC-SIGN
•  3rd
90 % of IFNγ+ CD8 T cells
•  Sindbis virus envelope targets the
Dendritic Cell receptor, CD209 (DC-SIGN)
45.3 mm1 (±18.1)
Time on
Study
(Days)
*Data represents all tests performed to date and include 12 patients. **The dark green bar represents data
from Study Day 84 following completion of LV305. Additional analyses (Pt 1-1) after ~2 years shows
further increase in clonality to 27% (extended light green bar)
1.0
1.0
ZVex
Expired
In active f/u at time of
this analysis
NED
0.8
0.8
Tumor Burden at Entry
Alive and in f/u post PD
100 % of IFNγ+ CD4 T cells
Envelope:
DC Targeting:
Progressive Disease
NED
NY-ESO-1 Expression
Sarcomas
≥ 50%
Stable Disease
Anti-NY-ESO-1
Antibodies
LV305 Induced Specific Anti-NY-ESO-1 T Cell
Immune Responses in Sarcoma Patients
% of IFNγ+ CD8 T cells
•  LV305 is a novel hybrid viral vector from the ZVexTM platform that expresses NY-ESO-1 RNA and is
designed to target DCs in vivo and stimulate CD8 T cells against this cancer testis antigen.
•  NY-ESO-1 is a tumor-associated antigen whose function is unknown. It is expressed only in cancer
and in normal testis in adults.
•  Expression (by IHC) observed in many different malignancies with high expression of 70-100%
reported in the sarcoma subtypes: synovial sarcoma and myxoid / round cell liposarcoma and
moderate expression in melanoma (24-45%), ovarian (14-43%), and NSCLC (11-25%).
•  Excellent immunologic target: preclinical and clinical data demonstrate CTLs directed against NYESO-1 can specifically target and kill antigen bearing cancer cells with no off-target effects.
FACS (Tetramer assay; intracellular
cytokine staining, ICS, post stim. )
% Evaluable pts with Response
II. RATIONALE / BACKGROUND
Cell Phenotyping for
T cell profiles
NED
T cell receptor deep sequencing
Stage
NY-ESO-1
% Expression
Mt Sinai Assay: CD4, CD8 bead
separation  2-3 wk stim  IFNγ
ELISPOT
Current
Status*
NED
0.8
0.8
Melanoma
Short-term
stimulation ELISPOT
assay
Humoral Response
0.6
0.6
8 (21%)
Specific T cell Assay
24 mths
0.4
0.4
Ovarian
General Cell Assay
12 mths
Proportion
Progression
Free Free
Proportion
Progression
Gender
Exploratory Biomarker: % Change in
TCR Clonality
1st Tumor
Restaging*
Proportion Surviving
Surviving
Proportion
0.4
0.6
0.4
0.6
Age Median (range)
LV305*
Doses
Pre- and post- LV305 peripheral blood,
leukapheresis, plasma, tumor samples examined
Sarcomas
N=
Clinical Outcome: Sarcomas
↑ Background: Immune approaches that stimulate specific anti-tumor cytotoxic T cells (CTLs) can have single
agent activity, be synergistic with check point inhibitors (CPIs) and enhance adoptively transferred T cells. LV305
is a replication-incompetent, integration-deficient, hybrid viral vector based on the ZVex platform. It is designed to
target dendritic cells in vivo and induce the expression of NY-ESO-1 in order to potently generate and expand anticancer CTLs. In this first-in-human study, the safety, immunogenicity and efficacy of LV305 were examined in
patients (pts) with sarcoma or carcinoma. Methods: Pts with previously treated, advanced or metastatic
malignancies expressing NY-ESO-1 (IHC) were eligible. In Part 1, Dose Escalation, 3 pts enrolled into each of 4
cohorts to receive 3 or 4 intradermal injections every 3 weeks of 108, 109 or 1010 vector genomes (vg) per dose.
Cohort advancement followed a 3+3 design and safety was reviewed with a DSMB. In Part 2, additional pts were
treated at the max dose/MTD. Results: In Part 1, no DLT or SAEs were observed in the 12 sarcoma
patients; all related AEs were grade 1/2. In Part 2 (1010 vg dose), only 1 grade 3 AE was reported in 27 pts (12
sarcoma, 5 melanoma, 9 ovarian and 1 NSCLC). Of evaluable sarcoma pts, NY-ESO-1 specific CD4 12/23 (52%),
CD8 12/23 (52%) and CD4 and/or CD8 16/23 (70%) were induced by LV305. Clinical responses included:
sarcoma, 1 PR (recent SD to PR change {Study Day 579}, 606+ days), 13 SD (defined as > 84 days, range 136 –
585+ days); melanoma 4 SD; ovarian, 2 SD; and NSCLC 1 SD. In sarcoma pts, median PFS was 140 days and
7/11 pts with pretreatment PD had SD or PR following LV305. Conclusions: LV305 demonstrated acceptable
safety up to 1010 vg and induced significant anti-NY-ESO-1 T cell responses in advanced malignancies. Clinical
benefit (PR/SD) was seen in 14/24 pts with sarcoma, have been durable > 1 year in 5 pts and includes a late
conversion of SD to PR. The median PFS for sarcomas was similar to that of trabectedin as reported in a recent
US Ph3 study. The induction of immune responses, favorable safety profile and clinical activity indicate LV305 is
an active agent that warrants further investigation.
(ClinicalTrials.gov # NCT02122861)
ZVex
Immune Response Measurements
All Patients: Pretreatment Characteristics
I. ABSTRACT
Percent Change By RECIST From Baseline (%)
1MD
Days Post First Dose of LV305
0
0
5
5
10
10
Months
Months
15
15
20
20
•  It is now under development in the prime-boost agent, CMB305, which is under
evaluation as a single agent (NCT02387125) and in a randomized Ph2 combination study
with atezolizumab in sarcoma (NCT02609984).