801 prime™ il-15 (rptr-147): preliminary clinical results ......prime™ il-15 (rptr-147):...
TRANSCRIPT
-
PRIME™ IL-15 (RPTR-147): Preliminary clinical results and biomarker analysis from a first-in-human Phase 1 study of IL-15 loaded peripherally-derived autologous T cell therapy in solid tumor patients
Erika P. Hamilton1, Sarah Nikiforow2, Philip D. Bardwell3*, Christine M. McInnis3, Jeffrey Zhang3, George Blumenschein, Jr.4, Mihaela Cristea5, Keren Osman6 , Anthony Shields7, Marlyane Motta3, Sanela Bilic3, Oliver Schoenborn-Kellenberger3, James A. Rakestraw3, Shawn P. Carey3, Elena Geretti3, Karsten Sauer3, Tim Harris3, Tap Maniar3, Becker Hewes3, Thomas Andresen3, Jonathan B. Fitzgerald3†, Harriet Kluger8 1Sarah Cannon Research Institute, 2Dana-Farber Cancer Institute, 3Repertoire Immune Medicines, 4MD Anderson Cancer Center, 5City of Hope, 6Mount Sinai Medical Center, 7Karmanos Cancer Institute, 8Yale Cancer Center *presenting author †corresponding author [email protected]
BACKGROUND & METHODS
801
Patient Population and Safety Profile
Tumor Type Number of Patients
Melanoma 6Non-Small Cell Lung Carcinoma 4Renal Cell Carcinoma 2Head & Neck 2Appendiceal Carcinoma 1Ovarian Carcinoma 1Synovial Carcinoma 1
Table 1: Tumor types of the 17 patientswith advanced metastatic diseaserefractory to SOC who took part in thePRIME IL-15 study.
Safety Summary
• No Dose Limiting Toxicities • 10 SAEs o Majority of SAEs were due to diseaseo A single patient had three grade 2 infusion reactions
• Events all were resolved • Patient had history of similar reactions to previous
biologic therapies• No cytokine release syndrome, neurotoxicity or other
concerning immune-related toxicity o At highest cell dose, 2 patients had transient elevated
IFNγ and IL-18 levels• 5 related non-serious AEs all grade 1-2, resolved (other
than Grade 2 fatigue)• Dose escalation meeting for 360M/m2 dose: Investigators &
Sponsor agreed to escalate to the next dose level
Figure 4
Figure 2
Figure 3
Figure 1
Flow Cytometry: Non-significant Increase of NK & CD8+ T Cells in Circulation at 360M cells/m2
A non-significant increase in the average cell number of NK & CD8+ T cells but not CD4+ T cells was observed at the highest cell dose. This is consistent with the expected mechanism of action and pharmacokinetics of IL-15.
1 2 4 8 16 32 641E-6
1E-5
1E-4
1E-3
Days
Freq
uenc
y of
Vβ
Clo
nes
001-0001001-0002001-0003009-0001012-0001003-0001006-0002
0 30 60 900
5
10
15
Days
Num
ber o
f Vβ
Clo
nes
Screening
C2D15
C3D15
Pre-t
x biop
sy
1st p
ost-tx
biop
sy
2nd p
ost-tx
biop
sy
001-0001
Product Specific Clones Show Persistence in Blood and Tumor
Product-specific clones
Peripheral Blood Biopsies
TCR Vβ chains were sequenced (Adaptive Biotech) from peripheral blood PBMC samples (n=7 patients) and matched FFPE tumor biopsies (n=1 patient). Product-specific clones were identified by focusing on clones that were not detected in the apheresis orpre-treatment blood samples (red boxes). The clones were tracked over time to estimate cellular PK. Experiments to identify theantigen-specificity of the T cell clones are ongoing.
• PRIME IL-15 T cell therapy (RPTR-147) has a favorable safety profileo No DLTs observed up to and including 360M cells/m2 doseo Nanogel formulation attached to cells results in low systemic exposure to IL-15Fco Dose-Escalation is proceeding
• Preliminary evidence of clinical activityo 10 of 17 late-stage tumor patients experienced stable diseaseo In 4 patients, stable disease lasted longer than 6 months
• Pharmacodynamic changes in immune system and tumor microenvironment were consistent with MOAo Increase in tumor infiltrating CD8 and CD4 T cells observed post infusion o Evidence of persisting product-specific T cell clones in blood and tumor (analysis of antigen
specificity ongoing)• Ongoing biomarker analysis will inform future clinical strategies to optimize PRIME IL-15 immunotherapy
o Determine product reactivity towards individual antigens and assess for epitope spreadingo Proprietary antigen decoding technologies will be applied to track epitope-specific CD8 and
CD4 clonotypes in products, periphery and tumorso Deeper understanding of the effects of PRIME IL-15 therapy on the tumor microenvironment
CONCLUSIONSRPTR-147 has been well-tolerated to date with preliminary evidence of biological activity
Trial registered with clinicaltrials.gov NCT03815682 The study was approved by local institutional IRBs after acceptance of the IND by the FDA. Written informed consent was obtained from patients for publication of this poster and any accompanying images.
PRIME IL-15 Antigen Primed Multi-Clonal T Cells Loaded with an IL-15Fc Nanogel
Antigen Cassette 1
PRAME
Survivin
WT-1
NY-ESO-1
SSX2
SurfaceModifier
CleavableCrosslinker
IL-15FcIL-15Fc NanogelPRIME IL-15
(PRIME T cells with IL-15 payload)
Study Design: A phase 1/2, first-in-human, multi-center study to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of RPTR-147 administered i.v. as a monotherapy in patients with relapsed/refractory metastatic or locally-advanced solid tumors
PRIME IL-15 Results in Low Systemic Exposure of IL-15Fc
• The 360M/m² dose of PRIME IL-15 contained 3X more IL-15Fc than the MTD of ALT-8031, but produced less than a tenth of the systemic exposure to free IL-15Fc
o PRIME IL-15 is designed to function in an autologous manner, so low exposure is expected
o In cohorts treated with 20, 40 and 120 M cells/m2 IL-15Fc was not detected
o IL-15Fc PK curve of PRIME IL-15 is >10X less than ALT-803 at 10µg/kg (CMAX ~150ng/mL i.v.)1
o There was no ADA observed1. Romee R, Cooley S, Berrien-Elliott MM, et al. First-in-human phase
clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation. Blood. 2018;131(23):2515-2527.
• Dose level is in million of cells per m2• Arrow indicates continued on study• Analysis cut off 12 October 2020
• 10 of 17 patients with Stable Disease• 4 patients with SD lasting > 6 months
• 2 melanoma, 1 RCC, 1 NSCLC
Swimmer Plot : Best Overall Response Majority of Evaluable Matched Biopsies Demonstrate an Increase in CD8 & CD4 T cell Tumor Infiltrates
Pre-T
x biop
sy
1st P
ost-T
x biop
sy
2nd P
ost-T
x biop
sy0
500
1000
1500
2000
CD8
Cell
dens
ity(#
cel
ls/m
m2 )
2500
Pre-T
x biop
sy
1st P
ost-T
x biop
sy
2nd P
ost-T
x biop
sy0
1000
2000
3000
4000
CD4
Cell
dens
ity(#
cel
ls/m
m2 )
Each line is a separate patient
increased
No increase
increased
No increase
Increase in infiltrating CD8 T cells in 5/7 pre-/post-treatment matched biopsies
Increase in infiltrating CD4 T cells in 4/6 pre-/post-treatment matched biopsies CD8 density
550 cells/mm2CD4 density*
362 cells/mm2
*Only lymphocytes are countedmacrophages are manually excluded
Expression of Targeted TAAs in Tumor Biopsies was confirmed by RNASeq and IHC
Protein Expression by PRAME IHC in Melanoma Patients
Screening C1/2D15 C3D15
0
100
200
300
H-S
core
001-0001-Pt1001-0003-Pt3006-0002-Pt10006-0003-Pt11006-0005-Pt14
• Tumor associated antigen(TAA) expression by RNASeq of patient biopsies compares well with TCGA database across multiple tumor types (RCC, NSCLC, & HNSCC- data not shown)
• Example of RNASeq expression of the 5 TAAs and PRAME expression by IHC are shown below.• As expected, PRAME expression is high in the majority of melanoma patients (4/5)
Figure legend: FFPE tissue curls from patient biopsies were used for whole transcriptome RNASeq and the data was normalized to public databases (TCGA & GTEx) by using the Recount2 algorithm (doi.org/10.1038/nbt.3838). The peach open bars represent the mean TPM values for TAA antigen expression within specific tumor types. The green bars represent an average normal expression across a variety of healthy tissues. IHC=immunohistochemistryH-score = [1 × (% cells 1+) + 2 × (% cells 2+) + 3 × (% cells 3+)]; range 0-300
Metastatic Melanoma Patients
PRAME NY-ESO-1 SSX2 Survivin WT10
5
10
15
Tran
scip
ts p
er m
illio
n (T
PM)
P01-01-BaselineP01-03-BaselineP012-01-BaselineP06-02-C2D15P06-03-C1D15P06-05-BaselineOcular Melanoma
MelanomaTCGANormal tissueMean of medians
PRAME IHCH-score = 60
Isotype control
Product Description: The cell product was derived from rare peripheral anti-tumor T cell clones that were primed against a multi-antigen cassette containing tumor associated antigens (TAA). Autologous anti-TAA T cells were generated with a proprietary dendritic cell priming process and then loaded with an IL-15Fc nanogel to generate PRIME IL-15 product.
Apheresis
Immune Agonist Delivery PlatformDENDRITIC Priming TechnologyIsolate cells
Monocytes
T cells
D D
Antigen cassettes
Dendritic cell
T cell priming by dendritic cells
TAntigen-trainedT cells
T
Cytokines/Immune modulators
PRIME T Cells Armed with Immuno-modulators
Frozen Drug Product for
Repeat Dosing
T
T
M
Dose Escalation
IL-15Fc Dosing Level
2 mcg/kg
4 mcg/kg
11 mcg/kg
33 mcg/kg
93 mcg/kg
MTD of ALT-803 (soluble IL-15Fc)1
Current Safe Dose of PRIME IL-15
Cell Dose Level(cells/m2)
20 Millionn=1
40 Millionn= 3-6
120 Millionn= 3-6
360 Millionn=3-6
1 Billion n=6
0 5 10 15 20 25100
1000
10000
100000
1000000
Time (hr)
IL-1
5Fc
Conc
. (p
g/m
L) 10 µg/kg ALT-803 (reported)
360M/m2 PRIME IL-15: (n=5)
LLOQ
160M PRIME IL-15: 006-0003
Tumors Types Specified
Melanoma
NSCLC
Bladder
Head & Neck
RCC
DLBCL
Sarcoma
Ovarian
RESULTS
0 5 10 15 20 25 300.0
0.5
1.0
1.5
2.0
2.5
NK cells
0 5 10 15 20 25 300.0
0.5
1.0
1.5
2.0
2.5
CD4+ cells
Fold
-cha
nge
0 5 10 15 20 25 300.0
0.5
1.0
1.5
2.0
2.5
CD8+ cells
Days after first dose
360 (n=5)
120 (n=6)20 (n=1)
40 (n=3)Other (110,160)
Figure 5
Figure 6
Pre-
trea
tmen
t (C1
D1 b
lood
)Ap
here
sis (~
Day-
28)
TCR-Vβ freq. vs. TCR-Vβ freq. plots
T-cell Drug Substance
Freq. Range = 10-6 to 10-1
Figure 8
Figure 7
www.repertoire.com
mailto:[email protected]?subject=SITC%202020%20Poster%20Inquiryhttps://doi.org/10.1038/nbt.3838https://www.repertoire.com/
PRIME™ IL-15 (RPTR-147): Preliminary clinical results and biomarker analysis from a first-in-human Phase 1 study �of IL-15 loaded peripherally-derived autologous T cell therapy in solid tumor patients