801 prime™ il-15 (rptr-147): preliminary clinical results ......prime™ il-15 (rptr-147):...

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 jfitzgerald@repertoire.com

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

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mailto:jfitzgerald@repertoire.com?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