Key learnings from bringing a fully personalized cancer ...€¦ · Key learnings from bringing a...

Key learnings from bringing a fully personalized cancer neoantigen vaccine into the clinic

Immuno-Oncology SummitBoston, August 9, 2019

Agnete B FredriksenPresident & CSOVaccibody AS

[email protected]

Vaccibody Product Pipeline

PROGRAM DISCOVERY PRE-CLINICAL PHASE I PHASE II PHASE III

MELANOMA

LUNG (NSCLC)

BLADDER

RENAL

HEAD AND NECK

VB10.16

VB10.NEO

VB10.NEO + NKTR-214HEAD AND NECK

PRECANCEROUS

CERVICAL LESIONS

VB10.16 + Atezolizumab (CPI)*CERVICAL

Non-confidential 2

Vaccibody – Proprietary Vaccine Technology Platform

Antigen moiety

Target to Antigen

Presenting Cell

Dimerization for

crosslinking target

receptor

Vaccibody

DNA Vaccine Plasmid

VB10.NEO

Vaccibody in

Protein Format

Exchangeable

DNA Cassette

n=x

In vivo expression

The Vaccibody Technology Platform was developed based on the concept of targeting antigen to APC in order to create more efficacious vaccines.

Non-confidential 3

DeltoidMuscle

Mechanism of action: the multiple effect of MIP-1α as targeting unit

Administration (i.m.) of DNA

plasmid

In vivo protein expression

and secretion

Target – Attract – Mature – Deliver –Cross-present

MIP-1α: Skewing the immune system to a CD8+ killer T-Cell response

▪ Direct targeting & attraction of antigen presenting cells, high local vaccine concentration

▪ Enhanced T cell immunity obtained with fewer and lower doses

▪ Faster and longer lasting immune responses

▪ Stronger potential to kill cancer cells

Tumour

The Vaccibody uses the muscle cell as a factory

Targeting is elicited by the MIP-1α chemokine4Non-confidential

VB10.NEO – A Robust Vaccine Format

VB10.NEO-XX

• >90 different VB10.NEO constructs with >450 neoepitopes constructed to date with up to 40

neoepitopes.

• Order or position of neoepitopes generally do not affect their immunogenicity

VB10.NEO-XDVB10.NEO-X

Non-confidential5

Naked DNA plasmid ideal for personalized manufacturing

Proven Safety

Simple, Rapid and

Generalized process

Simple Formulation

VersatileEasy i.m. Delivery

Effective Homologous

BoostCD8 prone

DNA plasmid is an ideal platform for bringing individualized neoantigen vaccines to the market as a viableproduct at reasonable COGS

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Patient Friendly, simple Vaccine Delivery

Small, handy, easy to use

Minimal pain compared to electroporation

Cost effective

Applicable for multiple immunizations

✓

✓

✓

✓

Needle free injection✓

High patient compliance✓

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VB10.NEO generates a broader immune response profile dominated by CD8+ T cells than competing technologies

* Tested IFN-γ CD4 and CD8 T cell response against 10 identical neoepitopes from B16 melanoma

Pep 1 Pep 2 Pep 3 Pep 4 Pep 5 Pep 6 Pep 7 Pep 8 Pep 9 Pep10

• Castle et al., 2012 and Kreiter et al., 2015

• Aurisicchio et al., 2019

Peptide and RNA vaccines induces primarily CD4 T cell responses, while VB10.NEO induces strong, and dominating CD8 responses to the identical neoepitope sequences

Non-targetd DNA vaccines induced a CD8 response towards 2 of 6 tested neoepitopes

B16 melanoma modelPeptide* CD4

CD8

RNA* CD4

CD8

Non-targetedDNA

CD4 nt nt Nt nt

CD8

VB10.NEO CD4

CD8

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Confirmation of VB10.NEO’s unique ability to induce strongneoepitope-specific CD8 responses

MC38 colon carcinoma

VB10.NEO Peptide + poly I:C + anti-CD40 mAb

-VB10.NEO induces a strong CD8 T cell response, combined with a CD4 response to 5 of 6 MC38 neoantigens.

-3 of these neoepitopes have been shown to be non-immunogenic delivered as peptide + adjuvant

-Confirmation of VB10.NEO’s ability to induce stronger CD8 responses to neoantigens

Yadav et al., 2014

Reps

Aatf

Adpgk

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Vaccibody Induces Tumor Protection as Monotherapy

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d ) T u m o r ta k e in re c h a lle n g e d m ic e v a c c in a te d

w ith V B 1 0 .N E O C T 2 6 -X X v 2 a lo n e o r in

c o m b in a tio n w ith a n ti-P D -1

D a y s p o s t tu m o r in je c tio n

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%)

V B 1 0 .N E O C T 2 6 -X X v 2

V B 1 0 .N E O C T 2 6 -X X v 2 + a n t i-P D -1

P B S

p = 0 .0 0 2

➢Vaccibody vaccination induces strong CD8+ T cell responses and tumor protection as Monotherapy

➢Combination with anti-PD-1 immunotherapy induced enhanced anti-tumour responses in mice involving complete tumour regression of large, established tumours

➢ Long-term memory responses ensure effective anti-tumour responses after a 2nd tumour challenge in surviving mice with no sign of tumour growth

Control

Vaccibody

PBS

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Vaccibody Combination Therapy

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Vaccibody Monotherapy

40% tumour free

70% tumour free

N=10 N=10N=10

Re-challenged mice are protectedCT26 coloncarcinomamodel

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Neoepitope-specific CD8 T cells are crucial for tumour protection

Depletion of CD8 T cells prohibit tumour protection in VB10.NEO vaccinated mice, indicatinga crucial role of neoepitope-specific CD8 T cells for anti-tumour efficacy

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P B S

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Individual growth curvesAverage, all groups

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VB10.NEO+ anti-CD8VB10.NEO VB10.NEO + anti-CD4

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Neoepitope-specific T cells traffic to the tumor after VB10.NEO vaccination

• Neoepitope specific T cells induced after VB10.NEO-vaccination traffics to the tumor.

• The distribution is quite different whichprovides insight into clinically relevant neoepitope selection.

T cell response to individual neoepitopes in SPLEEN

T cell response to individual neoepitopes in TUMOR

M01

M06

M08

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M43

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M01

M06

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M31

M43

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M79

M89

M106

M135

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M171

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A -6

VB10.NEO induce «hot» immune signature in tumour-bearing mice

VB10.NEO + CPI VB10.NEO Control

Cold<-----> hotLow exp. <-----> high exp.

VB10.NEO VB10.NEO+CPI

Control

Influx of cytotoxic T cells

Control

VB10.NEO + CPI

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D -9

C -3

VB10.NEO

G2 F1 E4 D1 C3 D9 A3 A6

VB10.NEO creates a hot intratumoural immune signature

Ag presentation Tumor cell killing


ControlVB10.NEO VB10.NEO

+CPIControl

CT26 colon carcinomaNon-confidential

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VB10.NEO proven to induce an effective anti-tumour response

14


Control

Influx of cytotoxic T cells in tumor (TILs)

VB10.NEO induceunique neoepitope-specific CD8+ T cell

responses

T cells traffic to thetumor

Creates «hot» immune signatures in tumor-bearing mice

T cells in tumor areable to kill tumor cells

in vitro

Complete tumourregression is observed

in vivo

TILs recognize and kill tumor cells

Effector:target cell ratio

160:1 80:1

Neoepitope-specificT cell response in

tumor

Neoepitope-specificCD8+ T cell

response in spleen

Tumor protective immune responses elicited in

vaccinated mice

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M01

M06

M08

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M31

M43

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M69

M79

M89

M106

M135

M149

M152

M171

M172

M173

M174

M175

M176

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N-

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Effector:target cell ratio

160:1 80:1

VB10.NEO engages the entire cancer immunity cycle

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Aatf

Adpgk

Irgq

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Control

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NeoRANKTM

In vivo mouse experiments

IFN-γ ELISpot (CD8/CD4)➢ > 350 neoantigens➢ 2 mouse strains➢ 4 tumour models

Anti-tumour efficacy

Development of NeoRANKTM

VB10.NEOPatients

Neoantigen filtering and rankingTrained and verified on in vivo mouse data

+++ criteria rel. for clinical response +++

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LiteratureExternal data sets

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Clinical Trial VB N-01

VB N-01: An open labelled first human dose phase 1/2a study to evaluate safety, feasibility and efficacy of multiple dosing with individualised VB10.NEO immunotherapy in patients with locally advanced or metastatic melanoma, NSCLC, clear renal cell carcinoma, urothelial cancer or squamous cell carcinoma of head and neck, who did not reach complete responses with current standard of care immune checkpoint blockade

VB10.NEO

Melanoma

NSCLC

Clear Renal Cell Carcinoma

Urothelial Cancer

Squamous Cell Carcinomaof the Head and Neck

• Approved CPI as SOC• Moderate to high mutational load

VB N-01

n=40-91

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Melanoma VB10.NEO ≤ 10

NSCLC VB10.NEO ≤ 10

RCC VB10.NEO ≤ 10

Urothelial VB10.NEO ≤ 10

SCCHN VB10.NEO ≤ 10

Interim analysis

Safety and immunogenicity acceptance criteria

Expansion

Stage 1 Stage 2

Part A Part B n≤51~40

First selected tumour entity

Futility analysis

+ 9 + 8

Second selected tumour entity

Third selected tumour entity

+ 9

+ 9

+ 8

+ 8

Study Design and Current Status, VB N-01

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▪ 100% vaccine manufacturing success for all patients with a successful biopsy so far

▪ 20 neoepitopes selected for all patients in the trial

VB10.NEO induce immune responses to the majority of selected neoepitopes

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Patient

Indication

TMB#months onCPI beforeVB10.NEO

Disease at VB10.NEO start

01-002

SCCHN Low 32 Relapsed

01-004

SCCHN Low 15 stable

01-001

RCC low 18 stable0

2 5

5 0

7 5

1 0 0

%

• First patients are all low TMB and with SD as

best response to long-term CPI treatment.

• 1 patient progressed beforeVB10.NEO

treatment.

First 3 patients tested after 6 vaccinations

• High% of immunogenic neoepitopes selected with

NeoSELECT prediction.

• Majority of neoepitopes increased by VB10.NEO

• Boosting pre-existing as well as de novo responses

Immunogenic

increased

de novo

VB10.NEO boost pre-existing and induce strong de novo immune responses

Patient 01-004

• Strongly increased T cell responses to the majority of the selected neoepitopes observed afterVB10.NEO

vaccination.

• Biggest fold increase and highest number of de novo responses observed for patient 01-004 (10 of 12 neoepitopes).

20

Patient 01-002

pep 1

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SP

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* * * ** * ** * ** * * ** * *

de novo responses3 in red

pep 1

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* ** * * ** * ***

Patient 01-004

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VB10.NEO increase neoantigen-specific T cell responses in the first RCC patient analysed after 6 vaccinations (W22)

Patient 01-001

Very strong neoantigen-specific immune responses detected.

VB10.NEO induces an increased T cell response to the majority of the selected neoepitopes.(85%)

even in patients with a significant baseline response.

2121

de novo responses3 in red

pep 1

pep 2

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* * * ** ** * ** * ** * ***

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Main findings and interesting questions

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• Patients with stable disease after long-term CPI treatment seem to have low TMB.

• NeoSELECT has a strong ability to identify immunogenic neoepitopes.•

• VB10.NEO is able to increase the immune response to the majority of the selectedneoepitopes.

• The baseline response and the number of de novo responses were surprisinglydifferent among the patients tested so far.

• Is boosting pre-existing T cell responses and/or induction of de novo responses themost important to improve clinical responses?

• How important is the breadth of the immune response?

• Is a certain level of T cells needed?

Unique Study Design and Treatment Schedule VB N-01

6 weeks

12 months

Sequencing, Synthesis &

Manufacturing

VaccinationPrime

VaccinationMaintenance

Follow Up

24 months

0 3 6

1 2 3

10 14 18 22 26 30 34 38 42 46 50

4 5 6 7 8 9 10 11 12 13 14

Consent +

Biopsy

Week

Dose #

CPI treatment>12 weeks

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• Inclusion criteria: previous treatment with CPI for >12 weeks and stable disease (or partialresponse or mixed response) at enrollment. Limited tumour reduction expected from continous CPI treatment only

Tsimberidou et al., 2018 2323

Key learnings VB N-01 clinical study

• Biopsies

• TCC

• Clonality, VAF, variant callers, heterogeneity versus NeoSELECT parameters

• Low TMB after long-term CPI treatment

• Multiple providers in manufacturing chain

Challenges

• Implication of different indications

• Inclusion criteria >12 weeks on CPI

• Boosting pre-existing T cells versus generation of de novo T cellsLearnings

• 100% success in manufacturing VB10.NEO for all patients with positive biopsy

• 100% successful with top 20 neoepitope choice

• DNA vaccine manufacturing proven to be ideal for PCV

• Strong immunogenicity against majority of neoantigens even in patients with low TMB

Successes

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Bempegaldesleukin (NKTR-214) has the potential to significantly expand T cells

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Combination of VB10.NEO and NKTR-214 greatly synergizes

Total T cell response per spleen

VB 1 0 .N E O

C T 2 6 -X X

VB 1 0 .N E O

C T 2 6 -X X

+ N K T R -2 1 4

0

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21 05

31 05

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M 001

M 002

M 007

M 008

M 010

M 030

M 065

M 069

M 075

M 086

M 088

M 092

M 103

M 104

M 106

M 108

M 112

M 114

M 115

M 125

• Combination of VB10.NEO and bempegaldesleukin (NKTR-214) synergizes to elicit greater breadthand depth of neoantigen-specific T cell responses than each individual treatment

• Adding NKTR-214 (from day 18) to a VB10.NEO and anti-PD-1 treatment induce rapid, complete and durable tumour regression of small tumours and long-lasting stabilization of large tumours.

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Melanoma VB10.NEO ≤ 10

NSCLC VB10.NEO ≤ 10

RCC VB10.NEO ≤ 10

Urothelial VB10.NEO ≤ 10

SCCHN VB10.NEO ≤ 10

SCCHN VB10.NEO + NKTR-214 ≤ 10

Interim analysis

Expansion

Stage 1 Stage 2

Part A Part B n≤51~50

First selected tumour entity

+ 9 + 8

Second selected tumour entity

Third selected tumour entity

+ 9

+ 9

+ 8

+ 8

1

2

3

4

5A

5B

Expansion of the study planned in 2019– add NKTR-214 and expansion cohorts

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• First patient enrolled planned 2019• Prepare for interim analysis first indication to trigger expansion

Vaccibody’s Solution to Personalised Cancer Treatment

Vaccibody provide a Rapid, Cost-effectiveand Efficacious solution

NeoSELECTTM

-Needle-free

-Target, Attract, Mature, Deliver, Cross-present

-Rapid, strong, long-lasting

-CD8 dominated

-DNA: Robust, rapid, cost-effective, stable, safe

-up to 40 neoepitopes

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Insight from clinicalexperience

Vaccibody Dreamteam!

Non-confidential 29

www.vaccibody.com

Key learnings from bringing a fully personalized cancer ...€¦ · Key learnings from bringing a...

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