DISCLOSURES

Roche/MSD-Merck/Celgene: Research Funding

Roche/Celgene/AstraZeneca/Amgen/MSD/Novartis/Sanofi-

Aventis/Pierre Fabré: Advisory Board or Consultant

No conflict of interest with respect to this topic

I am clinical oncologist (not immunologist unfortunately…)

OUTLINE

i. Definitions and framework

ii. Types of neoantigens

iii. Types of cancer vaccines

iv. Strategies with “vaccine effects”

v. Clinical results and trials ongoing

vi. Final remarks

Definitions

• Vaccine: a preparation of microbial antigen, often combined

with adjuvants, that is administered to individuals to induce

protective immunity against microbial infections

• Antitumoral vaccines: array of approaches that seek to

generate and/or amplify antitumor immunity through tumor

antigens, often with APC, or direct modulation of the tumor.

Considered active immunotherapy

Infiltration of T cells

into tumours

5

Generation of cancer immunity is a cyclic process self-propagating

Dendritic cells process

tumour-derived antigens2

T cells are primed and

activated by dendritic

cells presenting

tumour-derived antigens

3

Trafficking of T cells

to tumours4

Killing of tumour

cells by T cells 7The

cancer–

immunity

cycle

Recognition of tumour

cells by T cells6

1Tumour cell death releases

tumour-derived antigens

Adapted from Chen DS, Mellman I. Immunity 2013;39:1–10.

Vaccine targets

Melero I. Nat Rev 2014

Cancer vaccination needs immunization with tumor

antigens: non-mutated (TAA, cancer-testis, oncofetal

antigens) or mutated-tumor specific antigens (TSA)

Butterfield LH. BMJ 2015;350:h988

Types of cancer vaccines

1) Peptide based,

MHC I restricted

epitopes on TAAs

2) DNA, RNA based

3) Autologous APCs in TAA

based vaccines

4) Tumor cells, engineered

with cytokines or

adjuvants

5) Viral based vaccines

Butterfield LH. BMJ 2015;350:h988

Types of cancer vaccines

Butterfield LH. BMJ 2015;350:h988

1) Peptide based,

MHC I restricted

epitopes on TAAs

2) DNA, RNA based

3) Autologous APCs in TAA

based vaccines

4) Tumor cells, engineered

with cytokines or

adjuvants

5) Viral based vaccines

Butterfield LH. BMJ 2015;350:h988

Vaccines in clinic, a disappointing story….

Rosenberg, Nat Med 2004

Manufacturing Process Overview:

Sipuleucel-T (APC8015)

3-4 Days

PA2024 ANTIGEN ADDED

Collects patient’s blood cells

Further enrichment of mononuclear cells

APC activation/antigen processing

Final formulation

SIPULEUCEL-T (FDA APPROVAL 2010)

Autologous APC+ TAA (PAP)+ GM-CSF

Manufacturing Process Overview:

Sipuleucel-T (APC8015)

3-4 Days

PA2024 ANTIGEN ADDED

Collects patient’s blood cells

Further enrichment of mononuclear cells

APC activation/antigen processing

Final formulation

SIPULEUCEL-T (FDA APPROVAL 2010)

Autologous APC+ TAA (PAP)+ GM-CSF

B cell T cellMonocyte NK cellBasophilRed Blood Cells EosinophilNeutrophilPlatelets

Granulocytes

In vitro culture

Buoyant Density Centrifugation Steps (BDS77 and BDS65)

Apheresis (APH)

Final product formulation (FP)

SIPULEUCEL-T

B cell T cellMonocyte NK cell

In vitro culture

Buoyant Density Centrifugation Steps (BDS77 and BDS65)

Apheresis (APH)

Final product formulation (FP)

PA2024

SIPULEUCEL-T

SIPULEUCEL-T

Clinical trials with vaccines

Melero I. Nat Rev 2014

Types of cancer vaccines

Butterfield LH. BMJ 2015;350:h988

1) Peptide based,

MHC I restricted

epitopes on TAAs

2) DNA, RNA based

3) Autologous APCs in TAA

based vaccines

4) Tumor cells, engineered

with cytokines or

adjuvants

5) Viral based vaccines

Sharma Science 2015

VACCINE EFFECT: EVERY TUMOR HAS ITS ACHILLES HEEL…

Galluzzi L, Gomes-de Silva LC, Dewittee H, et al.

Combinatorial strategies for the induction of immunogenic cell death. Front Immunol. Mar 2015

Damage Associated

Mollecular Patterns

DAMPs

Galluzzi Cancer Immunol Res AACR 2016

1. Frederick D et al. CCR 2013. 2. Ebert P et al. Immunity 2016.

Dual MAPK pathway inhibition PD-L1 inhibition

MAPK Inhibitor-Induced Changes1,2

• Increased melanoma antigen expression

• Decreased immunosuppressive cytokine production

• Increased CD8+ T-cell infiltration

• Increased T-cell clonalitya

• Increased PD-L1 expression

• Class I MHC upregulation

CD8+ T cell per Tumor Cell

ND MEKi

Targeted therapies: MAPKi in melanoma BRAF mut

• A Phase III study evaluating atezo + cobi + vem vs placebo + cobi + vem in patients with BRAF V600 mutant advanced melanoma is planned

• Key study objectives− Primary: investigator-assessed PFS− Secondary: PFS (IRF-assessed), OS, ORR, DOR, Safety, PK

Phase III Study of Atezo + Cobi + Vem in BRAF V600 Mutant Melanoma (NCT02908672)

aVemurafenib dose will decrease to 720 mg BID + placebo 240 mg BID beginning day 22 of vem + cobi doublet treatment phase.bCobimetinib administered on 21 days on/7 days off schedule.IRF, independent review facility; PK, pharmacokinetics.

R 28 days Treatment until PD or toxicity

Previously Untreated Advanced Melanoma

• BRAF V600 mutation• ECOG PS 0-1• Measurable disease• No significant history of

liver disease

N = 500

Vem 960mg BIDa

Cobi 60mg QDb

Atezo 840mg q2wVem 720mg BID + Vem Placebo 240mg BID

Cobi 60mg QDb

Vem 960mg BIDa

Cobi 60mg QDb

Placebo q2wVem 960mg BIDCobi 60mg QDb

Immunovirotherapy:

T-VEC – an HSV-1-derived oncolytic immunotherapy

designed to produce local and systemic effects

1. Hawkins LK, et al. Lancet Oncol 2002;3:17–26; 2. Fukuhara H, Todo T. Curr Cancer Drug Targets 2007;7:149–55; 3. Amgen. Imlygic® Summary of Product Characteristics. Section 5.1; 4. Pol JG, et al. Virus Adapt Treat 2012;4:1–21; 5. Melcher A, et al. Mol Ther 2011;19:1008–16; 6. Dranoff G. Oncogene 2003;22:3188–92; 7. Liu BL, et al. Gene Ther 2003;10:292–303; 8. Andtbacka RHI, et al. J Clin Oncol 2015;33:2780–8.

Proposed mechanism of action for T-VEC.TDA, tumour-derived antigen.

Oncology

Tumour cells rupture for an

oncolytic effect1–4

GM-CSF

Tumour cell lysis TDAs

2

T-VEC replication in tumour

tissue1–3

Local effect:

virus-induced tumour-cell lysis

T-VECTumour

cells

Healthy cells

1

Systemic

antitumour immune

response3,5,6

Systemic effect:

antitumour immune response

TDAs

CD8+ cytotoxic

T cell

CD4+ helper T cell

Dendritic cell activated by

GM-CSF

3

Death of distant

cancer cells5–8

Distant dying

tumour cell

4

Dual Mechanism of Action:

Talimogene Laherparepvec + Pembrolizumab

CD = cluster of differentiation

GM-CSF = granulocyte-

macrophage

colony-stimulating factor

MHC = major histocompatibility

complex

PD-1 = programmed death

receptor 1

PD-L1 = programmed death

ligand 1

TDA = tumor-derived antigen

Figure adapted from Chen DS, et al. Immunity. 2013;39:1-10.

Luke JJ, et al. Oncotarget. 2015;6:3479-3492.

Ribas A. N Engl J Med. 2012;366:2517-2519.

4. T cell proliferationand migration

7. T cell mediated tumor cell death and release of new array of TDAs

2. Dendritic cell maturation

Mature dendritic cellTDA

Immature dendritic cell

Blood vessel

3. T cell activation

6. T cell tumor recognition

PD-L1/PD-L2

PD1

Pembrolizumab binding

T cell

Tumorcell

Local Effect

T cell

Dendritic cell

Systemic Effect

Talimogene laherparepvec

1. Tumor cell lysis

Immature dendritic cell

Tumor cells

GM-CSF

TDA

Tumor bed

5. T cell tumor infiltration

+

+

T cell receptor

PD1

PD-L1/PD-L2

MHC

TDA

B7

T cell

CD28

Pembrolizumab binding

Schumacher Science 2015

Melero Nature Rev Cancer 2015

Vaccines future, combinations…

Butterfield LH. BMJ 2015;350:h988

Closing remarks and future perspectives

� Goal of tumor vaccines is always the same, activation of

tumor specific T cells

� Neoantigens non-mutated (immunogenic but low avidity) or

mutated (immunogenic, high avidity but extremely difficult to

identify)

� Several types of vaccines

* Classical: peptides, DNA-RNA, APCs, tumor cells, virus

* “Vaccine effect” concept: CT, RT, targeted Tx, viroTx…

� Immunomonitoring crutial for tailor therapy

� In the era of immune checkpoints mAbs, vaccination

strategies should be investigated inside combos

Thank you so much!