2-. dr. luis de la cruz merino -...
TRANSCRIPT
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.
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
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
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
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
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
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