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Bases biológicas de la moderna inmunoterapia en el tratamiento del cáncer
Luis de la Cruz Merino. Sº Oncología Médica Hospital Universitario Virgen Macarena, Sevilla ([email protected])
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OUTLINE
i. Definitions, background and framework
ii. Clinical results and trials ongoing (just with immune-checkpoint inhibitors)
iii. New toxicities
iv. Strategies with “vaccine effects”
v. Biomarkers
vi. Final remarks
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Infiltration of T cells into tumours
5
Generation of cancer immunity is a cyclic process self-propagating
Dendritic cells process tumour-derived antigens
2
T cells are primed and activated by dendritic cells presenting tumour-derived antigens
3
Trafficking of T cells to tumours
4
Killing of tumour cells by T cells 7
The cancer–
immunity cycle
Recognition of tumour cells by T cells
6
1 Tumour cell death releases tumour-derived antigens
Adapted from Chen DS, Mellman I. Immunity 2013;39:1–10.
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Targets for immunotherapy
Melero I. Nat Rev 2014
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Neoantigens: non-mutated (TAA, cancer-testis, oncofetal antigens) or mutated-tumor specific antigens (TSA)
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Neoantigens: non-mutated (TAA, cancer-testis, oncofetal antigens) or mutated-tumor specific antigens (TSA)
Butterfield LH. BMJ 2015;350:h988
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Juergens RA. Biomark Cancer. 2016;8(Suppl 2):1-13
Distribution of cancer immunotherapy clinical
trials by Cancer Site, total trials: 484
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Melero CCR 2013 12
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SUPERVIVENCIA GLOBAL TRAS 5 AÑOS DE SEGUIMIENTO
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Target Antibody Molecule Development stage
PD-1
BMS-936558 Fully human IgG4 Phase III multiple tumors
(melanoma, RCC, NSCLCa, HNSCC)
MK-3475 Humanized IgG4 Phase I-II multiple tumors
Phase III NSCLC/melanoma
CT-011 Humanized IgG1 Phase II multiple tumors
PD-L1
MEDI-4736 Engineered human IgG1 Phase I-II multiple tumors
MPDL-3280A Engineered human IgG1 Phase I-II multiple tumors
Phase III NSCLC
MSB0010718C Fully human IgG1 Phase I solid tumors
Clinical Development of Inhibitors of PD-1
Immune Checkpoint
www.clinicaltrials.gov
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Melanoma: Checkmate 066
Long SMR 2014
Robert NEJM 2014
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Nivolumab Improved Survival vs Dacarbazine in Patients with Untreated Advanced Melanoma: Survival Yearly Update
(Checkmate 066)
Atkinson SMR 2015
???
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Motzer N Engl J Med. 2015 Sep 25
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Reck NEJM Oct 2016
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Summary of irAEs across clinical trials
irAE (%) Pembrolizumab Nivolumab Ipilimumab Nivo+Ipi Pembro+Ipi
Diarrhea 14,4-16,9 11,2-19,2 22,7-33,1 44,1 12
Colitis 1,8-3,6 1,0-1,3 8,2-11,6 11,8 6
Hepatitis 1,1-1,8 3,4-6,4 1,2-7,1 30,0 30
Hypothyroidism 8,7-10,1 4,4-8,6 2,0-4,2 15,0 17
Hyperthyroidism 3,2-6,5 1,9-4,2 1,0-2,3 9,9 8
Hypophysitis <1 <1 2,3-3,9 7,7 11
Pneumonitis <1 1,9-1,3 0,4-1,6 6,4 7
Rash 13,4-14,7 9,3-21,7 14,5-20,9 28,4 53
Pruritus 14,1-14,4 16,0-18,8 24,4-35,4 33,2 28
20 Lavinia Spain, et al. Future Medicine 2015 Georgina Long SMR 2015
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ANTI-CTLA4 AND ANTI-PD1 PITFALLS IN CLINICAL DEVELOPMENT
• Weaknesses of clinical trials: - Brain mets (up to 40% advanced melanoma pts): underrepresented - Autoimmunity diseases up to 8% population: excluded - What should we do with this patients?
• Absence of predictive biomarkers (by now…)
• Optimal duration of anti-CTLA4 and anti-PD1 treatment in responders unknown
• How much time will we need to use anti-PD1 therapy in daily
practice? Which will be the cost??
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New concepts: vaccine-like effects
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
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Sharma Science 2015
VACCINE EFFECT: EVERY TUMOR HAS ITS ACHILLES HEEL…
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VACCINE EFFECT: EVERY TUMOR HAS ITS ACHILLES HEEL…
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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
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Galluzzi Cancer Immunol Res AACR 2016
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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
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• 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 q2w
Vem 720mg BID + Vem Placebo 240mg BID
Cobi 60mg QDb
Vem 960mg BIDa
Cobi 60mg QDb
Placebo q2w
Vem 960mg BID
Cobi 60mg QDb
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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.
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-VEC Tumour
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
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Dual Mechanism of Action: T-VEC + 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 proliferation and migration
7. T cell mediated tumor cell death and release of new array of TDAs
2. Dendritic cell maturation
Mature dendritic cell TDA
Immature dendritic cell
Blood vessel
3. T cell activation
6. T cell tumor recognition
PD-L1/PD-L2
PD1
Pembrolizumab binding
T cell
Tumor cell
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
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Schumacher Science 2015
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Melero Nature Rev Cancer 2015
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Sharma Science 2015
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Greenplate EJC 2016
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Dijkstra JAMA 2016
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Dijkstra JAMA 2016
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SITC Congress 2016
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SITC Congress 2016
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First site to be opened: June 02, 2017
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Greenplate EJC 2016
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Yuan J J Immunother Cancer 2016
Biomarkers, biomarkers, biomarkers…
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Closing remarks and future perspectives
i. New immunotherapy has come to stay
ii. New immunotherapy is no longer an empiric approach
iii. Benefit OS demonstrated in many tumors: melanoma, NSCLC, kidney, head and neck, bladder…
iv. New paradigms: assessment of response, toxicity
v. Most of the patients/tumors DO NOT benefit of modern IT
vi. Combinations seem to increase efficacy in some tumors
vii. Biomarkers are lacking by now and extremely necessary to identify populations sensitive to immunotherapy
viii. We have a long way to go…