Bases biológicas de la moderna inmunoterapia en el tratamiento del cáncer

Luis de la Cruz Merino. Sº Oncología Médica Hospital Universitario Virgen Macarena, Sevilla (lcruz-ibis@us.es)

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

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.

Targets for immunotherapy

Melero I. Nat Rev 2014

Neoantigens: non-mutated (TAA, cancer-testis, oncofetal antigens) or mutated-tumor specific antigens (TSA)

Neoantigens: non-mutated (TAA, cancer-testis, oncofetal antigens) or mutated-tumor specific antigens (TSA)

Butterfield LH. BMJ 2015;350:h988

Juergens RA. Biomark Cancer. 2016;8(Suppl 2):1-13

Distribution of cancer immunotherapy clinical

trials by Cancer Site, total trials: 484

Melero CCR 2013 12

SUPERVIVENCIA GLOBAL TRAS 5 AÑOS DE SEGUIMIENTO

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

Melanoma: Checkmate 066

Long SMR 2014

Robert NEJM 2014

Nivolumab Improved Survival vs Dacarbazine in Patients with Untreated Advanced Melanoma: Survival Yearly Update

(Checkmate 066)

Atkinson SMR 2015

???

Motzer N Engl J Med. 2015 Sep 25

Reck NEJM Oct 2016

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

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??

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

Sharma Science 2015

VACCINE EFFECT: EVERY TUMOR HAS ITS ACHILLES HEEL…

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 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

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

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

Schumacher Science 2015

Melero Nature Rev Cancer 2015

Sharma Science 2015

Greenplate EJC 2016

Dijkstra JAMA 2016

Dijkstra JAMA 2016

SITC Congress 2016

SITC Congress 2016

First site to be opened: June 02, 2017

Greenplate EJC 2016

Yuan J J Immunother Cancer 2016

Biomarkers, biomarkers, biomarkers…

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…