Bases biológicas de la moderna inmunoterapia en el tratamiento del cáncer

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1 Bases biológicas de la moderna inmunoterapia en el tratamiento del cáncer Luis de la Cruz Merino. Sº Oncología Médica Hospital Universitario Virgen Macarena, Sevilla

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3 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

4 Tumour cell death releases tumour-derived antigens Generation of cancer immunity is a cyclic process self-propagating 1 2 Dendritic cells process tumour-derived antigens Killing of tumour cells by T cells 7 The cancer immunity cycle 3 T cells are primed and activated by dendritic cells presenting tumour-derived antigens Recognition of tumour cells by T cells 6 4 Trafficking of T cells to tumours 5 Infiltration of T cells into tumours Adapted from Chen DS, Mellman I. Immunity 2013;39:1 10.

5 Melero I. Nat Rev 2014 Targets for immunotherapy

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

7 Neoantigens: non-mutated (TAA, cancer-testis, oncofetal antigens) or mutated-tumor specific antigens (TSA) Butterfield LH. BMJ 2015;350:h988

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11 Distribution of cancer immunotherapy clinical trials by Cancer Site, total trials: 484 Juergens RA. Biomark Cancer. 2016;8(Suppl 2):1-13

12 Melero CCR

13 SUPERVIVENCIA GLOBAL TRAS 5 AÑOS DE SEGUIMIENTO

14 Target Antibody Molecule Development stage PD-1 Clinical Development of Inhibitors of PD-1 Immune Checkpoint BMS MK-3475 Fully human IgG4 Humanized IgG4 Phase III multiple tumors (melanoma, RCC, NSCLCa, HNSCC) 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 MSB C Fully human IgG1 Phase I solid tumors

15 Melanoma: Checkmate 066 Long SMR 2014 Robert NEJM 2014

16 Nivolumab Improved Survival vs Dacarbazine in Patients with Untreated Advanced Melanoma: Survival Yearly Update (Checkmate 066)??? Atkinson SMR 2015

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18 Motzer N Engl J Med Sep 25

19 Reck NEJM Oct 2016

20 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, Lavinia Spain, et al. Future Medicine 2015 Georgina Long SMR 2015

21 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??

22 1) Peptide based, MHC I restricted epitopes on TAAs New concepts: vaccine-like effects 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

23 VACCINE EFFECT: EVERY TUMOR HAS ITS ACHILLES HEEL Sharma Science 2015

24 VACCINE EFFECT: EVERY TUMOR HAS ITS ACHILLES HEEL

25 Damage Associated Mollecular Patterns DAMPs Galluzzi L, Gomes-de Silva LC, Dewittee H, et al. Combinatorial strategies for the induction of immunogenic cell death. Front Immunol. Mar 2015

26 Galluzzi Cancer Immunol Res AACR 2016

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31 Targeted therapies: MAPKi in melanoma BRAF mut Dual MAPK pathway inhibition PD-L1 inhibition MAPK Inhibitor-Induced Changes 1,2 Increased melanoma antigen expression Decreased immunosuppressive cytokine production Increased CD8+ T-cell infiltration Increased T-cell clonality a Increased PD-L1 expression Class I MHC upregulation CD8+ T cell per Tumor Cell ND MEKi 1. Frederick D et al. CCR Ebert P et al. Immunity 2016.

32 Phase III Study of Atezo + Cobi + Vem in BRAF V600 Mutant Melanoma (NCT ) A Phase III study evaluating atezo + cobi + vem vs placebo + cobi + vem in patients with BRAF V600 mutant advanced melanoma is planned Previously Untreated Advanced Melanoma BRAF V600 mutation ECOG PS 0-1 Measurable disease No significant history of liver disease N = 500 Vem 960mg BID a Cobi 60mg QD b R 28 days Treatment until PD or toxicity Vem 960mg BID a Cobi 60mg QD b Atezo 840mg q2w Vem 720mg BID + Vem Placebo 240mg BID Cobi 60mg QD b Placebo q2w Vem 960mg BID Cobi 60mg QD b Key study objectives Primary: investigator-assessed PFS Secondary: PFS (IRF-assessed), OS, ORR, DOR, Safety, PK a Vemurafenib dose will decrease to 720 mg BID + placebo 240 mg BID beginning day 22 of vem + cobi doublet treatment phase. b Cobimetinib administered on 21 days on/7 days off schedule. IRF, independent review facility; PK, pharmacokinetics.

33 Immunovirotherapy: T-VEC an HSV-1-derived oncolytic immunotherapy designed to produce local and systemic effects Local effect: virus-induced tumour-cell lysis Systemic effect: antitumour immune response 1 Healthy cells 2 GM-CSF 3 Dendritic cell activated by GM-CSF CD4+ helper T cell 4 T-VEC Tumour cells Tumour cell lysis TDAs TDAs CD8+ cytotoxic T cell Distant dying tumour cell T-VEC replication in tumour tissue 1 3 Tumour cells rupture for an oncolytic effect 1 4 Systemic antitumour immune response 3,5,6 Death of distant cancer cells 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: ; 6. Dranoff G. Oncogene 2003;22: ; 7. Liu BL, et al. Gene Ther 2003;10: ; 8. Andtbacka RHI, et al. J Clin Oncol 2015;33: Proposed mechanism of action for T-VEC. TDA, tumour-derived antigen.

34 Dual Mechanism of Action: T-VEC + Pembrolizumab Tumor cell PD-L1/PD-L2 Pembrolizumab binding PD1 CD = cluster of differentiation GM-CSF = granulocytemacrophage colony-stimulating factor MHC = major histocompatibility complex PD-1 = programmed death receptor 1 PD-L1 = programmed death ligand 1 TDA = tumor-derived antigen 7. T cell mediated tumor cell death and release of new array of TDAs 6. T cell tumor recognition 5. T cell tumor infiltration Tumor bed TDA Figure adapted from Chen DS, et al. Immunity. 2013;39:1-10. Luke JJ, et al. Oncotarget. 2015;6: Ribas A. N Engl J Med. 2012;366: T cell Immature dendritic cell Systemic Effect 4. T cell proliferation and migration Talimogene laherparepvec Blood vessel Tumor cells 1. Tumor cell lysis GM-CSF TDA Immature dendritic cell Local Effect Pembrolizumab binding PD-L1/PD-L2 Dendritic cell MHC TDA B7 CD28 T cell 2. Dendritic cell maturation + + Mature dendritic cell 3. T cell activation T cell PD1 T cell receptor

35 Schumacher Science 2015

36 Melero Nature Rev Cancer 2015

37 Sharma Science 2015

38 Greenplate EJC 2016

39 Dijkstra JAMA 2016

40 Dijkstra JAMA 2016

41 SITC Congress 2016

42 SITC Congress 2016

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44 First site to be opened: June 02, 2017

45 Greenplate EJC 2016

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51 Biomarkers, biomarkers, biomarkers Yuan J J Immunother Cancer 2016

52 Closing remarks and future perspectives i. New immunotherapy has come to stay ii. iii. iv. New immunotherapy is no longer an empiric approach Benefit OS demonstrated in many tumors: melanoma, NSCLC, kidney, head and neck, bladder 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