Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle

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L'Institut national du cancer, la Fondation Arc et la Ligue contre le cancer ont organisé le séminaire de préparation à l'appel à projet "Programme d'Actions Intégrées de Recherche (PAIR) sur les cancers de l'enfant" qui s'est tenu le 13 avril 2016 à Paris.

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  • > Over the last decade, a tremendous amount of data has been published on how cancers generate immune tolerance.
    > We know now that within the tumor micro-environment, there are subsets of myeloid cells, which, together with the Tumor cells, sustain the development of a type of lymphocytes, called regulatory T-cells or Tregs.
    These Tregs are a subset of CD4+ T-cells identified by the expression of a transcription factor called FOXP3 and have the ability to inhibit specifically the immune response directed against the tumor.

    In order to treat cancers, people have been focusing so far on the tumor cells.
    A paradigm shift is happening today in cancer therapy where instead of targeting the tumor cells, new molecules are designed to target the immune system in order to break the cancer tolerance and stimulate the anti-tumor immune response.
  • Interestingly, it has also been shown recently that inflammatory cells of the myeloid lineage are of bad prognosis in NB.
  • Immunothérapie des cancers, nouveaux concepts - Aurélien Marabelle

    1. 1. Programme d’Actions Intégrées de Recherche en cancérologie pédiatrique (PAIR Pédiatrie) Maison de la Chimie - 13 avril 2016
    2. 2. Immunothérapie des cancers, nouveaux concepts Aurélien Marabelle, MD, PhD Directeur Clinique du Programme d’Immunothérapie DITEP, Pr JC Soria INSERM 1015, Pr L Zitvogel GUSTAVE ROUSSY
    3. 3. Qu’est ce que l’immunothérapie ? Cytokines Sang Inné AdaptatifMoelle
    4. 4. Chemotherapy - 1930s Paul Ehrlich - alkylating agents 1943 nitrogen mustard - lymphoma Surgery – 1890 Halsted performs first radical mastectomy Radiotherapy – late 19th - Becquerel and Rontgen, Marie Curie 1898 radium identified, 1903 first successful cancer tx
    5. 5. Immunothérapies du Cancer Shekarian T, Wittmann S, Caux C, Marabelle A. Paradigm shift in oncology: targeting the immune system rather than cancer cells. Mutagenesis 2014
    6. 6. Cancer immunotherapy: “the beginning of the end” or “the end of the beginning” ? Durant JR. N Engl J Med 1987; 316:939-41.
    7. 7. April 19, 2015 April 20, 2015 April 19, 2015 June 2, 2013 June 2, 2013 Nov 19, 2014 June 30, 2011 Nov 16, 2014 Aug 19, 2010 June 2, 2012 June 28, 2012
    8. 8. FOXP3 FOXP3 FOXP3 IMMUNO- TOLERANCE IMMUNO- SURVEILLANCE Tregs Cancer Cells DCs TAMs MDSCs NKs CD8+ T-cells CD4+ T-cells DCs - Adapté de Colombo MP, et al Nat Rev Cancer. 2007 Nov;7(11):880-7. Le Système Immunitaire peut aussi promouvoir le cancer !
    9. 9. Changement de Paradigme Cellule Tumorale Paradigme Historique: Cibler les Cellules Tumorales Lymphocyte Nouveau Paradigme: Cibler les Cellules Immunitaires
    10. 10. Activation / Inhibition du Lymphocyte
    11. 11. Anticorps Immunomodulateurs dirigés contre des “checkpoints” immunitaires
    12. 12. THERAPIES CIBLANT L’IMMUNITE Hodi et al. Abstract #3008 ASCO 2008 Screening Week 12 Week 14 Week 72 Schadendorf D, J Clin Oncol 2015. Anti-CTLA4
    13. 13. Before BRAFi After 15 weeks of BRAFi After 23 weeks of BRAFi Wagle N, et al. JCO. 2011 Aug 1;29(22):3085-96 Chapman PB et al. N Engl J Med 2011;364:2507–16. THERAPIES CIBLANT LA TUMEUR
    14. 14. Nouveaux Types de Réponses en Oncologie Immune-Related Response Criteria
    15. 15. Bompaire et al Invest New drugs 2012 Nouvelles Toxicités en Oncologie
    16. 16. Hayden EC. Antibody alarm call rouses immune response to cancer. Nature. 2012 Jun 6;486(7401):16. anti-PD-1 / anti-PD-L1 immunotherapy
    17. 17. Spectre d’Activité des Anti-PD-1/PD-L1 Marabelle A, Routy B, Michels J, Kroemer G, Zitvogel L. Prime time for Immune-Checkpoint Targeted Therapy at ASCO 2015. Oncoimmunology 2016. in press. AMM AMM
    18. 18. Pembrolizumab Antitumor Activity -100 -80 -60 -40 -20 0 20 40 60 80 100 ChangeFromBaselinein TumorSize,% Melanoma1 (N=411) KEYNOTE-001 -100 -80 -60 -40 -20 0 20 40 60 80 100 ChangeFromBaselinein TumorSize,% NSCLC2 (N=262) KEYNOTE-001 -100 -80 -60 -40 -20 0 20 40 60 80 100 ChangeFromBaselinein TumorSize,% Gastric5 (N=39) KEYNOTE-012 -100 -80 -60 -40 -20 0 20 40 60 80 100 ChangeFromBaselinein TumorSize,% Urothelial4 (N=33) KEYNOTE-012 -100 -80 -60 -40 -20 0 20 40 60 80 100 ChangeFromBaselinein TumorSize,% H&N3 (N=61) KEYNOTE-012 -100 -80 -60 -40 -20 0 20 40 60 80 100 ChangeFromBaselinein TumorSize,% TNBC6 (N=32) KEYNOTE-012 -100 -80 -60 -40 -20 0 20 40 60 80 100 ChangeFromBaselinein TumorSize,% cHL7 (N=29) KEYNOTE-013 1. Daud A et al. 2014 SMR; 2. Garon EB et al. ESMO 2014; 3. Chow LQ et al. ESMO 2014; 4. O’Donnell P et al. 2015 Genitourinary Cancers Symposium; 5. Muro K et al. 2015 Gastrointestinal Cancers Symposium; 6. Nanda R et al. SABCS 2014; 7. Moskowitz C et al. 2014 ASH Annual Meeting; 8. Alley EA et al. 2015 AACR. -100 -80 -60 -40 -20 0 20 40 60 80 100 ChangeFromBaselinein TumorSize,% Mesothelioma7 (N=25) KEYNOTE-028
    19. 19. Mais les réponses tumorales aux immunothérapies sont durables JCO, April 20, 2015. Durabilité des réponses tumorales des CBNPC sous nivomulab (anti-PD-1, BMS)
    20. 20. Immune-Targeted mAbs provide Survival Benefits Motzer RJ, et al. NEJM 2015. nivolumab docetaxel Non Sq NSCLC Borghaei H, et al. NEJM 2015.
    21. 21. Nivolumab (BMS) Pembrolizumab (MSD) Atezolizumab (Roche/Genentech) Durvalumab (AZ/Medimmune) Avelumab (Pfizer) Anti-PD-1 Anti-PD-L1 Approved Ipilimumab (BMS) Tremelimumab (AZ) Anti-CTLA-4 Approved Know your Immune Checkpoint Antibodies
    22. 22. What is the Future of Oncology ?
    23. 23. Chemotherapy + PD-1/PD-L1 Blockade in 1st line NSCLC Giaccone et al, ESMO 2015
    24. 24. The Future of Oncology ?
    25. 25. Larkin J, et al. N Engl J Med 2015. Anti-CTLA4 Anti-PD-1 Anti-PD-1 + Anti-CTLA4
    26. 26. AGONISTIC ANTAGONISTIC This is just the beginning
    27. 27. But also Target Innate Immune Cells! DCs αCD40 TAMs αCSF1R αCD47 NK Cells αKIR αCD137 αNKG2A
    28. 28. The Future is Bright Bi Spe Oncolytic Virus Cancer Vaccines CAR T-cells Oral Immuno Modulator
    29. 29. 30 25 mg BID 50 mg BID 100 mg BID 300 mg BID Off study treatment Epacadostat + pembrolizumab in Metastatic Melanoma (Incyte, NCT02178722) Gangadhar et al. SITC 2015. Abstract #07 ORR = 58% (11/19)
    30. 30. Lenalidomide + aPD-1 in Multiple Myeloma ORR = 76% (13/17) San Miguel et al, ASH 2015
    31. 31. The Future is Bright Bi Spe Oncolytic Virus Cancer Vaccines CAR T-cells IDO inhibitors T-VEC EMA approval Q4 2015
    32. 32. in situ immunization
    33. 33. T-VEC + anti-PD-1 in Melanoma -100 -75 -50 25 50 -25 0 75 100 ORR = 56% (9/16) PercentageChangefromBaseline Stage IV M1c (N=7) Stage IV M1b (N=2) Stage IV M1a (N=1) Stage IIIc (N=5) Stage IIIb (N=1) All 16 patients were followed at least 12 weeks from the first dose of pembrolizumab and must have had an evaluable response. Stable disease must be > 77 days to be considered evaluable. 34Long G V et al, SMR congress 2015, San Franisco, USA
    34. 34. The Future is Bright Bi Spe Oncolytic Virus Cancer Vaccines CAR T-cells IDO inhibitors
    35. 35. T-CELL CAR T-CELL Nature Reviews Cancer, 13, 525–541 (2013) Adoptive T-cell Therapy
    36. 36. N Engl J Med. 2014 Oct 16;371(16):1507-17
    37. 37. The Future is Bright Bi Spe Oncolytic Virus Cancer Vaccines CAR T-cells IDO inhibitors Blinatumomab EMA approval Q4 2015
    38. 38. Bispecific T-cell Engaging mAbs
    39. 39. Blinatumomab on Chemotherapy-Refractory MRD in B- ALL Blinatumomab in ALL & NHL
    40. 40. The Future is Bright Bi Spe Oncolytic Virus Cancer Vaccines CAR T-cells IDO inhibitors T-VEC EMA approval Q4 2015 Blinatumomab EMA approval Q4 2015
    41. 41. aPD-1/aPD-L1 aOX40 aCD137 aGITR aKIR IDOi Oncolytic Virus Vaccines TLR ago RIG ago STING ago CHEMOTHERAPY RADIOTHERAPY TKI TCE BiSpe mAbs 2016 : Combinaisons! aCTLA4
    42. 42. Asgharzadeh., et al. Journal of Clinical Oncology. 2012 Tumor Associated Macrophages in High-Risk Neuroblastoma CD163+IHCstaining Macrophages Good Prognosis Neuroblastoma Bad Prognosis Neuroblastoma Stage IV, MYCN NA, >18months
    43. 43. Yu, A. L. et al. (2010). Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for Neuroblastoma. The New England Journal of Medicine, 363(14), 1324–34. Rationnel pour l’Immunotherapie des Neuroblastomes
    44. 44. Impact Pronostic des Isoformes NKp30 dans les NB de Haut Risque Semeraro M, et al. Clinical impact of the NKp30/B7-H6 axis in high-risk neuroblastoma patients. Sci Transl Med 2015;7:283ra55.
    45. 45. Niveaux d’Expression Variables du CMH I dans les Cancers Pédiatriques Haworth KB, et al. Characterization of MHC Class I and β-2-Microglobulin Expression in Pediatric Solid Malignancies to Guide Selection of Immune-Based Therapeutic Trials. Pediatr Blood Cancer 2016;63:618–26.
    46. 46. Challenge #1: How do we overcome resistance to immunotherapy? Ott et al. Pembrolizumab in SCLC. WCLC 2015
    47. 47. Challenge #2: Immune Toxicity 7.7% 18.6% 39.6% 0.0% 5.0% 10.0% 15.0% 20.0% 25.0% 30.0% 35.0% 40.0% 45.0% nivolumab ipilimumab nivo+ipi Grade 3-4 Adverse Events with anti-CTLA4 + anti-PD-1 Grade 3-4 Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 2015.
    48. 48. Challenge #3: Financial Toxicity Nature. 2013 May 30;497(7451) Immunotherapy's cancer remit widens. Ledford H. ipilimumab
    49. 49. On treatment Off treatment First response Ongoing response 0 8 16 24 32 40 48 64 72 8056 Time (weeks) NIVOLUMAB+IPILIMUMAB Time to and Durability of Response in Patients Who Discontinued Due to Toxicity The Good News: We Might Not Need To Treat for Long Larkin et al. Abstract Number 3303. ESMO 2015.
    50. 50. Institut national du cancer ● 52, avenue André Morizet ● 92513 Boulogne-Billancourt Cedex ● France ● Tél. +33 (0) 1 41 10 50 00 ● e-cancer.fr plus d’informations sur e-cancer.fr
    51. 51. Kluger HM. Safety and activity of pembrolizumab in melanoma patients with untreated brain metastases. J Clin Oncol 2015;33:abstr 9009. Goldberg SB. Activity and safety of pembrolizumab in patients with metastatic NSCLC with untreated brain metastases. J Clin Oncol 2015;33:abstr 8035. Activity of anti-PD-1 against Brain Mets
    52. 52. in situ immunization
    53. 53. William Coley Streptococcus pyogenes “…on May 2, 1891, I inoculated a case of sarcoma” “At the end of two weeks, the tumor had disappeared”
    54. 54. Copyright © 2012 American Medical Association. All rights reserved. Treatment of Lymphangiomas With OK-432 (Picibanil) Sclerotherapy: A Prospective Multi-institutional Trial Arch Otolaryngol Head Neck Surg. 2002;128(10):1137-1144. doi:10.1001/archotol.128.10.1137 Patient 3 with a stage I lymphangioma of the left side of the neck. Photographs taken before (A) and after (B) a single injection demonstrate a complete response to OK-432 treatment. Figure Legend:

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