Les anticorps monoclonaux dans tous leurs états: Des avancées dans le traitement des hémopathies malignes Norbert Vey Beirao et al. TVJ 2016 Delivery Systems for Immunotherapy mAb BITE α-CD3 single- Linker chain Ab α-CDxx Ab V H VL Ac. Immuno-conjugués (ADC) • 4 ADC enregistrés • Un boom depuis 2013 • 30 ADC en développement clinique en oncologie Beck et al. Nat Rev. 2017 Gemtuzumab ozogamycin in the frontline therapy of AML (FDA re-approved 2017) H. Dombret. EHA 2012 Educational Book Safety issues: Safety issues: - -MyelosuppressionMyelosuppression - -Hepatic Hepatic toxtox/SOS/SOS Hills, R et al., Lancet Oncol 2014 Brentuximab Vedotin: an anti-CD30 MMAE antibody drug conjugate FDA and EMEA approved for CD30+ refractory/relapsed Hodgin Lymphoma and Anaplastic Large cell NHL Brentuximab Vedotin in refractory/relapsed Hodgkin Lymphoma OS following treatment with brentuximab vedotin. Ajay K. Gopal et al. Blood 2015;125:1236-1243 ©2015 by American Society of Hematology Anti-CD22 immunoconjugué: Inotuzumab ozogamycine dans les LAL Inotuzumab phase III (INO-VATE) BCP-ALL, R/R Kantarjian, N Engl J Med. 2016 Aug 25;375(8):740-53 Inotuzumab phase III (INO-VATE) BCP-ALL, R/R Duration of remission Overall Survival Progression-free Survival Kantarjian, N Engl J Med. 2016 Aug 25;375(8):740-53 Comment progresser? Les points critiques Choix de la cible Choix du linker Choix du cytotoxique Caractéristiques d’une cible idéale (Ag) • Expression large dans la pathologied’intérêt • Spécificité • Accessibilité • Internalisée (pas obligatoire/ effet “by-stander”) • Expression dans le compartiment souche L’efficacité de l’Ac non conjugué correspondant n’est pas indispensable (exemple du Brentuximab) Caractéristiques du linker et du payload idéal • Linker – Stable dans le sang – Hydrolysable dans la cellule – Ratio ADC/Ac non conjugué élevé • Payload – Activité cytotoxique +++ (pMol) – Hydrophilie – Échappement aux pompes à efflux – Disponibilitéd’une “poignée chimique” ADCs in clinical development (MMAE only) Beck et al. Nat Rev. 2017 Les anticorps bispécifiques: des applications multiples Kontermann & Brikmann, Drug Discov. Today, 2015 Diversité des formats d’Ac bispécifiques Kontermann & Brikmann, Drug Discov. Today, 2015 Blinatunomab: CD19xCD3 bispecific T-cell engager Blinatumomab phase III (TOWER) LAL-B, R/R, molecular response Topp M et al., EHA 2016 Blinatumomab phase III (TOWER) Overall Survival (Intent-to-Treat) Topp M et al., EHA 2016 Flotetuzumab CD123 x CD3 Bispecific DART Protein “Anti-CD123” Anti-CD3 • DART bispecific platform – Multiple applications across different diseases – Predictable manufacturability – Long-term stability – Ability to tailor half-life and valency CD123 x CD3 DART • Optimal variable light and heavy chain pairing allows for • Activation Target Tumor tighter conformation and closer proximity between effector T Cell • Cytokine release Cell Cell • Expansion Killing (CD3+) cells and target (CD123+) cells • Differentiation Tumo • Flotetuzumab (MGD006/S80880) mode of action: r Cell redirected T-cell killing of CD123+ cells Root, et al. Antibodies 2016, 5, 6 Chichili, et al. SciTransl Med. 2015 May 27;7(289) 20 Anti-Leukemic Activity at Threshold Dose ≥ 500 ng/kg† Of 14 patients treated with flotetuzumab in dose escalation phase at threshold dose ≥ 500 ng/kg/day who received ≥ one cycle of treatment and had post-treatment bone marrow biopsy TF Treatment Group • Rapid responses after single cycle TF TF Cohort 2: 100à50 0 ng/kg/day of therapy in majority of patients 4 Days On/ Cohort 2a: 30à100à500 ng/kg/day 3 Days Off that respond (cycles ≤ 2) Cohort 3: 30à100à 700ng/kg/day Cohort 7: 30à100à 500ng/kg/day TF 7 Days On Cohort 8: 30à100à 700ng/kg/day • Objective resp. rate TF TF (CR/CRi/MLF/PR): 6/14 pts (43%) AML AML MDS AML AML AML AML AML AML AML AML AML AML AML • CR Rate: 4/14 (28%) (CR/CRi) SD/OB SD/OB Change in BM Blast Count from Baseline (%) PR MLF 1 CRi 1 CRi2 CR 3 CRm 4 CR = Complete Response; CRm = molecular CR; CRi = Complete Response with incomplete hematological improvement; MLF = Morphologic Leukemia-free state; PR = Partial Response; SD/OB = Stable Disease/Other Anti-Leukemic Benefit; PD= Progressive Disease; (Modified ELN 2017 criteria) † Data cut-off Aug. 1, 2017; presented at ESMO 2017 Vey et al. ESMO 201721 Other bispecific mAbs in clinical development Kontermann & Brikmann, Drug Discov. Today, 2015 Delivery Systems for Immunotherapy mAb BITE CART Infusion react. TLS TLS Target-related CNS CRS Constitutional CNS CRS „off-target“ Efficacy Tolerability PD-1 and CTLA-4. Philippe Armand Blood 2015;125:3393-3400 ©2015 by American Society of Hematology Phase IB/II Study of Nivolumab in Combination with Azacytidine in Patients with Relapsed AML (Naval Daver et al. ASH 2016) • Treatment: – AZA 75mg/m2 Days 1-7 with nivolumab 3mg/kg on Day 1 and 14. Courses were repeated approximately every 4-5 • 51 pts with a median age of 69 years (range, 45 – 90) • Efficacy: – 35 pts are evaluable for response: – CR/CRi: 6 (18%)) – HI: 5 (15%) • Tolerance – 4- and 8-wk mortality were 0 and 6% – Grade 3/4 and Grade 2 immune mediated toxicities were observed in 7 (14%) and 6 (12%) ICP blockade clinical trials in AML/MDS Combo Drug Company Drug Phase Patient # Patient Segment(s) LOT NCT M.D. Anderson, Idarubicin+ I/II 75 Patients with AML, MDS 1st line (II) NCT02464657 BMS cytaribine Patients with AML in Remission post- NIH/NCI None* II 80 Maintenance NCT02275533 chemo +/- ipilimumab M.D. Anderson, and or II 120 Patients with various risk MDS 2nd line NCT02530463 BMS Vidaza 6 cohorts nivolumab M.D. Anderson, Patients with AML at high risk for None II 30 Maintenance NCT02532231 BMS relapse M.D. Anderson, Patients With Refractory/ Relapsed Vidaza II 54 2nd line+ NCT02397720 BMS AML Lirilumab +/- 1st line (high M.D. Anderson, nivolumab II 80 Patients with various risk MDS risk); 2nd line NCT02599649 BMS and/or (low risk) Vidaza 4 cohorts Participants with blood cancers (MDS, pembrolizumab Merck None I 156 2nd line+ NCT01953692 MM, HL, MLBCL, NHL, FL, DLBCL) 1st line cohort Patients with intermediate/high/very Atezolizumab Roche +/- Vidaza I 46 and 2nd line NCT02508870 high-risk MDS cohort Subjects With MDS Who Fail to Achieve CC-486 +/- Durvalumab Celgene II 194 an Objective Response to Vidaza or 2nd line NCT02281084 durvalumab Dacogen Anti-KIR phase I in elderly AML • AcMo humanisé IgG4 (Innate Pharma, Marseille, France) NK cell from – lie KIR2DL1-2-3, et S1-2 donor – Bloque liaison KIR à HLA-C Tumor cell • Etude phase 1 d’IPH2101: 23 patients >60 ans en RC1 from transplanted KIR- – MTD non atteinte à 3 mg/kg ligand patient mismatc – EI modérés et transitoires (fièvre, frissons, rash) h • Etude phase 1 du lirilumab (IPH2102): 20 patients multipathologie – MTD non atteinte à 10 mg/kg – EI modérés et transitoires (fièvre, frissons, rash) – Saturation complète des KIR >12 wks à >1 mg/kg Vey et al. Blood 2012 Vey et al. Oncotarget 2017 Romagne, Blood, 2009 EFFIKIR: placebo-controlled randomized study of lirilumab in the maintenance of CR1 AML: Leukemia-Free Survival N=152 P= 0.929 P= 0.144 Vey et al. ASH 2017 Conclusion • Les progrès technologiques ont permis de développer une grande variété de formats d’anticorps • L’efficacité est variable selon les maladies • Un effort majeur est à faire pour évaluer rapidement ces approches • Et surtout, tester leurs combinaisons Activer les cellules T: rationnel pour l’utilisation des anti-PD1/PDL1, anti-CTLA4 CPi clinical trials in AML/MDS Drug Company Combo Drug Phase Patient # Patient Segment(s) LOT NCT Idarubicin+ M.D. Anderson, BMS I/II 75 Patients with AML, MDS 1st line (II) NCT02464657 cytaribine NIH/NCI None* II 80 Patients with AML in Remission post-chemo Maintenance NCT02275533 +/- ipilimumab M.D. Anderson, BMS II 120 Patients with various risk MDS 2nd line NCT02530463 and or Vidaza 6 cohorts nivolumab M.D. Anderson, BMS None II 30 Patients with AML at high risk for relapse Maintenance NCT02532231 M.D. Anderson, BMS Vidaza II 54 Patients With Refractory/ Relapsed AML 2nd line+ NCT02397720 Lirilumab +/- nivolumab 1st line (high risk); M.D. Anderson, BMS II 80 Patients with various risk MDS NCT02599649 and/or Vidaza 2nd line (low risk) 4 cohorts Participants with blood cancers (MDS, MM, HL, pembrolizumab Merck None I 156 2nd line+ NCT01953692 MLBCL, NHL, FL, DLBCL) 1st line cohort Patients with intermediate/high/very high-risk Atezolizumab Roche +/- Vidaza I 46 and 2nd line NCT02508870 MDS cohort CC-486 +/- Subjects With MDS Who Fail to Achieve an Durvalumab Celgene II 194 2nd line NCT02281084 durvalumab Objective Response to Vidaza or Dacogen Anticorps anti-CD20 : RITUXIMAB dans les LAL • CD20+ : 30 à 50% des LAL-B • L’expression du CD20 est associé à un facteur de mauvais pronostic l Etude de phase III (Maury et al., NEJM, 2016) Expression du CD20>20% : ajout de 16-18 perfusions de RITUXIMAB au protocole d’inspiration pédiatrique GRAALL-2005 pour les LAL-B 65 71 % % 64 52 % % Développement des anti-CD20 Singh et al. JCST 2015 Vadastuximab Talirine (SGN-CD33A; 33A) Clinical studies of Vadastuximab Talirine (SGN-CD33A) • Vadastuximab Talirine Monotherapy in Older Patients with Treatment Naive CD33-Positive AML (Dale L. Bixby et al. Abs 590, ASH 2016): – N=26 pts – 30- and 60-day mortality rates = 0% and 15%. – CR= 23% Cri=31% MLFS= 19% – Tox: myelosuppression • Vadastuximab Talirine Plus Hypomethylating Agents in Frontline Older Patients with AML (Amir T. Fathi et al., Abs 591 ASH 2016): - 53 patients (age 75 years; range, 60- 87) - 33A: 10 mcg/kg, IV every 4 weeks on the last day of HMA - 17 of 36 responders (47%) achieved MRD negativity by flow cytometry Mécanismes de résistance aux ADC • Down-regulation de l’Ag • Augmentation du recyclage à la surface de la cellule • Diminution du trafic intra-cellulaire • Efflux du payload • Absence de pénétration intra-tumorale Ciblage de CD33: exemple des avancées possibles Beck et al.