Immunotherapy in haematological malignancies Michele Ghielmini Oncology Institute of Southern Switzerland Bellinzona
Conflicts of interest Roche Celgene Mundipharma Janssen Gilead Bayer Millenium
What do we mean by immunotherapy when speaking about lymphoma? MONOCLONAL ANTIBODIES Naked Radio-immunotherapy Immuno-toxins ENGAGING T-CELLS Interferon Vaccination Immune checkpoint inhibition CAR T cells Bispecific antibodies
Rituximab: mechanisms of action
Patients usually respond to upfront R RR of prolonged rituximab in first-line FL Colombat 2001 (n= 50) 73% Hainsworth 2002 (n= 60) 73% Witzig 2005 (n= 37) 72% Ghielmini 2005 (n= 202) 75% Kimby 2008 (n= 123) 78% Ardeshna 2010 (n= 192) 85%
R vs R2 in FL patients in need of treatment 90 80 Week 10 Week 23 p<0.0001 p=0.002 75% 82% Proportion of patients (%) 70 60 50 40 30 20 45% 61% PR CR/CRu 10 0 Rituximab (N=77) Rituximab (N=77) Kimby E, et al. ASH 2014; Abstract 799
FL: the response to upfront rituximab (RR 70%) can be long lasting if maintained EFS 1 PFS 2 1.0 1.0 0.8 Median EFS = 4.4 years 0.8 Median PFS = 7.4 years Probability 0.6 0.4 1 year 1 month 0.6 0.4 1 year 5 years 0.2 0.0 Median EFS = 2.5 years Prolonged Standard p = 0.045 1 2 3 4 5 6 7 8 9 10 0.2 0.0 0 Median PFS = 3.5 years P=0.04 1 2 3 4 5 6 7 8 9 Years since start of treatment Time from randomisation (years) 1. Martinelli G, et al. J Clin Oncol 2010;28:4480 84 2. Taverna C, et al. ASH 2013; Abstract 508
Two Types of anti-cd20 mabs Type I Type I Type II CD20 clustering in B-cell membrane ++ - Type II Induction of CDC ++ + Induction of ADCC ++ ++ Induction of apoptosis + ++ = no activity; + = some activity; ++ = significant activity Cragg MS, et al. Curr Dir Autoimmun 2005 Glennie MJ, et al. Mol Immunol 2007 Teeling JL, et al. Blood 2004
Chl vs R-Chl vs G-Chl in CLL Elderly non-fit patients, 1. line PFS Tendency of a superior OS with obinotuzumab Goede V et al. N Engl J Med 2014
Obinutuzumab vs rituximab in relapsed inhl preliminary analysis of the GAUSS study In FL: ORR GA101: 44.6% R: 26.7% p = 0.01 Sehn LH, et al. ASH 2011. Abstract 269
Targeted irradiation: radio-immuno-therapy 90 Yttrium 131 Iodine Properties (Zevalin) (Bexxar) Half-life 64 hours 192 hours 90 Y 131 I Energy emitter Beta (2.3 MeV) Gamma (0.36 MeV) Beta (0.6 MeV) Path length χ 90 5 mm χ 90 0.8 mm Urinary excretion Dosing Administration Minimal 7% in 7 days Based on weight and platelet count Outpatient Extensive/variable 46-90% in 2 days Clearance based dosing using whole body dosimetry Inpatient or restrictions to protect family/public
Radio-immunotherapy as initial therapy for indolent NHL 100 I-131 Tositumomab 1 n=76 patients, 95% OR, 75% CR 1.0 90-Y Ibritumomab 2 n=50 patients, 94% OR, 86% CR Survival (%) 80 60 40 20 0 Overall survival Progression-free survival 0 1 2 3 4 5 6 7 8 Years after dosimetric dose Cumulative survival 0.8 0.6 0.4 0.2 0.0 0 GELF criteria GELF criteria not met GELF criteria met Global Censored data 12 24 36 48 60 72 84 Progression-free survival (months) GELF, Groupe d'etude des Lymphomes Folliculaires 1. Kaminski MS, et al. N Engl J Med 2005;352:441 49 2. Ibatici A, et al. Br J Haematol 2014;164:710 16
Brentuximab vedotin (SGN35) Anti-CD30 conjugated to an antitubulin agent MMAE microtubule-disrupting agent anti-cd30 monoclonal antibody ADC binds to CD30 Internalised in lysosome MMAE is released MMAE disrupts microtubule network
Brentuximab vedotin (SGN-35) FDA approved for R/R HL and ALCL 102 post-auto transplant HL ORR 75% CR 34% 7 mos (20 mos in CRs) 58 relapsed or refractory ALCL ORR 86% CR 53% median duration of response 13 mos Shustov et al., Abstr. 125, ICML-11 Younes et al., Abstr. 160, ICML-11
Brentuximab vedotin in PTCL-NOS and AITL n=29 (11 AITL and 18 PTCL-NOS) R/R 2 prior lines Primary refractory: 55% % change in tumour size from baseline 100 50 0-50 -100 Maximum Tumour Volume Reduction AITL PTCL ORR 36%, 50% in AITL (4/11 CR) Responses also in low/ undetectable CD30 by IHC AITL, angioimmunoblastic T-cell lymphoma PTCL-NOS, peripheral T-cell lymphoma not otherwise specified Oki Y, et al. ICML-12 2013 Abstract 152
What do we mean by immunotherapy when speaking about lymphoma? MONOCLONAL ANTIBODIES Naked Radio-immunotherapy Immuno-toxins ENGAGING T-CELLS 1. Interferon 2. Vaccination 3. Immune checkpoint inhibition 4. CAR T cells 5. Bispecific antibodies
Can transplant cure? Autologous: no Allogeneic: yes Cumulative proportion surviving 1.0 0.8 0.6 0.4 0.2 0 But at the cost of important risks and side effects Today, with RIC, the curve is possibly here, but with 50% GVH and 30% extensive GVH Months after transplantation Allogeneic Autologous 0 20 40 60 80 100 120 140 Hosing et al., Ann Onc 2003
Therapeutic strategies to overcome immune tolerance to cancer TCR Engineered T Cell 4.- CAR 5.- BiTE CD3 CD19 CD20 Native T cell TCR MHC I/II PD1 PD-L1 PD-L2 Malignant B Cell 1.- Cytokines 2.- Tumor vaccines 3.- Immune checkpoint inhibitors Batlevi C, Matsuki E, et al: Nature Rev Clin Oncol 2015 (Accepted)
Interferon prolongs survival in FL META-ANALYSIS 10 randomised trials, 1922 patients Survival benefit of 2 years (p=0.0008) if IFN given With (NOT after) intensive chemotherapy At a dose of 5 million UI At a cumulative dose of 36 million UI / month Rohatiner AZS, et al. J Clin Oncol 2005;23:2215 23
Vaccines are directed against idiotypes
Vaccinated patients developing anti-idiotype Ab have a longer response after chemotherapy Humoral Other Other Humoral Analysis of 136 patients with FL receiving idiotype (Id) vaccination Humoral represents patients with specific anti-id Abs Weng WK, et al. J Clin Oncol 2004;22:4717 24
Negative vaccine trial Mitumprotimut-T vs placebo Freedman A, et al. J Clin Oncol 2009;27:3036 43
Positive vaccine trial Analysis of patients with advanced stage previously untreated FL Schuster SJ, et al. J Clin Oncol 2009;27:2
Responses of HL to anti-pd1 in R/R HL Nivolumab: RR 87%, CR 17% 100 75 Pembrolizumab: RR 66%, CR 21% Change from baseline, % 50 25 0-25 -50-75 -100 Armand P, et al. ASH 2014; Abstract 289 Moskowitz CH, et al. ASH 2014; Abstract 290
PD-1 blockade by pidilizumab plus rituximab in relapsed FL Efficacy Safety n= 29 pts No gr 3 4 AEs ORR 66% (CR 52%) Median PFS 19 months Westin JR, Lancet Oncol 2014;15:69 77
9p24.1 amplification and PD-1L cell-surface expression in HL and MLBCL cell lines. PD-1L Copy number PD-1L Copy number Green M R et al. Blood 2010;116:3268-3277
HRS Cells Express High Levels of PDL-1 Hodgkin and Reed Sternberg (HRS) Cells EBV Infection 9p24.1 Gene amplification JAK2 PDL1 CD30
PDL1 Expression in classical and NLP Hodgkin Lymphoma PDL1 in chl PDL1 in NLPHL Histiocytes HRS cells Hodgkin cells Histiocytes Courtesy of Chiu A, MSKCC
Two strategies to engage T- cells against B-cell lymphoma
CAR-T cells (Chimeric Antigen Receptor) Kochenderfer JN, Rosenberg SA. Nat Rev Clin Oncol 2013;10:267 76
CAR-T cells therapy Kochenderfer and Rosenberg, Nat Rev Clin Oncol, 2013
CAR-T cells clinical results NCI, Bethesda Responses in relapsed patients 4/5 FL 7/8 CLL 6/7 DLBCL (4 CR) 3/10 pat in relapse after allo-bmt (donor-derived CAR-T) Side effects: - Severe hypotensions - Severe neurologic Kochenderfer et al,, Blood 2013 and JCO 2014.
Summary of available data for CAR T cells in R/R ALL 19-28z (MSKCC/Juno; n=39) 1 CTL019 (CHOP/UPenn/ Novartis; n=39) 2,3 Population Adults >18 years Children (age not specified) 2 Status after conditioning chemotherapy, prior to CAR T-cell treatment CD19-CAR (NCI/Kite; n=20) 4 Children/young adults (1 30 yr) MRD+ CR (<5% BMB) 46% 23% 2 25% MRD- (<0.01% BMB) 0% 15% 2 0% Status after conditioning chemotherapy and CAR T-cell treatment CR/CRi 87% 92% 70% MRD- (in evaluable patients) 81% 82% 60% Clinically significant/ 23% 27** 3 29 severe CRS Neurotoxicity (%)* 28 (Grade 3/4) 43** 3 29 *Any grade or no details of grade; **Total n=30 1. Park JH, et al. Oral presentation at ASCO 2015. Abstract 7010; 2. Grupp S, et al. Oral presentation at ASH 2014. Abstract 380 3. Maude SL, et al. N Engl J Med 2014;371:1507 17; 4. Lee DW, et al. Lancet 2015;385:517 28
Bi-specific antibodies Design and mode of action of bispecific T-cell engager (BiTE ) antibody constructs Frankel SR, Baeuerle PA. Curr Opin Chem Biol 2013;17:385 92
CR after Blinatumomab in ALL patients refractory or relapsed after allotransplant All responders Sex Female Male Age 18 to <35 35 to <55 55 to <65 65 Prior Salvage 0 12 Primary refractory Prior SCT 3 Yes No Yes No Bone marrow blasts <50% 50% 189 43 0 20 40 60 80 100 N 70 119 90 46 28 25 38 77 42 32 16 173 64 125 59 130 CR/CRh % 95% CI 46 41 43 46 36 44 50 47 36 34 38 43 45 42 73 29 36 50 34 58 32 51 33 54 31 61 19 56 24 65 33 67 35 58 22 52 19 53 15 65 36 51 33 58 33 51 60 84 22 38 Topp MS, et al. Lancet Oncol 2015;16:57 66; Topp MS, et al. EHA 2014, Abstract S722 and oral presentation CR/CRh rate, %
Conclusions (for lymphomas) Chemotherapy is not likely to obtain more in B-cell malignancies Future progress most likely to be obtained by targeted drugs and immunotherapy One avenue of success may be the engagement of T cells against malignant B cells