Att använda immunförsvaret vid behandling av cancer Jonas Mattsson, M.D., Ph.D. Professor in Cell Therapy Center for Allogeneic Stem Cell Transplantation (CAST) Karolinska University Hospital 2 Immunologi Från det latinska ordet ”immunis” som betyder undantagen 3 Immunsystemets fyra ”hörnstenar” Specifikt Selektivt Adaptivt Minne 4 5 Immunförsvarets uppdelning Immunitet Ospecifika Immunförs Antigenvaret presenterande celler, makrofager, neutrofila Fysiska barriärer NKcell Eosinofila, Mastceller T-cell B-cell Specifika försvaret 6 T-cellerna är immunförvarets regering och ”elittrupp” 7 Hur T-celler ”dödar” 8 9 Antikroppar mot cancer 10 T-cell–mediated immune response Tumor-specific antigens Antitumor effector mechanisms dendritic cell Tumor cell Naïve cytotoxic T cell Activated cytotoxic T cell Tumor cell • The body’s immune response can detect and destroy tumor cells through activated T cells and other mechanisms (1) • Tumor cells express multiple antigens that are not expressed in normal tissue (2) 1. May KF Jr et al. In: Prendergast GC et al. Cancer Immunotherapy. 2nd ed. Elsevier; 2013:101–113. 2. Chen DS et al. Immunity. 2013;39(1):1–10. 11 T-cellen kan både slås av och på.... Immune checkpoint receptors style 12 Tumörcellen blockerar T-cellen.... Hämning Antigen PD-1 PD-1 Activated cytotoxic T cell PD-L1 PD-L2 Tumor cell Inactivated cytotoxic T cell PD-L2 PD-L1 Tumor cell 13 Antikroppar kan aktivera T-celler mot cancer Hämning Aktivering Blockerande antikropp PD-1 PD-1 PD-L2 Inactivated cytotoxic T cell PD-L1 Tumör cell PD-L2 Activated cytotoxic T cell PD-L1 Tumör cell 12 14 PD-1-hämmare i kombination med cytostatika mot lungcancer PFS Langer et al, Lancet Oncology, 2016 15 Resultat vid Hodgkin lymfom 80 90 60 40 20 192 (93%) patients had a reduction in tumor size 0 -20 -40 Cumulative Event Rate, % 100 Change From Baseline 100 80 70 60 50 40 30 20 -60 10 -80 0 0 -100 3 6 9 12 15 1 0 0 Months n at risk 145 Median number of treatment cycles: 13 (range,1-21) Treatment is ongoing in 120 (57%) patients Median follow-up: 10.1 (1.0-15.0) months Data cutoff: September 25, 2016 • • 89 31 Median (range) time to response: • 2.8 (2.1-8.8) months Response duration ≥6 months: 75.6%† Bispecifik antikropp vid ALL 17 So many combos ....So Little time. . Slide Courtesy of Holbrook Kohrt, Stanford University 18 T-celler mot cancer 19 Patient med livshotande EBV lymfom Kvinna 18 år med leukemi Transplanterad med navelsträngsblod Kommer in till avdelningen med hög feber 3 mån efter stamcellstransplantation Svullna lymfkörtlar Biopsi visar lymfkörtelcancer UHLIN et al. Cancer Immunol Immunotherapy 2010, 59:473-477 20 Selektion av T celler Kliniskt resultat Kliniskt resultat (2) Chimeric Antigen Receptors (CARs) • CARs contain antigen receptors such as the heavy and light chain variable regions of antibodies connected by a linker (scFv). • CARs include signaling molecules such as CD3-zeta and CD28. M.H. Kershaw et al. Nature Reviews Immunology Vol. 5 pg. 928-940 Nov. 2005 24 Selektion av T-celler Separation av vita blodkroppar Specifika T celler mot cancer Patient Expansion av cancerspecifika T-celler T-celler börjar uttrycka receptor mot cancercell Införsel av vektor i T-celler 25 Upenn clinical results Over 150 patients have been treated with CD19 CARs (CLL, ALL, NHL) Pediatric ALL cohort (N=25): 22/25 CRs (88%) 6 relapses, including 2 CD19(-) relapses All ALL (N=30) (pediatric plus adult): 27/30 CRs (90%) 6 total relapses Short followup (median 6 months, range 2-18 months) 26 Upenn: Overall Survival after CD19 CAR Overall Survival infusion in patients with ALL 1.0 6−month OS: 78% (95% CI: 64,95) Probability 0.8 0.6 0.4 0.2 0.0 0 90 180 270 360 450 540 630 N: 30 24 18 10 4 2 1 1 Days since infusion 27 CD19 CAR therapy for ALL (2013-2014) Publication/meeting date Number/age of subjects Complete remission rate Brentjens, Sci Transl Med, March 21, 2013 5 adults 100% Grupp, New Engl J Med, April 18, 2013 2 children 100 % Davila, Sci Transl Med, February 19, 2014 16 adults 88% Lee, Lancet, AOL, October 13, 2014 20 children 70% Maude, N Engl J Med, October 16, 2014 25 children, 5 adults 90% 100% Park, ASH 2014, December 6, 2014 27 adults 89% Frey, ASH 2014, December 6, 2014 12 adults 89% Biverkningar av CD19 CAR B cells aplasi Observerat hos alla patienter med respons Immunglobulin behandling Tumör lys syndrom (TLS) Många cancerceller dör snabbt vilket kan ge allvarlig njurpåverkan Cytokine release syndrome (CRS) reversibelt Svårighetsgrad relaterad till tumörbörda Påverkan på nervsystemet Signifikant konfusion och afasi (svårt att prata) Händer endast hos ett fåtal patienter 29 30 TACK! Karolinska, Solna Karolinska, Huddinge 31