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
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Immunologi Från det latinska ordet immunis som betyder undantagen 3
Immunsystemets fyra hörnstenar Specifikt Selektivt Adaptivt Minne 4
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Immunförsvarets uppdelning Immunitet Ospecifika Immunförs varet Antigenpresenterande celler, makrofager, neutrofila NKcell Eosinofila, Mastceller Fysiska barriärer Specifika försvaret T-cell B-cell 6
T-cellerna är immunförvarets regering och elittrupp 7
Hur T-celler dödar 8
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Antikroppar mot cancer 10
Tumor-specific antigens T-cell mediated immune response dendritic cell Antitumor effector mechanisms 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... Antigen Hämning PD-1 Activated cytotoxic T cell PD-L1 PD-L2 Tumor cell Inactivated cytotoxic T cell PD-1 PD-L2 PD-L1 Tumor cell 13
Antikroppar kan aktivera T-celler mot cancer Hämning Aktivering Blockerande antikropp PD-1 Inactivated cytotoxic T cell PD-L2 Tumör cell PD-L1 Activated cytotoxic T cell PD-1 PD-L2 PD-L1 Tumör cell 12 14
PD-1-hämmare i kombination med cytostatika mot lungcancer PFS Langer et al, Lancet Oncology, 2016 15
Change From Baseline Cumulative Event Rate, % Resultat vid Hodgkin lymfom 100 100 80 90 60 40 20 0-20 -40-60 192 (93%) patients had a reduction in tumor size 80 70 60 50 40 30 20 10-80 -100 0 0 3 6 9 12 15 Months n at risk 145 89 31 1 0 0 Median number of treatment cycles: 13 (range,1-21) Treatment is ongoing in 120 (57%) patients Median (range) time to response: 2.8 (2.1-8.8) months Response duration 6 months: 75.6% Median follow-up: 10.1 (1.0-15.0) months Data cutoff: September 25, 2016
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
Probability Upenn: Overall Survival after CD19 CAR Overall Survival infusion in patients with ALL 1.0 0.8 6 month OS: 78% (95% CI: 64,95) 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, 5 adults 100% March 21, 2013 Grupp, New Engl J Med, 2 children 100 % April 18, 2013 Davila, Sci Transl Med, 16 adults 88% February 19, 2014 Lee, Lancet, 20 children 70% AOL, October 13, 2014 Maude, N Engl J Med, 25 children, 90% October 16, 2014 5 adults 100% Park, ASH 2014, 27 adults 89% December 6, 2014 Frey, ASH 2014, 12 adults 89% December 6, 2014
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
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TACK! Karolinska, Solna Karolinska, Huddinge 31