T-cell–mediated immune response

advertisement
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
Download
Random flashcards
Ölplugg

1 Cards oauth2_google_ed8be09c-94f0-4e6a-8e55-87a3b14a45db

Svenska

105 Cards Anton Piter

organsik kemi

5 Cards oauth2_google_80bad7b3-612c-4f00-b9d5-910c3f3fc9ce

Multiplacation table

156 Cards Антон piter

Create flashcards