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Tumor Immunotherapy
Slides kindly provide by Prof. Chatchai Tayapiwatana, CMU
RituximabAnti-CD20
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GENERACIÓ DE LA VACUNA
Extracció d’una mostra de sang per a l’obtenció de DCs
Aïllament dels monòcits i diferenciació ex vivo a DCs
Virus autòlegs obtinguts per plasmafèresis
Pulsing dels virus i les DCs aulòlegs
Obtenció de la vacuna terapèutica
Dendritic cells
Autologous virus Inactivation
Lymphopheresis Culture
Autologous vaccine
GENERACIÓ DE LA VACUNA
Extracció d’una mostra de sang per a l’obtenció
de DCs
Aïllament dels monòcits i diferenciació ex vivo a DCs
Virus autòlegs obtinguts per plasmafèresis
Pulsing dels virus i les DCs aulòlegs
Obtenció de la vacuna terapèutica
Monocytes
Immunization
Inactivated virus
?
Development of Tumor Vaccines
Types of Tumor Vaccines
Strategies for enhancing immune responses to tumors
Immunotherapy w/ Cytokine Gene-Transfected Tumor Cells
Systemic Cytokine Therapy for Tumors
Adoptive Cellular Therapy
Ex vivo activate CTLs or NK cells
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CAR-T-cell Immunotherapy
Chimeric antigen receptor
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Chimeric antigenreceptors(CARs)
oCARs areengineeredreceptorsonimmuneeffectcell.
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http://www.discoverymedicine.com/Michael-S-gee/files/2014/11/discovery_medicine_no_fhtml?id=2|attachment_5
Chimeric antigen receptor (CAR)
Antigen binding componentExpressed on outside of cell;This can be part of an antibody, or other moleculeusually binds HIV envelope on infected cellsHLA independent;
Signaling ComponentSends signal into the cellDirects the cell to kill HIV infected target
CD3ζ
BindsViral protein
enhance antigen recognition and cellular activation
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Engineered NK cells with “Chimeric antigen receptors” (CAR)
Chimeric antigenreceptors(CARs)
o AdoptiveTcellstherapygeneticallymodifiedfortargetedcytotoxic
cellkillingholdsconsiderablepromiseandfortreatmentoftumorcells
orchronicviralinfections.
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Targetedcell-killingstrategies
toachievedbyadoptivetransferofautologous CD8Tcellsgenetically
modifiedtoexpressaCARrecognizinganintactsurfaceantigen
preferentiallyexpressedonthesurfaceoftargetcells.
3. Infuse the "boosted" T-cells into
the patient.
Overview: Adoptive T cell therapy
1. Isolation of TILs or tumor specific T-cells
from blood
2. Expand and activate T-cells ex vivo
Target therapy with Tumor specific T cells
Cancer: MelanomaAutologous tumor infiltrating lymphocytes (TILs); “Live drug”
AdvantagesHigh response rate (>50%), Long-term remission, Less toxic & gentler to the patient
Limitation: Extraction of TILs, Cell manufacturing
Possible alternateT cell Engineering (CAR-T cells)
Rosenberg SA & Dudley ME 2009 Current Opinion of Immunology
Adoptive T cell therapy: CAR-T cells
Antigen specific domain
CAR-T cells (Chimeric antigen receptor-T cells0
T cells transduced with tumor-specific CARCAR: Single fusion molecule with antigen specificity plus signaling domainThree types of CAR: First/second/generations
Based on co-stimulatory receptorsCancer: Solid tumor & hematological malignancies
Maus M V et al. Blood 2014;123:2625-2635
“Live drug”
Tumor recognition independent of HLA
(no HLA typing needed)
Multiple anti-tumor immuno-modulators can be engineered
Target variety of antigens (protein,
carbohydrate, glycolipid)
Advantages of CAR T cells
Clinical significance of CAR-T cells
Target CAR Cancer Objective response
CD19 CAR:CD28-CD3ζ Lymphoma and CLL
N=7: 1CR, 5 PR & 1SD
CAR:CD137-CD3ζ ALL 2CRCAR:CD28-CD3ζ ALL 5CR
CD20 CAR:CD137-CD28-CD3ζ
NHL N=3: 1PR, 2NED
CEA CAR-CD3ζ (1st gen) Colorectal & breast
N=7: minor responses in two patients
GD2 CAR-CD3ζ (1st gen) Neuroblastoma
N=19: 3CR
ERBB2 CAR:CD28-CD137-CD3ζ
Colorectalcancer
N=1, patient died
Kershaw et. al. 2013 Nature Reviews cancer
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