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