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IN The Name of GodIN The Name of God

ImmunotheraImmunotherapypy

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TitlesTitles

IntroductionIntroductionImmunomodulatorsImmunomodulatorsAntibodiesAntibodiesImmunoconjugatesImmunoconjugatesCellular Strategies Cellular Strategies

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introductionintroduction

DefinitionDefinition: use of cells, : use of cells, molecules, and genes of the molecules, and genes of the immune system for the therapy of immune system for the therapy of infectious disease, autoimmunity, infectious disease, autoimmunity, neoplastic disease, and GVHD neoplastic disease, and GVHD

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Passive Passive immunotherapyimmunotherapy: : involving antibodies, cells, and involving antibodies, cells, and immunocojucatesimmunocojucates

Active immunotherapyActive immunotherapy: involving : involving mobilization of the immune mobilization of the immune system by the administration of system by the administration of vaccines or immunomodulatores vaccines or immunomodulatores which increase immunogenicity of which increase immunogenicity of antigenantigen

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IMMUNOMODULATORSIMMUNOMODULATORS

Intact microbesIntact microbesThymic hormones and Thymic hormones and

analogs analogs Cytokines Cytokines Soluble Co-stimulatory Soluble Co-stimulatory

molecules molecules

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Intact MicrobesIntact Microbes

BCG and Corynehbacterium BCG and Corynehbacterium parvumparvum

Streptococcus pyogenes and Streptococcus pyogenes and Propionibacterium avidumPropionibacterium avidum

Other Immunostimulatory Other Immunostimulatory Bacterial AgentsBacterial Agents

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BCG and Corynebacterium BCG and Corynebacterium parvumparvum

Mechanism of action: Mechanism of action: Enhance uptake of antigen by Enhance uptake of antigen by

APC and MQAPC and MQUp regulation co-stimulatorUp regulation co-stimulatorPresentation of peptide to T cellPresentation of peptide to T cellStimulation CTLs and Ths Stimulation CTLs and Ths

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Applications in cancerApplications in cancer

Atteneuated vaccine BCG and heat-Atteneuated vaccine BCG and heat-killed or killed or formalin-inactivatedformalin-inactivated coryne coryne bacterium parvumbacterium parvum

BCG may effects in bladder cancer. BCG may effects in bladder cancer. Enhance lymphocyte and ILs Enhance lymphocyte and ILs

BCG in developed gastro carcinoma BCG in developed gastro carcinoma is effective with chemotherapyis effective with chemotherapy

Recombinant BCG for secretion Recombinant BCG for secretion IL-IL-2,IFN2,IFN, GM CSF. Enhance , GM CSF. Enhance immune responseimmune response

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Streptococus pyogene and Streptococus pyogene and Propionibacterium avidumPropionibacterium avidum

Mechanism of action: Mechanism of action:

Picibanil a lyophilized prepation of Picibanil a lyophilized prepation of inactivated S. P that enhance inactivated S. P that enhance nonspecific T cell cytotoxicity , nonspecific T cell cytotoxicity , LAK activity, and MQ activation LAK activity, and MQ activation

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Other Immunostimulatory Other Immunostimulatory Bacterial AgentsBacterial Agents

Bacterial Derivatives:Bacterial Derivatives:Muramyldipeptid DerivativesMuramyldipeptid DerivativesTrehalose Dimycolate DerivativesTrehalose Dimycolate DerivativesBacterial DNA Fractions:Bacterial DNA Fractions:CpG MotifCpG Motif

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Muramyldipeptid DerivativesMuramyldipeptid Derivatives

Is the major active Is the major active immunomodulatory of immunomodulatory of bacterial cell walls essential bacterial cell walls essential for the mycobacterial for the mycobacterial immunomodulatory activity immunomodulatory activity

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Mechanism of actionMechanism of action

Ligand for TLR 4 and TLR 2 Ligand for TLR 4 and TLR 2 on DCs and MQ that lead to on DCs and MQ that lead to activation of innate immune activation of innate immune systemsystem

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Applications in Cancer and Other Applications in Cancer and Other diseasesdiseases

Synthetic MDP analogs Synthetic MDP analogs caused nonspecific resistance caused nonspecific resistance against HIV, influenza, herpes against HIV, influenza, herpes simplex, vaccinasimplex, vaccina

Synthetic MDP analogs are Synthetic MDP analogs are potent inducer of IL-2, IL-6, potent inducer of IL-2, IL-6, TNFTNF, and IFN, and IFN

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Trehalose Dimycolate DerivativesTrehalose Dimycolate Derivatives

Mechanism of action:Mechanism of action: stimulate stimulate resistant of host to infections with resistant of host to infections with bacteria, viruses, and parasites.bacteria, viruses, and parasites.

Application in cancer:Application in cancer: mycolic acids mycolic acids and their derivatives can mobilize and their derivatives can mobilize the immune response against the immune response against weakly immunogenic tumors weakly immunogenic tumors

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Bacterial DNA FractionsBacterial DNA Fractions

Bind to TLR-9 and caused Bind to TLR-9 and caused antitumor activation that depend antitumor activation that depend to activation of NKCto activation of NKC

Exclusively are found in bacterial Exclusively are found in bacterial DNADNA

Nonmethylated CpG motif Nonmethylated CpG motif stimulate production of IgG stimulate production of IgG

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Mechanism of ActionMechanism of Action

Have effects indirect and direct on Have effects indirect and direct on both adaptive and native both adaptive and native responsesresponses

Increase cytotoxicity activation of Increase cytotoxicity activation of NKCNKC

Mitogenic for B and T cellMitogenic for B and T cellInduce secretion IL-12, IFNInduce secretion IL-12, IFN, and , and

TNFTNF from Th1 from Th1

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Application in Cancer and other Application in Cancer and other diseasesdiseases

As adjuvant or a partial of DNA As adjuvant or a partial of DNA vaccine vaccine

DNA CpG stimulate immune response DNA CpG stimulate immune response against hepatit B, HIV-1, influenza, against hepatit B, HIV-1, influenza, malaria, leishmaniasis, listeria malaria, leishmaniasis, listeria monocytogenesmonocytogenes

CpG can promote development of CpG can promote development of autoimmune when adjuvant for self autoimmune when adjuvant for self antigen antigen

For melanoma and ranal carcinomaFor melanoma and ranal carcinoma

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Thymic Hormones and Thymic Hormones and AnalogsAnalogs

Include:Include: thymopoietin, thmulin, thymic thymopoietin, thmulin, thymic homoral factor, and thymosin homoral factor, and thymosin

Application:Application: are used as immunostimulatory are used as immunostimulatory therapy for infectious diseases that induce therapy for infectious diseases that induce the expression of differentiation markers on the expression of differentiation markers on T cells and can modulate T-cell prolifration T cells and can modulate T-cell prolifration

And enhance function of Th cells and CTLsAnd enhance function of Th cells and CTLsAnalog:Analog: Methylinosine monophosphat Methylinosine monophosphat

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Cytokines and cancer Cytokines and cancer therapytherapy

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IL-2IL-2 IL-2 have antitumor activateIL-2 have antitumor activate20% patients with renal carcinoma is 20% patients with renal carcinoma is

improvedimprovedMixed of recombinant IL-2 and IFN-Mixed of recombinant IL-2 and IFN- have have

better response better response Use of rIL-2 as adjuvant therapy in DC-Use of rIL-2 as adjuvant therapy in DC-

based vaccinesbased vaccines IL-2 activated LAK cellIL-2 activated LAK cell

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IFN-IFN-

Have more effect in treat of hairy cell Have more effect in treat of hairy cell leukemia, lymphoma, and chronic leukemia, lymphoma, and chronic myelogenous leukemiamyelogenous leukemia

IFN-IFN- inhibite cell growth by inducing inhibite cell growth by inducing G1 arrestG1 arrest

IFN-IFN- has prolonged the survival of has prolonged the survival of patients with renal carcinoma patients with renal carcinoma

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IFN-IFN-Have ability to augment the cytotoxic Have ability to augment the cytotoxic

activity of CTLs and NK cellsactivity of CTLs and NK cells Increase the expression of MHC on Increase the expression of MHC on

various cellsvarious cellsHas been used in patients with Has been used in patients with

metastatic renal cell cancermetastatic renal cell cancerAnd 15% patients with colorectal And 15% patients with colorectal

cancercancer

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TNF-TNF-

In combination with cytotoxic In combination with cytotoxic drugs drugs

Give encouraging results in Give encouraging results in metastatic melanoma, soft metastatic melanoma, soft tissue sarcoma, and tissue sarcoma, and metastatic colorectal cancer metastatic colorectal cancer

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Therapy of Other DiseasesTherapy of Other Diseases

Cytokines represent an effective strategy for Cytokines represent an effective strategy for treating infectious disease, acute or chronic treating infectious disease, acute or chronic inflamation and in angiogenesisinflamation and in angiogenesis

FGF, IFN-FGF, IFN-, IL-10, IL-11, and IL-12,VEGF, and , IL-10, IL-11, and IL-12,VEGF, and GM-CSF, (rh)IL-11 has been evaluated in GM-CSF, (rh)IL-11 has been evaluated in patients with active rheumattoid arthritispatients with active rheumattoid arthritis

Anti-inflamatory cytokines (IL-10) and Anti-inflamatory cytokines (IL-10) and cytokines that inhibit Th2 cells (IL-12 and cytokines that inhibit Th2 cells (IL-12 and IFN-IFN-) have been used in the treatment of ) have been used in the treatment of asthma and allergyasthma and allergy

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VEGF: repair of ischemic VEGF: repair of ischemic myocardiamyocardia

FGF: healing of second-FGF: healing of second-degree burnsdegree burns

rGM-CSF : has been used rGM-CSF : has been used successfully to heal successfully to heal cutaneous wounds and ulcers cutaneous wounds and ulcers

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Cytokine receptorsCytokine receptors

Effective in inflammation Effective in inflammation diseasesdiseases

Soluble cytokine receptors Soluble cytokine receptors participate in the control of participate in the control of cytokine activitycytokine activity

By inhibiting the ability of By inhibiting the ability of cytokines to bind to their cytokines to bind to their receptor receptor

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Soluble Co-Stimulatory Soluble Co-Stimulatory MoleculesMolecules

CTLA-4, CD28, B7.1, B7.2, CTLA-4, CD28, B7.1, B7.2, and CD40L require to and CD40L require to activation of immune cellsactivation of immune cells

Strategies to inhibit these Strategies to inhibit these interaction to prevent interaction to prevent autoimmunity and graft autoimmunity and graft rejection rejection

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CD152CD152

CD152 interact CD28 on T-CellsCD152 interact CD28 on T-CellsCD152-Ig binds to CD80 and CD86 and CD152-Ig binds to CD80 and CD86 and

thereby inhibit interaction between thereby inhibit interaction between APCs and T cellsAPCs and T cells

This lead to suppression of both This lead to suppression of both cellular and humoral immune cellular and humoral immune responsesresponses

Anti CD40L:Anti CD40L: can inhibit interaction can inhibit interaction between T cell and B cell or APCsbetween T cell and B cell or APCs

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AntibodiesAntibodies

HistoryHistoryClinical ConsiderationsClinical ConsiderationsAffinityAffinityPersistence and SizePersistence and SizeEffector FunctionsEffector Functions ImmunogenicityImmunogenicity

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HistoryHistory

Used polyclonal antibodies in Used polyclonal antibodies in pastpast

mAbs first are used in 1975mAbs first are used in 1975mAbs with low immunogenicity mAbs with low immunogenicity

are obtain by production of are obtain by production of chimeric and humanized mAb chimeric and humanized mAb with recombinant DNA with recombinant DNA technology in (1986)technology in (1986)

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Clinical ConsiderationsClinical Considerations

IgG is preferred isotype for IgG is preferred isotype for therapeutic human mAbtherapeutic human mAb

Because: 1- low molecular weith Because: 1- low molecular weith mm 2- more 2- more resistant resistant nn 3- 3- easy to preparationeasy to preparation

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AffinityAffinity

One theory postulate that high One theory postulate that high affinity mAbs cannot penetrate affinity mAbs cannot penetrate deeply into the tumors deeply into the tumors

another theory postulate that another theory postulate that most effective tumor targeting is most effective tumor targeting is achieve using high affinity mAbs achieve using high affinity mAbs

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Persistence and SizePersistence and Size

Persistence of IgG in circulation:1- Persistence of IgG in circulation:1- their molecular size 2- their ability to their molecular size 2- their ability to interact with the FcRn by Fcinteract with the FcRn by Fc

mAb without Fc can better mAb without Fc can better penetration to tumor but have penetration to tumor but have decreased half lifedecreased half life

Mouse mAbs rapidly remove from Mouse mAbs rapidly remove from human circulation because human human circulation because human FcR can not bind to murine mAbsFcR can not bind to murine mAbs

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Effector functionsEffector functions

IgG1 is the best selection for IgG1 is the best selection for recruiting effector cells and recruiting effector cells and activation of MQactivation of MQ

ADCC is a more general mechanism ADCC is a more general mechanism of lysis of nucleated cells than CDC of lysis of nucleated cells than CDC

Because is down regulated by the Because is down regulated by the presence of regulatory proteins presence of regulatory proteins (CD59)(CD59)

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Immunogenicityy

The major impediment to therapy The major impediment to therapy with mouse mAbs is that patients with mouse mAbs is that patients rapidly develop human antimouse rapidly develop human antimouse antibody (HAMA)antibody (HAMA)

HAMA: 1- anti isotype 2- anti HAMA: 1- anti isotype 2- anti idiotypeidiotype

Fc region is more immunogenic Fc region is more immunogenic than Fv regionthan Fv region

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IgG and mAbs in Clinical IgG and mAbs in Clinical praticepratice

The FDA has approved th use of IVIG The FDA has approved th use of IVIG in three clinical situation:in three clinical situation:

(a) replacement therapy for (a) replacement therapy for immunodeficiencies:Brutons X-Linkedimmunodeficiencies:Brutons X-Linked

(b) prevention and treatment of (b) prevention and treatment of infectious diseases: against a wide infectious diseases: against a wide variety of bacterial and viral diseasesvariety of bacterial and viral diseases

(c) therapy of autoimmune disorder: (c) therapy of autoimmune disorder: myasthenia gravismyasthenia gravis

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Monoclonal AntibodyMonoclonal Antibody

First mAb to treat cancer isFirst mAb to treat cancer is Rituximab Rituximab in in 1997: a chimeric IgG1 anti human CD20 for 1997: a chimeric IgG1 anti human CD20 for B cell lymphmaB cell lymphma

another mAb is another mAb is epratuzumabepratuzumab : a humanized : a humanized IgG1 anti-CD22 antibody for B cell lymphmaIgG1 anti-CD22 antibody for B cell lymphma

Treatment of breast cancer with Treatment of breast cancer with TrastuzumabTrastuzumab

First mAb to be used in non neoplastic First mAb to be used in non neoplastic diseases was diseases was InfliximabInfliximab for Rheumatoid for Rheumatoid Arthritis and Crohns Disease Arthritis and Crohns Disease

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Bispecific Monoclonal Anti Bispecific Monoclonal Anti bodybody

Have two arm: one arm recognize Have two arm: one arm recognize target cell and another arm target cell and another arm recognize effector cell or toxic recognize effector cell or toxic molecules molecules

BsmAb are used for deliver cytotoxic BsmAb are used for deliver cytotoxic drug or toxin to cancer celldrug or toxin to cancer cell

These toxins such as saporin, Ricin, These toxins such as saporin, Ricin, vinca alkaloidvinca alkaloid

T cell Tumorcell

CD3

Ag

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ImmunoconjugatesImmunoconjugates

ImmunotoxinsImmunotoxinsChemoconjucatesChemoconjucatesAntibody-Directed Enzyme Prodrug Antibody-Directed Enzyme Prodrug

TherapyTherapyRadioimmunoconjugatesRadioimmunoconjugates ImmunoliposomesImmunoliposomesOther Emerging Immunoconjugate Other Emerging Immunoconjugate

StrategiesStrategies

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ImmunotoxinsImmunotoxins

mAbs bind to powerful toxin that mAbs bind to powerful toxin that purified from plants, fungi, or purified from plants, fungi, or bacteriabacteria

After binding to the target the toxic After binding to the target the toxic must be internalizedmust be internalized

For example RIP (ribosome For example RIP (ribosome inactivating protein) binds to 60S inactivating protein) binds to 60S subunit of ribosome and cleave 28S subunit of ribosome and cleave 28S rRNA rRNA

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ChemoconjucatesChemoconjucates

mAbs bind to conventional cytotoxic drugsmAbs bind to conventional cytotoxic drugsThe first chemocojucate was obtain by The first chemocojucate was obtain by

binding chlorambucil to Igbinding chlorambucil to IgChemotherapy agents such asChemotherapy agents such as doxorubicin doxorubicin, ,

indarubicinindarubicin,, methotroxate methotroxate, , mytomycinmytomycin, and , and et al conjugate with several mAbset al conjugate with several mAbs

Clinical application: 1- enhance absorption Clinical application: 1- enhance absorption of drugs 2- decrease cytotoxic to normal of drugs 2- decrease cytotoxic to normal cells 3- prolong available drug to tumor cellscells 3- prolong available drug to tumor cells

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ADEPTADEPT

Use of mAb-enzyme conjucated Use of mAb-enzyme conjucated directed against tumor associated directed against tumor associated antigenantigen

Bind to tumor cellBind to tumor cell Injection prodrug into patients Injection prodrug into patients Prodrug convert to drug by enzyme Prodrug convert to drug by enzyme Effect to tumor cellEffect to tumor cell

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RadioimmunoconjucatesRadioimmunoconjucates

Obtained by coupling mAbs to radionuclideObtained by coupling mAbs to radionuclideTumor cell killing occurs by the ionizing Tumor cell killing occurs by the ionizing

effects of emitted radioactive particleseffects of emitted radioactive particlesAmount of radioactive mAb delivered to a Amount of radioactive mAb delivered to a

tumor can be measured by imagingtumor can be measured by imagingSeveral radionuclides have been used Several radionuclides have been used

(a) beta-emitter (rhenium-188) (a) beta-emitter (rhenium-188) (b) alfa-emitter (astatine-211) (b) alfa-emitter (astatine-211) (c) electron capture radionuclies (iodine-(c) electron capture radionuclies (iodine-125) 125)

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ImmunoliposomesImmunoliposomes

Lipid vesicules that is uni lamellar and Lipid vesicules that is uni lamellar and multi lamellarmulti lamellar

Conjugate with mAbsConjugate with mAbsCarry vast rang of drug regardless of Carry vast rang of drug regardless of

size and solubility and a much larger size and solubility and a much larger drug per vesicule drug per vesicule

Decrease systemic cytotoxicity of Decrease systemic cytotoxicity of drugsdrugs

Immunolposomes are used for Immunolposomes are used for delivering chemotherapy drugs to delivering chemotherapy drugs to ovarian cancer, and B cell lymphoma ovarian cancer, and B cell lymphoma

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Other Emerging Other Emerging Immunocojugate StrategiesImmunocojugate Strategies

Monoclonal Antibody-Photosensitizer Monoclonal Antibody-Photosensitizer conjugatesconjugates

Monoclonal Antibody-Cytokine Monoclonal Antibody-Cytokine ConjugatesConjugates

Monoclonal Antibody-Super Antigen Monoclonal Antibody-Super Antigen ConjugatesConjugates

Monoclonal Antibody-RNAse Monoclonal Antibody-RNAse ConjugatesConjugates

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Monoclonal Antibody-Monoclonal Antibody-Photosensitizer conjugatesPhotosensitizer conjugates

Photosensitizer is conjugated Photosensitizer is conjugated with mAbswith mAbs

To better targeting of To better targeting of photosensityzer to tumor cellsphotosensityzer to tumor cells

This approach is called antibody- This approach is called antibody- targeted photolysis or targeted photolysis or photoimmunotherapyphotoimmunotherapy

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Monoclonal Antibody-Cytokine Monoclonal Antibody-Cytokine ConjugatesConjugates

Fusion protein that combined Fusion protein that combined targeting ability of mAb with biologic targeting ability of mAb with biologic activations of cytokineactivations of cytokine

They are used for obtained local They are used for obtained local concentration of cytokine concentration of cytokine

For example: IL-2 that are used for For example: IL-2 that are used for recruitment of T cells and induce T recruitment of T cells and induce T cells dependent antitumor responsecells dependent antitumor response

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Monoclonal Antibody-Super Monoclonal Antibody-Super Antigen ConjugatesAntigen Conjugates

Recombinant super antigen Staphylococcs Recombinant super antigen Staphylococcs enterotoxin A (SEA) enterotoxin A (SEA)

That bind only VThat bind only V chain of TCR no MHC chain of TCR no MHCThese hybrid molecule direct responsive T These hybrid molecule direct responsive T

cell into tumor sites and induce responsescell into tumor sites and induce responsesColon carcinoma, chronic B lymphatic Colon carcinoma, chronic B lymphatic

leukemia, and neuroblastoma have been leukemia, and neuroblastoma have been treated with mAB-SEA cojucated in vitro treated with mAB-SEA cojucated in vitro

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Monoclonal Antibody-RNAse Monoclonal Antibody-RNAse ConjugatesConjugates

mAbs coupled with RNAse mAbs coupled with RNAse RNAse inhibit protein synthesis by RNAse inhibit protein synthesis by

degrading ribosomal RNAdegrading ribosomal RNARNAse also degrade tRNA RNAse also degrade tRNA One potential problem in using mAb-One potential problem in using mAb-

RNAse- conjugates therapeutically is RNAse- conjugates therapeutically is the presence of inhibitors in the blood the presence of inhibitors in the blood and tissueand tissue

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Cellular SterategiesCellular Sterategies

Nonspecific Cellular TherapyNonspecific Cellular Therapy

Specific Cellular TransferSpecific Cellular Transfer

Genetically Engineered cellsGenetically Engineered cells

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Nonspecific Cellular TherapyNonspecific Cellular Therapy

Lymphokine-Activated Killer CellsLymphokine-Activated Killer CellsNatural Killer CellsNatural Killer CellsDendritic CellsDendritic CellsMacrophage-Activated Killer Macrophage-Activated Killer

CellsCells

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Lymphokine-Activated Killer CellsLymphokine-Activated Killer Cells

LAK cells are peripheral blood LAK cells are peripheral blood mononuclear cells that have been mononuclear cells that have been expanded ex vivo with IL-2expanded ex vivo with IL-2

May LAK cells enhance activation of MQ May LAK cells enhance activation of MQ

May LAK cells induce release cytokine May LAK cells induce release cytokine such as IFN-such as IFN-, TNF, TNF, and M-CSF , and M-CSF

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Natural Killer CellsNatural Killer Cells

NK cells are important in anti tumor NK cells are important in anti tumor immunity and graft rejection immunity and graft rejection

Because of their ability to target and Because of their ability to target and destroy cells in the body that fail to destroy cells in the body that fail to express of MHCexpress of MHC

Activation of NKC decrease number Activation of NKC decrease number of spontaneous tumors of spontaneous tumors

NKC with IL-2 have anti leukemia NKC with IL-2 have anti leukemia activation activation

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Dendritic CellsDendritic Cells

DCs are powerful APC because DCs are powerful APC because presentation of antigen in MHCpresentation of antigen in MHC and and MHCMHC

Only APCs that activate naïve T cellOnly APCs that activate naïve T cell Invivo DCs are stimulate by Invivo DCs are stimulate by

administration of local adjuvant BCG administration of local adjuvant BCG into tumor siteinto tumor site

DCs as adjuvant and immunotherapy DCs as adjuvant and immunotherapy vaccine vaccine

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Macrophage-Activated Killer Macrophage-Activated Killer CellsCells

TNF-TNF- is thougthto be the major cytokine is thougthto be the major cytokine responsible for MAK cell activityresponsible for MAK cell activity

Attempts have been made to increase Attempts have been made to increase their killing capacity by incubating them their killing capacity by incubating them with IFN-with IFN- and endotoxin and endotoxin

Attempts to increase the specificity of Attempts to increase the specificity of MAK cells by incubating them with tumor MAK cells by incubating them with tumor antigens to enhance antigen presentation antigens to enhance antigen presentation before the cells are reinjected into their before the cells are reinjected into their autologous donors autologous donors

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Specific Cellular TransferSpecific Cellular Transfer

Tumor-Infiltrating Tumor-Infiltrating LymphoctesLymphoctes

Graft-Versus-Leukemia T Graft-Versus-Leukemia T Cells and Graft –versus-Tumor Cells and Graft –versus-Tumor EffectsEffects

Regulatory T CellsRegulatory T Cells

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Tumor-Infiltrating LymphoctesTumor-Infiltrating Lymphoctes

TILs are obtained from tissue tumor TILs are obtained from tissue tumor by enzymatic and mechanical by enzymatic and mechanical digestion of tumor instance digestion of tumor instance

Patients with melanoma and renal cell Patients with melanoma and renal cell carcinoma have benefited from TIL carcinoma have benefited from TIL therapytherapy

In metastatic melanoma a 34% to In metastatic melanoma a 34% to 38% response rate was achieved38% response rate was achieved

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Graft-Versus-Leukemia T Cells and Graft-Versus-Leukemia T Cells and Graft –versus-Tumor EffectsGraft –versus-Tumor Effects

Barnes and associates first Barnes and associates first suggested the existence of a GVL suggested the existence of a GVL effect in 1956effect in 1956

When they noted eradication of When they noted eradication of leukemia in irradiated mice receiving leukemia in irradiated mice receiving allogenic bone marrow transplant allogenic bone marrow transplant

Donor T cells play a major role in GVLDonor T cells play a major role in GVL

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Regulatory T CellsRegulatory T Cells

Peripheral blood T cell with CD25 and Peripheral blood T cell with CD25 and CD4CD4

They arrest in G1/G0 phase of cycle They arrest in G1/G0 phase of cycle cellcell

Not producing IL-2, IL-4, and IFNNot producing IL-2, IL-4, and IFNAnergy of R-T cell are not reversibleAnergy of R-T cell are not reversibleMay these R-T cell have potential for May these R-T cell have potential for

control of autoimmune diseasescontrol of autoimmune diseases

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Genetically Engineered CellsGenetically Engineered Cells

Gene transfer to TIL before their Gene transfer to TIL before their injection to patients with metastatic injection to patients with metastatic melanomamelanoma

Transfected genes is cytokine and Transfected genes is cytokine and otherother

To prevent from systemic toxicity of To prevent from systemic toxicity of administration of high doses cytokine administration of high doses cytokine such as IL-2 and TNFsuch as IL-2 and TNF

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ConclusionsConclusions

There is no shortage of There is no shortage of immunotherapeutic agents or strategies immunotherapeutic agents or strategies that work successfully in micethat work successfully in mice

However translation into humans is However translation into humans is difficult, costly, and not always predictabledifficult, costly, and not always predictable

Furthermore, strategies that are highly Furthermore, strategies that are highly effective in one disease may be a total effective in one disease may be a total failure in anotherfailure in another

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Tanks for your Tanks for your attentionattention