Hadeel alharb

Outlines:

• Cancer immunotherapy

• Monoclonal antibody

• Immunosuppressive drugs :

• I.Selective inhibitors of cytokine production or function:

• II. Inhibitors of cytokine gene expression

• III. Cytotoxic drugs

• IV. Immunosuppressive antibodies

• V. Interferon

• Immunostimulants

• Cytokine-based therapies

WHAT IS IMMUNTHERAPY? • "treatment of disease by inducing,

enhancing, or suppressing an immune response

•Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, 

•while immunotherapies that reduce or suppress are classified as suppression immunotherapies.

1- Activation immunotherapies• Cancer immunotherapy

 - Cell-based therapies : ( Adoptive T-cell therapy, Dendritic

cell therapy)

- Antibody therapies (MONOCLONAL ANTIBODY)

-  cytokine therapies

2- Suppression immunotherapiesI.Selective inhibitors of cytokine production or function:

II. Inhibitors of cytokine gene expression

III. Cytotoxic drugs

IV. Immunosuppressive antibodies

V. Interferon

1 -Monoclonal antibodies • They are monospecific antibodies that are the

same because they are made by identical 

immune cells that are allclones of a unique

parent cell, in contrast to polyclonal antibodies

 which are made from several different immune

cells. Monoclonal antibodies have monovalent

 affinity, in that they bind to the same epitope.

- MAbs can be employed to find a single targeted substance,

such as an antigen on a cancer cell, and make it possible to

pinpoint the cell and destroy it. 

How do monoclonal antibody drugs work ?

1-Make the cancer cell more visible to the immune system.

• The immune system attacks foreign invaders in your body, but it doesn't

always recognize cancer cells as enemies. A monoclonal antibody can be

directed to attach to certain parts of a cancer cell. In this way, the antibody

marks the cancer cell and makes it easier for the immune system to find.

• The monoclonal antibody drug rituximab (Rituxan) attaches to a specific

protein (CD20) found only on B cells, one type of white blood cell. Certain

types of lymphomas arise from these same B cells. When rituximab

attaches to this protein on the B cells, it makes the cells more visible to the

immune system, which can then attack.

How do monoclonal antibody drugs work ? (cont)

2- Block growth signals.

•  Chemicals called growth factors attach to receptors on the

surface of normal cells and cancer cells, signaling the cells to

grow. Certain cancer cells make extra copies of the growth

factor receptor.

• Extra growth factor receptors allow cancer cells to grow faster

than the normal cells. Monoclonal antibodies can block these

receptors and prevent the growth signal from getting through.

• Cetuximab (Erbitux), a monoclonal antibody approved to treat

colon cancer and head and neck cancer

How do monoclonal antibody drugs work? (cont)

3-Stop forming new blood vessels.

•  Cancer cells rely on blood vessels to bring them the oxygen and nutrients they

need to grow. To attract blood vessels, cancer cells send out growth signals.

• Monoclonal antibodies that block these growth signals may help prevent a

tumor from developing a blood supply so that it remains small. Or in the case

of a tumor with an already-established network of blood vessels, blocking the

growth signals could cause the blood vessels to die and the tumor to shrink.

• The monoclonal antibody bevacizumab (Avastin) targets a growth signal called

vascular endothelial growth factor (VEGF) that cancer cells send out to attract

new blood vessels. Bevacizumab intercepts a tumor's VEGF signals and stops

them from connecting with their targets.

.

How do monoclonal antibody drugs?

4- Deliver chemotherapy to cancer cells. 

• By combining chemotherapy drugs with a monoclonal antibody, doctors

can deliver chemotherapy directly to the cancer cells.

• Ado-trastuzumab emtansine (Kadcyla) is one such drug approved to

treat HER2-positive breast cancer. Ado-trastuzumab emtansine contains

an antibody that attaches to the HER2 receptors on the breast cancer

cells. The cancer cells then ingest the antibody, which releases a few

molecules of chemotherapy.

• The chemotherapy only damages the cancer cells, leaving the

surrounding healthy cells undamaged.

• A number of monoclonal antibody drugs are available to treat various

types of cancer. Clinical trials are studying monoclonal antibody drugs

in treating nearly every type of cancer

How do monoclonal antibody drugs work ? (cont)

5- Deliver radiation to cancer cells• By combining a radioactive particle with a monoclonal antibody,

doctors can deliver radiation directly to the cancer cells. This

way, most of the surrounding healthy cells aren't damaged.

• Radiation-linked monoclonal antibodies deliver a low level of

radiation over a longer period of time, which researchers

believe is as effective as the more conventional high-dose

external beam radiation.

• Ibritumomab (Zevalin), approved for non-Hodgkin's lymphoma

How do monoclonal antibody drugs work ? (cont)

6-Antibody-directed enzyme prodrug therapy (ADEPT) involves the application of cancer associated monoclonal antibodies which are linked to a drug-activating enzyme.

• Subsequent systemic administration of a non-toxic agent results in its conversion to a toxic drug, and resulting in a cytotoxic effect which can be targeted at malignant cells.

• The clinical success of ADEPT treatments has been limited to date. However it holds great promise, and recent reports suggest that it will have a role in future oncological treatment

How do monoclonal antibody drugs work ? (cont)

Targeted Conditions in cancer treatment Cont.

6- Antibody-directed enzyme prodrug therapy (ADEPT) cont .

How do monoclonal antibody drugs work ? (cont)

It’s also possible to design bi-specific antibodies that can bind with their Fab regions both to target antigen and to a conjugate or effecter cell. In fact, every intact antibody can bind to cell receptors or other proteins with its Fc region.

Other Therapeutic Uses for MAB:• To suppress the immune system

Omalizumab (Xolair®). Binds to IgE thus preventing IgE from binding to mast cells. Shows promise against allergic asthma.-Lymphocyte depleting antibodies :• Alemtuzumab• treatment of B-cell chronic lymphocytic leukaemia,

immunoprophylaxis for renal transplants, GVHD, multiple sclerosis, rheumatoid arthritis

• Rituximab-treatment of B-cell non-Hodgkin's lymphomaantibody-mediated transplant rejection, SLE, vasculitis

• Anti-CD3 (OKT3) and two humanized anti-CD3 monoclonals. Bind to the CD3 molecule on the surface of T cells. Used to prevent acute rejection of organ, e.g., kidney, transplants. The humanized versions show promise in inhibiting the autoimmune destruction of beta cells in Type diabetes mellitus.

• For example ( muromonab-CD3 to treat transplant rejection.)

Other Therapeutic Uses for MAB:-Non-depleting antibodies and fusion

proteins :• Basiliximab and Daclizumab• prevention of allograft rejection in transplant

patients

-Tumour necrosis factor inhibitors• Infliximab and Adalimumab•rheumatoid arthritis, ankylosing

spondylitis, psoriatic arthritis, Crohn's disease

2-Adoptive T Cell Therapy

• Adoptive T cell therapy involves the isolation and ex vivo expansion of tumor specific T cells to achieve greater number of T cells than what could be obtained by vaccination alone.

• The tumor specific T cells are then infused into patients with cancer in an attempt to give their immune system the ability to overwhelm remaining tumor via T cells which can attack and kill cancer.

• There are many forms of adoptive T cell therapy being used for cancer treatment

2-Adoptive T Cell Therapy (cont.)

• culturing tumor infiltrating lymphocytes or TIL, isolating and

expanding one particular T cell or clone, and even using T cells that

have been engineered to potently recognize and attack tumors.

• Our approach has been to utilize T cells taken directly from the

patient’s blood after they have received a cancer vaccine. We have

found by “priming” rare tumor antigen specific T cells first, with

active immunization

• we are much more able to expand those T cells in the laboratory to

greater numbers for therapeutic infusion

2-Adoptive T Cell Therapy (cont.)

3-Dendritic Cell Vaccines• Dendritic cell vaccines are autologous vaccines (made from the

person in whom they will be used), and must be made individually for

each patient.

• The process used to create them is complex and expensive.

• Doctors remove some immune cells from the blood and expose them

in the lab to cancer cells or cancer antigens, as well as to other

chemicals that turn them into dendritic cells and help them grow. The

dendritic cells are then injected back into the patient, where they

should provoke an immune response to cancer cells in the body.

• Sipuleucel-T (Provenge), which is used to treat advanced prostate

cancer, is an example of a dendritic cell vaccine.

3-Dendritic Cell Vaccines (cont.)

Immunosuppressant agents

• I. Selective inhibitors of cytokine production or function:• 1) Calcineurin inhibitors • Cyclosporine• Tacrolimus (FK506)• 2) Sirolimus (rapamycin).

• II. Inhibitors of cytokine gene expression • Corticosteroids (Prednisone, Prednisolone, Methylprednisolone,

Dexamethasone) • III. Cytotoxic drugs iii.a Inhibitors of purine or pyrimidine synthesis (Antimetabolites):• (Azathioprine,Myclophenolate Mofetil, Leflunomide,Methotrexate)iii.B Alkylating agents:• Cyclophosphamide • IV. Immunosuppressive antibodies • that block T cell surface molecules involved in signaling

immunoglobulins• antilymphocyte globulins (ALG).• antithymocyte globulins (ATG).• Rho (D) immunoglobulin, Basiliximab,Daclizumab,Muromonab-CD3• V. Interferon

Immunosuppressant agents

Immunosuppressant agents I. Selective inhibitors of cytokine production or function cont

.

• IL-2 cytokine, a growth factor that stimulates the

proliferation of antigen-primed (helper) T cells, which subsequently produce more IL-2, IFNɣ, and TNFα. These cytokines collectively activate natural killer cells, macrophages, and cytotoxic T lymphocytes.

• Drugs that interfere with the production of IL-2, such as cyclosporine, and Tacrolimus (FK506) are also known as calcineurin inhibitors .

• Example of drugs that inhibit IL-2 action  is sirolimus (rapamycin)

I. Selective inhibitors of cytokine production or function cont

1) Calcineurin inhibitors (Cyclosporine )• Mechanism of action:• preferentially suppresses cell-mediated immune reactions, whereas

humoral immunity is affected to a far lesser extent.• Inhibits interleukin-2 production (IL-2) blocking activation of T

cells.• It also decreases proliferation and differentiation of T cells.• After diffusing into the T cell, CsA binds to cytosolic protein known

as cyclophilin (immunophilin) that acts as CsA intracellular receptors. Cyclosporine-immunophilin complex inhibits calcineurin,  a

phosphatase necessary for dephosphorylation of transcription factor  NFATc (cytosolic Nuclear Factor of Activated T cells). required for interleukins synthesis (IL-2).

NFATc  suppresses cell-mediated immunity

1 .Cyclosporine (CsA) cont.Mechanism of action cont.

I. Selective inhibitors of cytokine production or function (cont )

a. Cyclosporine (CsA) cont.•Therapeutic Uses:(CsA is used to prevent rejection of kidney, liver, and

cardiac allogeneic transplants and treatment autoimmune disorders like severe, active rheumatoid arthritis, and recalcitrant psoriasis that does not respond to other therapies.

Adverse Effects:  •Nephrotoxicity.

I. Selective inhibitors of cytokine production or function (cont )

b)Tacrolimus

• Mechanism of action:• TAC exerts its immunosuppressive effect in the same mechanism as CsA,

except that it binds to a different immunophilin protein , FKBP-12 (FK506-binding protein-12) creating a new complex (tacrolimus- FKBP12

complex) that inhibits calcineurin.•  Therapeutic Uses:• As cyclosporine 

• Adverse Effects:  • • Nephrotoxicity (more than CsA).

2 .Sirolimus (Rapamycin)

• Mechanism of action:• Sirolimus is to bind the cytosolic protein FKBP12 (in a manner

similar to tacrolimus), but instead of inhibition of calcineurin, Sirolimus-FKBP12 complex inhibits the mammalian target of rapamycin1 (mTOR).

• mTOR is a serine-threonine kinase that is essential for many cellular functions, such as cell-cycle progression, DNA repair, and  regulation of protein translation

• Binding of Sirolimus-FKBP12 complex to mTOR blocks the activated T -cells proliferation, B cell proliferation & immunoglobulin production.

• Unlike CsA and TAC, SRL does not owe its effect to lowering IL-2 production but, rather, to inhibiting the cellular responses to IL-2.

I. Selective inhibitors of cytokine production or function (cont )

Immunosuppressant agentsII. Inhibitors of cytokine gene expression:

Corticosteroids:

- The corticosteroids were the first pharmacologic agents to be used as immunosuppressives

both in transplantation and in various autoimmune disorders.

-They have both anti-inflammatory action and immunosuppressant effects.

-They are still one of the mainstays for attenuating rejection episodes .

-The most common agents are Prednisone, prednisolone, methylprednisolone, and

dexamethasone.

-Corticosteroids are first line therapy in transplantation to attenuating rejection episodes.

-They also used in autoimmune diseases as rheumatoid arthritis, systemic lupus

erythematosus and asthma.

Immunosuppressant agentsII. Inhibitors of cytokine gene expression: (cont)

Corticosteroids:

--On entering cells, they bind to the glucocorticoid receptor (GR) and then

glucocorticoid-GR complex translocates into the nucleus and interacts with DNA to

regulates the gene transcription of cytokines.

-formation of a protein that inhibits the enzyme phospholipase A2 which is needed

to allow the supply of arachidonic acid. Latter is essential for the formation of

inflammatory mediators• - Decrease production of cytokines IL-1, IL-2, interferon, TNF.• Stabilize lysosomal membranes.• Decrease generation of IgG, nitric oxide and histamine.• Inhibit antigen processing by macrophages.• Suppress T-cell helper function • Decrease T lymphocyte proliferation.

-The main adverse effects of GC are hyperglycemia, osteoporosis and

adrenal suppression.

Immunosuppressant agentsII. Inhibitors of cytokine gene expression:

(cont)

Immunosuppressant agentsIII. Cytotoxic drugs:

Alkylating agents:

- Cyclophosphamide is the most common cytotoxic agent which

acts by alkylation of the DNA and it is widely used as anticancer

in neoplastic diseases and immunosuppressant in autoimmune

disorders.

-Cyclophosphamide is a prodrug that is undergo some

modification in the liver to form the active compounds,

phosphoramide mustard and acrolein.

-Phosphoramide mustard reaction with DNA is considered to be

the cytotoxic step especialy to those rapidly deviding cells like

neoplastic and germ cells.

- Acrolein excreted in the urine but it can lead to fibrosis of the

bladder due to its toxicity in condition known as (Hemorrhagic

cystitis).

Immunosuppressant agentsIII. Cytotoxic drugs

Inhibitors of purine or pyrimidine synthesis (Antimetabolites):

1 -Azathioprine:

-It was the first agent used in organ transplantation as

immunosuppresive which is due to its nucleotide analog structure.

- Because of their rapid proliferation in the immune response,

lymphocytes (B &T) are predominantly affected by the cytotoxic

effects of azathioprine.

- Azathioprine Inhibits de novo synthesis of purines required for

lymphocytes proliferation.

-It used to prevent organ rejection following organ transplantation

and to treat a vast array of autoimmune diseases. 

Immunosuppressant agentsIII. Cytotoxic drugs

Inhibitors of purine or pyrimidine synthesis (Antimetabolites):

2 -Mycophenolates:

-Both Mycophenolate mofetil (MMF) and mycophenolate sodium (MPS) are

semisynthetic derivative of mycophenolic acid from fungus source.

- Both are prodrugs that are rapidly hydrolyzed in the gastrointestinal tract

to mycophenolic acid (MPA) which Inhibits de novo synthesis of purines.

-They are used in organ transplantation and in steroid-refractory

hematopoietic stem cell transplantation.

-They have a higher risk of CMV infection .

Immunosuppressant agentsIII. Cytotoxic drugs

Inhibitors of purine or pyrimidine synthesis (Antimetabolites):

3 -Leflunamide:

- It is a synthetic disease-modifying antirheumatic group of drugs-

antimetabolite immunosuppressant (DMARD).

-It acts by inhibiting de novo pyrimidine synthesis and has both

immunosuppressant and anti-inflammatory effects.

- It has been approved for the treatment of rheumatoid arthritis or psoriatic

arthritis .

- It slows the progression of the disease and  relief  the associated symptoms

such as joint tenderness and decreased joint and general mobility in patients.

-It is a teratogenic agent for both women and men and they should not have

babies before 2 years after termination of therapy have elapsed.

Immunosuppressant agentsIII. Cytotoxic drugs

Inhibitors of purine or pyrimidine synthesis (Antimetabolites):

4 -Methotrexate:

-MTX is synthetic antimetabolite used mainly in treatment of cancer, and

autoimmune diseases

-It acts by inhibiting the metabolism of folic acid. It Inhibits DHFR enzyme

required for folic acid activation (tetrahydrofolic) and as a result Inhibition of

DNA, RNA and protein synthesis occur.

- The main uses of MTX in cancer chemotherapy, autoimmune disorders and

in pregnancy termination (generally in combination with misoprostol).

- Pulmonary fibrosis and hepatotoxicity are the most serious side effects of

MTX.

Immunosuppressant agents

IV. Immunosuppressive antibodies 1-Muromonab CD-3:

-it is a murine monoclonal antibody

-directed against cell surface glycoprotein CD3 antigen of human T cells.

it is highly effective in the treatment of acute rejection in solid organ

transplants. Due to its monoclonal nature, each molecule is identical

because it is derived from a single antibody-producing clone also, it can be

used to deplete T cells from donor bone marrow prior to

transplantatione

Mechanism of Action:

It binds specifically to the CD-3 complex, which is involved in antigen

recognition and cell stimulation, on the surface of T lymphocytes.

Immediately after administration CD-3-positive T lymphocytes are abruptly

removed from the circulation,leading to disruption of T-lymphocyte function,

and depletion of circulating T cells with decreased immune response.

IV. Immunosuppressive antibodies:

2-Rh Immune Globulin:

Rh immune globulin contains antibodies to the Rh factor in blood.

The antibodies come from donors who have become sensitized to the Rh factor. Giving

these Rh antibodies to an Rh-negative pregnant woman prevents her immune system

from producing its own Rh antibodies, which would attack her Rh-positive fetus's red

blood cells.

- to prevent development of an immunological condition known as Rhesus disease (or

hemolytic disease of newborn; erythroblastosis fetalis) of the next Rh positive

babies.

- When given at 28 weeks and within 72 hours of delivery of an Rh-positive child, it has a

success rate of greater than 99%

Adverse Effects:

Local pain ,Fever

IV. Immunosuppressive antibodies 3-IL-2-receptor antagonists:

-MABs (as discussed before)

4 -TNF-α receptor blockers:

- MABs (as discussed before)

5 - Alemtuzumab:• A humanized monoclonal antibody directed against surface protein

(CD52) an antigen found on the surface of normal and malignant lymphocytes

• It is approved for the treatment of B-cell chronic lymphocytic leukaemia and is undergoing Phase III clinical trials for the treatment of multiple sclerosis- Adverse effects:

include Cytokine storm syndrome, requiring premedication with acetaminophen, and diphenhydramine, in addition to neutropenia, and anemia

V.Interferons

Interferons are a family of naturally occurring, inducible

glycoproteins cytokines that are used clincally in many purposes.

They have different immunomodulating actions.

The interferons are synthesized by recombinant DNA technology.

Three types of interferon exist, α , β, and γ.

IFN- γ : Acts as immunostimulant. It increases expression of

MHC molecules, enhances the activity of macrophages and natural

killer cell, and stimulates production of IgG.

IFN- α, β : Act as inhibitors of cellular proliferation (cancer cells,

Immune cells and viral infections).

V.Interferons (Cont)Therapeutic uses: Treatment of certain infections e.g. Hepatitis B&C (IFN- α ).

Certain forms of cancer e.g. melanoma, renal cell carcinoma (IFN- α ).

Autoimmune diseases e.g. Rheumatoid arthritis(IFN- α & β ).

Multiple sclerosis (IFN- β): reduced rate of exacerbation.

Adverse effects:Fever, chills, myelosuppression.

Immunosstimulants

Immunosstimulants- Immunosstimulants :• are substances that stimulate the immune system

by inducing activation or enhancing the activity of any of its components.

Types of immunostimulant agents: 1- Synthetic drugs:(e.g Levamisole and Thalidomide) 2- Immunostimulant vaccines: (e.g. BCG vaccine) 3- Recombinant cytokines : (will be discussed later 4- interferons 5- Immunization vaccines (active and passive) 6-Immunostimulatory MAbs

1 -Synthetic drugs:

A.Levamisole:

• It has been used in humans to treat many parasitic worm infections, In

addition to its utilization as immunostimulant in combination with some

chemotherapeutic agents (like 5-FU) to treat many types of human

cancers like colon cancer, melanoma, and head and neck cancer.

• mechanism of action for its immunostimulating effects are not well

under stood. It is believed it enhances cell-mediated immune function in

peripheral T- and B-lymphocytes and stimulates phagocytosis by

monocytes. Its immune stimulating effects appear to be more

pronounced in the immune-compromised individuals.

2 -Interferone (INF-ɣ)

• INF-ɣ boosts the activity of macrophages and NK cells.• It stimulates the expression of MHC molecules and

production of IgG.• It causes cancer cells to produce more antigens ,

suppresses the growth of cancer cells and inhibits angiogenesis

• It is approved for use with some leukemias, lymphoma, renal cancer and melanoma in addition to prevention of secondary infections in chronic granulomatous diseases.

Adverse effects:• Flu-like symptoms – fever, chills, headache, GI

disturbance• Hypotension, Arrhythmia• CNS- depression and confusion

Immunosstimulants

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