PTN - Immunomodulators (Dolloff)

Question 1

What are the two possible mechanisms by which immunosuppresion leads to malignant neoplasms?

Answer 1

1. Loss of immunosurveillance
2. Stimulation of rapid proliferation of stem cells in an attempt to restore immune system

Question 2

What are the 3 primary indications for treating with an immunomodulatory drug?

Answer 2

1. Autoimmune and inflammatory diseases
2. Transplants and GVHD
3. Oncology

Question 3

What is the main difference between autoimmune and autoinflammatory processes?

Answer 3

Autoimmune processes are characterized by hyperactivity of the adaptive immune system.

Autoinflammatory processes are characterized by hyperactivity of the innate immune system.

Question 4

What are the 3 main side effects of cyclosporin?

Answer 4

1. Renal toxicity - dose-dependent and usually reversible
2. Hypertension
3. Neurologic toxicity - tremors and seizures

Question 5

What is the function and mechanism of action of azathioprine?

Answer 5

• Function: inhibits purine synthesis
• MoA:
  
  • Azathioprine converted into 6-mercaptopurine
  • 6-MP incorporated into replicating DNA and halts DNA replication –> cell cycle arrest

Question 6

Infliximab can be used to treat what 2 conditions?

Answer 6

Crohn’s Disease and Rheumatoid Arthritis

Infliximab is a monoclonal antibody against TNF-alpha. This will lead to a decrease in inflammation, which will limit autoimmune destruction of GI tract and joints.

Question 7

True or False: Pegfilgrastim has a longer half-life than Filgrastim.

Answer 7

True

This allows for more sustained duration of action and less frequent dosing

Question 8

6-mercaptopurine is an active metabolite of what pro-drug?

Answer 8

Azathioprine

Question 9

What is the mechanism of action of Filgrastim?

Answer 9

Filgrastim is a recombinant human Granulocyte-colony stimulating factor (G-CSF) and is used to increase production of neutrophils

Question 10

What two immunosuppressants have severe hepatotoxic effects?

Answer 10

Leflunomide and methotrexate

Question 11

What is the mechanism of action of methotrexate?

Answer 11

Inhibits dihydrofolate reductase, which blocks synthesis of TMP and purines

Question 12

What is the mechanism of cyclosporin and tacrolimus (FK506)? What enzyme is targeted by each?

Answer 12

Both involved in inhibition of transcription of IL-2 to prevent T-cell proliferation

Enzyme: calcineurin

Cyclosporin targets cyclophilin or FKBP

Tacrolimus targets FKBP

Question 13

What is the mechanism of action of etanercept?

Answer 13

Ligand-binding portion of human TNF-alpha receptor fused to Fc portion of human IgG1

Acts as a decoy receptor that binds TNF-alpha and prevents it form binding to its receptor

Question 14

Cyclosporine and azathioprine should be given in conjunction with what other drug, as a prophylactic for preventing rejection?

Answer 14

Glucocorticoids to inhibit inflammation

Question 15

What drug blocks dihydroorotate dehydrogenase? This prevents what?

Answer 15

Leflunomide

Prevents dihydroorotate dehydrogenase from forming pyrimidines

Question 16

True or false: Rapamycin (sirolimus) and cyclosporin can be used together without interaction.

Answer 16

False

Rapamycin interacts with cyclosporin –> increased concentration of both drugs in blood

Cyclosporin toxicity –> renal dysfunction

Rapamycin toxicity –> hyperlipidemia

Question 17

What is the structural analog of tacrolimus (FK506)?

Answer 17

Rapamycin (sirolimus)

Question 18

Rituximab is currently used for what condition?

Answer 18

Rheumatoid arthritis

Acts as a monoclonal antibody against CD20 (B-cell marker) - depletes all B-cells except plasma cells

Question 19

What is the drug which acts a soluble Fc receptor to IgG1, preventing the binding to TNF to cell membrane receptors?

Answer 19

Etanercept

Question 20

What drug targets mTOR?

Answer 20

Rapamycin (sirolimus)

Question 21

What immune response is more easily treated, primary or secondary?

Answer 21

Primary

Primary immune responses lack presence of memory cells, which can be difficult to erradicate. They also tend to work better prior to exposure.

Question 22

What is the mechanism of action of mycophenolate mofetil?

Answer 22

Inhibits IMP dehydrogenase, which decreases de novo purine synthesis (specifically of guanine)

Question 23

What is the mechanism of action of rituximab?

Answer 23

Binds to CD-20 on B-cells and kills B-cells

Question 24

What is Lenalidomide used to treat and what is its mechanism of action?

Answer 24

Lenalidomide (a derivative of thalidomide) is used to treat multiple myeloma

MoA: Inhibits cereblon, an E3 uqiquitin ligase

Question 25

What is the main side effect of Lenalidomide?

Answer 25

Teratogenicity

Question 26

True or False: Lenalidomide should be administered with an anticoagulant because it increases risk of developing clots.

Answer 26

True

Question 27

What does the drug Pembrolizumab target? What does it treat?

Answer 27

Pembrolizumab targets PD-1 and inhibits it from binding to T-cells, promoting an anti-tumor immune response.

Tumor cells upregulate PD-1 to prevent T-cells from attacking them.

Used to treat: melanoma, non-small cell lung cancer

Question 28

What is the difference between Sargramostim and Filgrastim?

Answer 28

Sargramostim is a granulocyte-macrophate-colony stimulating factor (GM-CSF), which upregulates production of neutrophils and monocytes form hematopoietic stem cells.

Filgrastim is a granulocyte-colony stimulating factor (G-CSF) and only stimulates production of neutrophils

Question 29

Drugs like Sargramostim and Filgrastim are used to treat what?

Answer 29

Neutropenia in patients with AIDS, who have just received chemotherapy, or who have just received an auto-stem cell transplant

Question 30

What is the mechanism of action of Ipilimumab? What is it primarily used to treat?

Answer 30

Ipilimumab binds to CTLA-4 on tumor cells and prevents it from binding to T-cells, decreasing tolerance and activating an immune response against the tumor cells.

Used to treat: melanoma