Immune System Stimulants

Question 1

What are the two types of immune system stimulants?

Answer 1

1. Cytokines

2. Hematopoetic agents

Question 2

What are the cytokines?

Answer 2

• Interferon alpha
• Interleukin 2
• Tumor Necrosis Factor Alpha

Question 3

What are the common characteristics of cancer cytokines?

Answer 3

1. Short half-lives
2. Not cytotoxic by themselves –> they recruit immune cells to do the actual cell kill (immune system has to recognize tumor cells as foreign)

Question 4

Despite their human origin, IL-2, IFN-alpha and TNF-alpha can have. . .

Answer 4

. . .serious, even fatal, side effects.

Question 5

How does Interleukin-2 work?

Answer 5

• Not directly cytotoxic - induces and expands a T-cell response cytolytic for tumor cells
• Used either alone or with adoptive cellular therapy (LAK or CIK cells)
• –Cells are produced by obtaining autologous lymphocytes, culturing them with x-irradiated tumor cells in the presence of IL-2 and then reinjecting them into the patient along with IL-2
• Short half-life (t1/2 = 13 minutes –> either continuously infused or given as multiple intermittent daily doses

Question 6

What are the side effects of high doses of IL-2?

Answer 6

• Activation and expansion of lytic lymphocytes cases inflammation, vascular leak an secondary release of other cytokines (such as TNF, interferon alpha) = CYTOKINE STORM
• Can produce mild/moderate fever/chills, diarrhea and wight gain or hand-foot syndrome (palmar-plantar erythrodysestesia)
• Serious toxicities such as thrombocytopenia, shock, respiratory distress, coma and fatal hypotension

Question 7

What are the three mechanisms of Interferon alpha?

Answer 7

1. Decreases production of fibroblast growth factor (FGF)
   - anti-FGF actions may be responsible for actions against leukemic stem cells in chronic myeloid leukemia
   - FGF is angiogenic
2. Inhibition of cell division of both normal and tumor cells
3. Increases class I MHC expression on tumor cells (actually restores normal MHC expression levels –> increased activity of cytotoxic T lymphocytes)

Question 8

What side effects are associated with Interferon alpha?

Answer 8

• Flu-like symptoms: fever, arthralgia, headache, fatigue
• Hypotension
• Myelosuppression
• Depression

Question 9

What does tumor necrosis factor alpha do?

Answer 9

• Similar to IL-1 in terns of actions: causes fibroblast proliferation, chemokine induction (IL-6, IL-8), T and B cell activation
• Effect on many cell types (at least 17 different kinds) - causes a decrease in the rate of proliferation of tumor cells while sparing normal cells
• Intra-arterial administration due to extremely short half-life and toxicity.
• Sever dose-limiting toxicity is malaise and flu-like symptoms - can cause hemorrhagic necrosis

Question 10

What immune system stimulants are hematopoietic agents?

Answer 10

• Erythropoietin
• Filgrastim
• Interleukin 11
• Romiplostim
• Sargramostim

Question 11

Wha tis the dose-limiting complication of many antineoplastic drugs?

Answer 11

Bone marrow suppression

Question 12

These are recombinant forms of several lineage-dependent colony stimulating factors. What do they result in the proliferation of?

• Erythropoietin
• Filgrastim
• Sagramostim
• Interleukin 11 & Thrombopoietin

Answer 12

• Erythropoietin –> red blood cells
• Filgrastim (G-CSF) –> neutrophils
• Sagramostim (GM-CSF) –> granulocytes, eosinophils, basophils, and monocytes
• IL-11 and Thrombopoietin –> platelets