Oncology 8/27 Brooks

Immune Overview & Immune Suppression I

negative regulator coreceptor on T-cell surface to downregulate T cell activation

CTLA-4

(1) and (2) cells are coinhibitory. (1) cells release (3) to inhibit (2), and (2) cells release (4) to inhibit (1)

T-helper 1 cells and T-helper 2 cells

TH1 releases IFN-y

TH2 releases IL-10

when CD80/86 on (1) cells binds T cells, the T cell is activated if it binds (2), and the T cell is downregulated if it binds (3)

1. antigen-presenting cells

2. CD28

3. CTLA4

3 highest proliferation cell types/regions/systems

1. hair

2. GI

3. immune

methotrexate: MOA, important activation step and protein, reversal agent, unique ADME

antifolate that inhibits dihydrofolate reductase (DHFR) to suppress RNA/DNA synthesis in high-proliferation cells

cell activity depends on folylpolyglutamate synthase (FPGS), retains MTX within cell

reversible biological effects by leucovorin

oral absorption is saturable, may be erratic in doses >25 mg/m²

methotrexate ADME property that relates to DDIs

cleared renally via tubular secretion, clearance slowed alongside other tubularly secreted drugs like NSAIDs, pencillins

sulfasalazine: unique ADME property, general MOA

uniquely activated to mesalazine by colonic bacteria

generally downregulates prostaglandin and cytokine activity

azathioprine: MOA, notable DDI

antimetabolite that is converted to 6-mercaptopurine (6-MP), which inserts into DNA and halts replication, less lymphoid proliferation

6-MP metabolized by xanthine oxidase (XO), inhibited by allopurinol, needs ¼ dose

MMF: name, MOA

mycophenolate mofetil

active drug hydrolyzed in vivo to more active mycophenolic acid (MA)

MA>MMF inhibit T and B cell response, including mitogenic activity, less purine synthesis

thalidomide: MOA, unique AEs, commonly combined with

MOA: inhibits angiogenesis, TNF-alpha

• also increases neutrophil phagocytosis and enhances some T-cell

teratogenic, also increases VTE risk, thus

commonly given with anticoagulant

leflunomide: MOA, unique property, toxicities

MOA: prodrug of teriflunomide, pyrmidine synthesis inhibitor

uniquely long half life of many weeks

toxic to kidneys, liver, and embryo/fetus

cyclophosphamide: MOA, unique risk

alkylating agent, adds alkyl group to nucleotide nitrogens —> leads to many fatal mistakes in DNA synthesis, especially in faster-proliferating cells where DNA repair has less time

due to these drugs activating DNA repair, they are likely to introduce mutations and create potential new malignancies

hydroxychloroquine MOA, unique property

MOA: alkalinizes pH of APC endosomes, less antigen processing, leads to less epitope loading into MHC and exposure to T cells

very long terminal half life of 40-50 days

calcineurin: what is it, which drugs affect and why, unique ADME of one drug, unique AE of one drug

calcineurin = phosphatase, involved in T-cell activation

inhibited by cyclosporine A and tacrolimus to downregulate cell-mediated immunity

cyclosporine A is a strong pGP inhibitor, may be used to improved chemotherapeutic efficacy

cyclosporine A has some risk of blood cancers, lymphoma, also some neuropsych AEs (seizure, AMS)

PSI: stands for, target, drugs and comparative half lives

proliferation signal inhibitors

target an immune complex that binds the molecular target of rapamycin (mTOR)

affected by sirolimus, everolimus

siroliumus longer half life (60 vs. 40 hrs)

what is IGIV? is it immune suppressive or activating?

IV immunoglobulin

immune activating in the increased presence of antibodies and B cell activity

immune suppressing because body interprets as a signal to downregulate T cells