Oncology Flashcards
What is immunosurveillance theory?
Theorises that cancer would occur at an “incredible rate” if host immune defenses did not prevent an outgrowth of continuously arising cancer cells. Evidence below
A) HIV individuals - increased malignancy
B) Immunodeficient mice (absent T/B cells) developed a variety of cancers
C) Tumours with high number of T cells within them have a better clinical outcome
What are immune checkpoints what are some examples of their therapeutic application?
Molecules expressed on T-cells that inactivate T cells
These are PD-1 and CTLA-4
CTLA-4: receptor on T-cell that negatively regulates T cells. It is activated by B7 proteins on APC e.g., dendritic cells. Thus, more antigens results in more CTLA-4 based activation.
PD-1: receptor on T-cell that binds to a ligand (PD-L1) expressed by tumour cell that makes the T-cell quiescent, preventing tumour rejection.
What is the role of combination immune checkpoint inhibitor therapy?
Synergy can occur with the use of anti-CTLA4 and anti-PD-1. Currently in trials but significant associated toxicity due to life-threatening side effects. 30% of patients have to discontinue therapy due to autoimmune toxicity
What is the activity of immune checkpoint inhibitor therapy in the brain?
Very efficacious as T cells can cross BBB
What do you need to be aware of during imaging-based surveillance of cancers when undertaking immunotherapy?
Tumours can become bigger before they get smaller due to T-cell invasion, but this does not mean that it is not responding to therapy
How do you manage immune-related toxicities from immunotherapy?
Steroids > 1mg/kg prednisolone
Anti-TNFalpha inhibitors (infliximab) - very effective at treating colitis
Mycophenolate - autoimmune hepatitis (T-cell suppressant)
IVIG and anti-CD19/anti-CD20 (B-cell mediated toxicities)
Who does melanoma affect and how common is it?
1 in 18 lifetime risk
Australia is 6.4% of global melanoma
11,000 cases a year in Aus
What are the significant mutations that determine treatment choices in melanoma?
Braf (50% of melanomas)
Ras (15% of melanomas)
NF1 (neurofibrimatosis)
How do you stage melanoma and why is it important?
Stage 1 & 2: primary melanoma
Stage 3: regional metastases
Stage 4: distant metastases
Influenced further by thickness, ulceration and mitotic rate
Staging determines treatment and prognosis
What is the significance of the Braf gene in melanoma?
Braf gene encodes for a serine kinase and a mutation here is commonly found in melanoma, allowing targeted therapy. This serine kinase receptor usually dimerises and initiates a downstream signaling pathway that has inherent negative feedback loops to regulate the receptor. The mutated form Braf V600E (valine exchanged for glutamic acid), is constitutively active and does not respond to negative feedback. Responds to Braf inhibitors but the efficacy does not last.
Braf inhibitors: vemurafenib, dabrafenib
How does the prevalence of Braf mutations vary with age in melanoma?
Younger people more likely to have Braf mutation. Those under 30 with melanoma have 100% chance of Braf mutation
Why is a Braf inhibitor commonly prescribed with a Mek inhibitor?
Two main reasons
1) Increased proliferation in cells with wildtype Braf
2) Reduced resistance
Braf inhibitors have the side effect of increased squamous cell skin cancers due to increased Braf signalling in cells with wildtype Braf. Introducing a MEK inhibitor prevents excessive downstream signaling to reduce the excessive cellular proliferation in normal cells with wildtype Braf.
What is the advantage of immunotherapy in melanoma?
Produces a durable response, efficacious beyond the time on treatment
Melanoma is a cancer with the MOST single nucleotide mutations (highest mutation load)
High mutation load cancers respond to anti-PD-1/PD-L1
What is the role of sentinel lymph node biopsy in melanoma?
Used to stage melanoma and select for adjuvant therapy
Inject the primary areas with a blue-dye colloid and identify the sentinel node. Biopsy the LN.
Does NOT have a survival benefit but DOES have a prognostic benefit
