Oncology Flashcards
What are neoantigens
Abnormal proteins expressed by the tumour Recognised by T cells
What are the 2 distinct signals required in T cell activation
TCR + Ag-MHC complex AND Co-stimulatory regulatory binding There are many kinds of co-stimulatory receptors. they can be stimulatory or inhibitory molecules. Activation of immune checkpoints leads to inhibitory signals. Examples of co-stimulatory receptors: CD28, CD27, GITR, CD40L Examples of inhibitory molecules/checkpoints: PDL1, PD1, CTLA4, CD80
CTLA-4 CTLA-4 antibodies
The antigen presenting cell presents the neoantigen to the TCR. B7 binds initially to CD28 and becomes activated. After activation, the CTLA-4 migrates onto the surface of the cell and it has a higher affinity to B7 and replaces CD28. That deactivates the T cell. This process occurs in normal viral infections after a few days. CTLA-4 antibodies will stop the CTLA_4 being activated and keeps the CD8 activated (Ipilimumab is the only PBS approved one)
Ipilimumab
anti-CTLA-4 antibody that keeps CD8+ on Leads to a sustained response
anti PD-1 antibody
The expression of PD-L1 and PDL1-PD1 binding causes the CD8+ cell to recognise the antigen as “self” and switches the CD8+ off e.g Pembrolizumab, nivolumab
What cancers have the highest mutation load
Melanoma Squamous Lung Lung adenocarcinoma Highest success w immunotherapy
Microsatellite instability
The condition of genetic hypermutability (predisposition to mutation) that results from impaired DNA mismatch repair (MMR). Rare May be more susceptible to immunotherapy (but not yet on PBS)
Pembrolizumab
PD-1 inhibitor (PD-1 is an inhibitory signal and will enable lymphocytes to kill cancer cells)
Autoimmune toxicities in immunotherapy - endocrine
hypophysitis thyroiditis type 1 diabetes
Management of checkpoint inhibitor toxicity
Low grade: - Dose delay - Increase monitoring frequency High grade: - Withhold checkpoint inhibitor - Steroids - Can consider adding second agent - e.g. Infliximab or mycophenolate
Melanoma BRAF mutation
BRAF V600 mutation It means the pathway does not require upstream activation of RAS and leads to uncontrolled proliferation of the melanoma. Present in 40% of melanomas BRAF inhibitors e.g. dabrafenib, vemurafenib, sabrafenib, encorafenib
MEK inhibitor
Can be added onto BRAF as combination medication the next step in the ROS-> BRAF -> MEK -> ERK pathway (e.g. TRAMETINIB) used in combination therapy with dabrafenib
Immunotherapy and target therapy for unresectable stage III and IV melanoma.
The evidence is that immunotherapy or target therapy should be first line for unresectable stage III and IV melanoma. BRAF600V mutation must be tested first. First line anti-PD1 immunotherapy in BRAF wild type improves progression-free survival and overall survival compared with ipilimumab (CTLA-4). Combination therapy (nivolumab and ipilimumab) is better than monotherapy with either agent. Available on PBS as combination for metastatic melanoma. Note that toxicity triples Used in brain mets Note that targeted therapy has good response rates but the response is not sustained. The PBS mandates that target therapy (BRAF/MEK inhibitor e.g. dabrafenib + trametinib) be used first if there is a BRAFV600 mutation. However, immunotherapy can be commenced is there is no response or further disease progression. Note that is there is no head to head trial with immunotherapy and target therapy
Melanoma adjuvant therapy
Targeted therapy works - Dabrafenib and trametinib combination therapy cf placebo in resection stage III melanoma increases relapse free survival for 20% Positive study but not PBS listed PD1 - nivolumab vs ipilmumab - nivolumab has 20% improvement in relapse free survival None of the PD1 adjuvant therapy has reported improvement in overall survival
Adjuvant treatment of colon ca
Stage 3 - clear adjavtage - oxaliplatin plus 5FU/capecitadine (3 mo) or single agent of eitehr of the above (6 mo) Stage 2 - not clear if adjuvant offers survival benefit (only consider in high risk stage 2)
Adjuvant treatment of rectal ca
T3 or node positive - neoadj chemoRT or RT Adj chemo if node +ve
Why is adjuvant chemo given
to decrease micrometastasis
What other is HPV associated with aside from cervial
anal and head/neck (oropharyngeal)
bevacizumab SE (and mechanism of action)
VGEF/angiogenesis inhibitor Hypertension and proteinuria
infusion 5FU SE
coronary artery spasm
B7 is expressed by the antigen presenting cell. What are the 2 clinically significant molecules it can bind to and what do they do to the T cell
CTLA-4 is expressed by the CD8+ T cell as an inhibitory molecule. When CTLA-4 and B7 binds, the CD8+is deactivated. CD28 is expressed by the CD8+T cell as a stimulatory molecule. When the CD28 and B7 binds, the CD8+ T cell becomes activated.
How does the immune-permissive vs immunosuppressive tumour microenvironment affect the target therapies chosen?
Immune-permissive TMEs have fewer somatic mutations (e.g. ALL). They have decreased antigen processing/presentation. Therefore, CAR-T-cell therapy that target a specific mutation would be predicted to be the most effective. Immunosuppressive TMEs have a high frequency of somatic mutations and therefore neoantigens. There is a high tumour infiltrating lymphocytes burden. Therefore, immunomodulating nAb therapy that increases lymphocyte activity would be more effective.
Are mismatch repair deficient or mismatch repair proficient colorectal tumours more receptive to PD-1 blockage?
Mismatch repair deficient tumours - because these tumours have more mutations and increased tumour infiltrating lymphocytes. The tumour cells usually upregulate PD-1 inhibition so PD-1 blockages is more effective in mismatch repair deficient tumours
When is sentinel node mapping recommended for melanomas
Clinically negative nodes and a primary melanoma >0.8mm thick or melanomas <0.8mm thick but with ulceration
