Immuno-Oncology Flashcards
are cancer cells considered to be self or non-self?
self
what are 4 obstacles in eliciting effective immune responses in cancer?
- cancer cells are self
- identifying specific peptides/costimulatory signals is hard
- tumours are heterogeneous (intra and interpatient) –> may need personalized therapy and hit multiple targets
- cancer cells actively evade the immune system
why is it difficult to identify specific peptides/costimulatory signals on cancer cells?
they are inconsistent btwn tumours and change over time
what are 3 ways that cancer cells actively evade the immune system?
- decreased antigen presentation (MHC I, antigen processing)
- tumour cells may thrive without triggering inflammation
- tumour cells may produce molecules to dampen the immune response
what are the 3 strategies of antibodies for cancer?
- target tumour cells
- target immune cells
- both
describe 2 types of antibodies targeting tumour cells
- MAb that cause cancer cell death
- MAb that delivery anti-mitotic agents, radioisotopes to cancer cells to decrease toxicity
what are 2 types of antibodies targeting immune cells?
- agonist antibodies for costimulatory receptors (press the gas pedal)
- checkpoint inhibitors at CTLA4, PD1 (release the brakes)
describe antibodies that target tumour cells and immune cells
“BI-SPECIFIC” antibodies where 1 arm binds cancer cells, 1 arm binds T cells
this allows cancer cell and T cell to be close enough to interact
what are 4 therapies used for cancer, besides MAb? how do they each work?
- oncolytic viruses –> viruses that replicate in cancer cells and kill them
- positive boosting signals –> cytokines that “press the gas pedal”
- cancer vaccinations –> using cytokines, viral vectors
- cellular therapy –> boost lymphocytes/DCs EX VIVO, then reintroduce into patient
how does anti-CD20 antibody work? is this direct or indirect killing?
binds CD20 on cancer cell and recruits NK cells to kill
direct killing
how does anti-CD30 conjugated to vedotin work? is this direct or indirect killing?
antibody binds CD30 on cancer cell, allow MICROTUBULE INHIBITOR called vedotin to kill the cell
direct killing
how do immune checkpoint inhibitors work? is this direct or indirect killing?
bind CTLA4 or PD1 on T cell so it can kill the tumour
indirect
what is melanoma?
cancer in melanocytes (skin, epithelial linings)
describe 3 initial treatments for melanoma
- surgery not feasible or advised
- resistant to chemotherapy and radiotherapy
- IL-2 treatment gives complete tumour regression in 5% of ppl with severe toxicity
describe the activity of CTLA4 on T cells
what does this lead to? (2)
upon T cell activation, CTLA4 outcompetes CD28 for B7
- blocks production of IFNgamma and IL-2 from signal 1/2
- shortens the interaction of T cell with APC
describe the activity of CTLA4 on T cells
what does this lead to?
CTLA4 binds B7 on DC
leads to DC making indoleamine 2,3-deoxygenase which catabolizes Trp –> T cells cannot function without Trp
what happens to CTLA4 deficient mice?
massive lymphoproliferation and organ damage –> lethal
what type of MAb is ipilimumab?
fully human
describe the 5 steps of drug development
- PRE-CLINICAL –> in vitro, animal studies
- PHASE 1 –> safety, pharmacokinetics
- PHASE 2 –> larger study on safety + efficacy
- PHASE 3 –> compare safety + efficacy to current standard treatment
- PHASE 4 –> on the market, continue to do tests and obtain data
describe the graph showing ipilimumab efficacy
3 groups –> ipilimumab, gp100 (diff treatment), ipilimumab + gp100
gp100 alone had reduced survival: ppl died more quickly
ipilimumab +/- gp100 had increased survival that plateaued around 3years –> indicating chance of long term survival
why did ipilimumab response change the way we look at images of tumours?
looking at radioactive glucose
patient had reduced tumour sites + developed more, then they all reduced but there still appeared to be tumour spots even when the patient was ok
since ipilimumab does not target the tumour itself, maybe the T cells are what is triggering the radioactive glucose bc they also have glucose
thus, the tumour sites we see may not necessarily be bad
what is the downside of checkpoint inhibitors? what does this lead to?
not very specific –> immune system may attack any body system –> immune-related adverse events (irAEs)
what organ systems does ipilimumab typically affect? (3)
skin, intestine, endocrine
how can you manage the immune-boosting side effects of ipilimumab? 4 examples
use immune suppressants
- corticosteroids
- anti-TNF alpha antibodies
- mycophenolate mofetil
- IV immunoglobulins
do anti-PD-1/PD-L1 have side effects?
yes, they are similar but not identical to anti-CTLA4
what does anti-PD-1/PD-L1 target?
chronically activated T cell, tumour cells
