Lecture 32: Cancer Flashcards
t/f cancer is known as the “emperor of all maladies”
t
Cancers derive from alterations in “self” cells that enable _____
autonomous proliferation
immune mechanisms contribute to both tumour ____ and _____
growth and control
what type of therapies try to support immune-mediated tumour growth?
tmmunotherapies
what are the 2 steps of tumour growth and metastasis?
- cell acquires DNA mutation(s) that cause excessive growth
- Tumour growth outpaces neighbouring cells
- tumor cells invade tissues and may impact function (considered malignant)
- tumour cells leave the primary site and seed in distal locations
tumour accumulate _____ mutations that enable autonomous growth
genetic
what are the 3 types of genes that underlie cancer?
- Proto-oncogenes
- Tumour suppressor genes
- cell death regulators
what are proto-oncogenes?
proteins that induce cell proliferation
if proto-oncogenes are present, the cancer is associated with ____ of function
gain
what is the role of tumour suppressor genes
restrict cell proliferation
if tumour-suppressor genes are present, the cancer is associated with ____ of function
loss
what is the function of cancer death regulators?
gain or loss of function impacts cancer growth (cells should be induced to die if they have irreparable DNA damage)
t/f some cancers have viral origins
t
what is the general mechanism of viral origin cancers?
generally associated with insertion and disruption of DNA leading to pro-proliferative features
t/f some viral cancers can be prevented by vaccination
t (ex; HPV)
development of cancer represents an accumulation of unrepaired _____, often occurred over time
DNA mutations
people with increased cancer risk may have an inborn error in one/more _____
oncogenes/tumour suppressors
_____ and _____ mechanisms eliminate most potentially cancerous cells before they cause problems
immunologic and non-immunologic
what are the 3 methods of immunoediting?
- elimination
- equillibrium
- esca[e
what is elimination by immunoediting?
cells that have been damaged exhibit characteristics of “stress” that enable detection and control by immune cells (immunosurveillance)
explain the equilibrium method of immunoediting
tumour cells have co-evolved with immune function; they co-exist
explain the escape method of immunoediting
tumour establishes conditions that enable growth despite the immune pressure
tumour cells are “self” so why cant lymphocytes detect them well?
most self-reactive lymphocytes are negatively selected in the thymus
what are two type of antigens that help lymphocytes recognize cancer cells?
- tumour-associated antigens
2. tumour-specific antigens
what are tumour-associated antigens?
self proteins that are either not selected against, or inappropriately expressed (wrong tissue, wrong time, over expressed)
what are tumor-specific antigens?
non-“self” proteins/peptides that arise from oncogenic virus infection or mutations that create new epitopes
lymphocytes may recognize tumour-associated/specific antigens and mount what type of immune response?
adaptive anti-tumour response
tumours with normal to high expression of MHC 2 interact with ___ cellls
T cells
tumours may downregulate ____ to evade recognition by T cells
MHC 1
if a tumour downregulates MHC1, that is a signal for what cells to come attack it?
NK cells
what are 5 ways tumours avoid recognition & cause further growth?
- establish pro-tumour (immunosuppressive) microenvironment
- Express co-inhibitory of immune checkpoints that slow/stop antii-tumor immune responses
- downregulate MHC1
- chronic inflammation which can cause tissue remodeling, blood vessel formation, metastasis and invasion
- resistance to apoptosis
what is an example of a co-inhibitory or immune checkpoint that slows/stops antitumour immune responses?
CTLA-4 and PD-L1
what are 2 MOA of medications that can be used in the treatment of cancer?
- MABs (Anti TAA/TSA)
2. Anti-checkpoint
what is the general MOA of MABs for treatment of cancer?
Anti-TAA/TSA and induce complement, ADCC
give 2 examples of MABs used in the treatment of cancer
- Rituximab
2. Trastuzumab
what is the general MOA of anti-checkpoint medications?
interfere with regulatory fx
give 4 examples of anti-checkpoint MABS medications used in the treatment of cancer
ipilimumab, bretuximab vedotin, pembrolizumab, atezolizumab
advanced melanoma treated with ____ and ____ is associated with significantly extended survival
anti-PD-L1 and anti-CTLA4
what are is the goal of BiTES, BiKEs and TriKEs?
redirect killing by engaging an antigen (or two) and an activating molecule (such as CD16)
in BiTES, BiKEs and TriKEs, what do: Bi/Tr; K; and E stand for?
- Bi/Tri: Bi or Tri specific
- K: killer, refers to NK; T cells
- E: enganger
_____ cells are autologous T cells engineered to express an antigen-specific receptor that binds to an antigen (MHC independent)
chimeric receptor (CAR)-T cells
chimeric antigen receptor (CAR) T cells are connected to intracellular signalling domain (usually ______) and 2nd and 3rd genration give co-stimulatory signals through ______ and/or _____
CD3z; CD28 and/or 4-1BB
chimeric antigen receptor (CAR) T cells take advantage of ______
normal T cell activation pathways and downstream signalling
chimeric antigen receptor (CAR) T cells may “overstimulate” and lead to ____
cytokine release syndrome
what is special about using chimeric antigen receptor (CAR) T cells for cancer?
they need to be engineered for each patient (personalized medicine) to avoid rejection reactions
what are the 5 steps in using CAR T-cells in cancer treatment?
- isolation of cells from hst
- equip cells w/ new TCR
- activation of cells
- expansion of cells
- re-infusion (go back into patient)
luxury “CAR” models attempt to relieve some challenges of ____
CAR-T cell therapies
CAR__ cells are associated w/ fewer side effects than CAR-T cells and do not need to be autologous
NK
the truck CAR model
use antitumor cytokines to make an anti-tumour microenvironment
the universal CAR model
no allogenic markers, universally accepted
what is the self-driving CAR model?
carrying a tumour homing chemokine receptor
what is armoured CAR model?
dysfunctioning immune checkpoint receptors; T cell resists immunosuppression and activates local immune cells
self-destruct CAR
externally-delivered signal stops the activity of the T cell
conditional CAR model
externally-delivered signal starts activity of the T cell
viruses are normally inhibited by ____ and/or ____ of infected cells
type 1 IFN and/or apoptosis
oncolytic viruses take advantage of the tumours loss of _____ and or _____ to grow
IFN-1 signalling and or apoptosis
what is the function of lysis on oncolytic viruses?
lysis allows virus to spread throughout the tumor AND recruits immune cells
what are the requirement for MAB treatment?
- identification of TAA/TSA
2. availability of cells w/i tumour if ADCC is mode of action
what are the requirements of BITES, BIKES, and TRIKES for cancer treatment?
identification of TAA/TSA
availability of cells w/i tumor/effective cells
what are the requirements for cancer treatment with checkpoint blockade?
- lymphocytes with anti-tumour activity (T and NK cells)
2. Lymphocyte infiltration to tumours
what are the requirements for treatment with CAR-T cells?
outgrowth of antigen loss variants (i.e. escape of mutants)
what are the requirements for treatment with CAR-NK cells?
outgrowth of antigen loss variants (i.e. escape mutants)
what are the requirements for treatment with oncolytic viruses?
if concurrently vaccinating, need to ID antigens
Virus must find and replicate in the tumor (and not elsewhere)
what is a potential pifall of MAB treatment?
outgrowth of antigen loss variants
risk of autoimmunity/off target effects
what are potential pitfalls of BITES, BIKES, TRIKES treatment?
may be immunogenic, not yet approved for clinical use
what are potential pitfalls of checkpoint blockade as cancer treatment?
- risk of autoimmunity
- outgrowth of antigen loss of variants
- loss of T cell fx if MHC 1 is down regulated
what are potential pitfalls of CAR-T cells?
- expensive
- potentially time consuming as cells need to be autologous
- severe sde effects (cytokine release syndrome)
what are potential pitfalls of CAR-NK cell treatments?
can be allogeneic
may be more affordable and available than CAR-T cells, but still pricy etc.
what are potential pitfalls of using oncolytic viruses for cancer treatment?
- virus infection needs to be carefully controlled
2. tumour can still inhibit virus infection (spread might be incomplete)
