Lecture 22 - Tumor Immunology & Immunotherapy Flashcards
how do tumours affect the immune system?
tumour evades the immune system
4 ways that tumours evade immune system
- recruit immunosuppressive cells
- ineffective tumour Ag presentation
- release immunosuppressive factors
- T cell checkpoint dysregulation
2 types of immunosuppressive cells recruited by tumour cells
- Tregs
- MDSCs
what are MDSCs?
myeloid derived suppressor cells
role of immunosuppressive cells in immune evasion?
protect the tumour
describe ineffective tumour Ag presentation
cells in TME are poor expressors of MHC on tumour cells –> escape cytolysis and suppress APCs, essentially blocking signal 1
how does TME cause T cell checkpoint dysregulation?
TME determines expression of co-stimulator and co-inhibitory molecules on T cells
- want to dysregulate co-stimulation
- want to promote co-inhibition (CTLA4, PD1)
what happens when T cells lack co-stimulation?
T cells become anergic –> no active T cells
how does the TME affect TCR?
DOWNREGULATES TCR to prevent transcription events required for T cell activation
to help their survival, what types of pathways do tumour cells not have?
tumour cells lack apoptotic or other cell destructive pathways
3 phases of cancer immunoediting process
- Elimination
- Equilibrium
- Escape
what happens in the ELIMINATION phase of immunoediting?
vulnerable tumour cells are cleared by immune system, but cells can acquire ability to avoid immune system
what happens in the EQUILIBRIUM phase of immunoediting?
driven by strong selective pressure from immune system
tumour not regressing or proressing
- tumour cells have adapted and accumulated evasion traits bc of genetic instability
- and cells with strongest tumour Ag have been eliminated
what happens in the ESCAPE phase of immunoediting?
tumour cells evade immune system
- tumours are more rapidly dividing with transfer of resistance from parent to daughter cell
what is immuno-oncology?
uses immunotherapy to treat cancer where the own body’s own immune system fights disease
what are 3 traditional approaches for cancer?
- surgery
- radiation
- cytotoxic/targeted therapy
what are passive immunotherapies?
act on the tumour but DO NOT REQUIRE the patient’s immune system to initiate response
2 types of passive immunotherapies
- tumour-directed mAb
- cell therapies
what are tumour-directed mAb?
Ab specific for Ag on tumours
3 types of tumour-directed Abs
- monoclonal/single Ag
- unconjugated
- conjugated
4 ways that mAbs can treat cancer
- mark cells for destruction
- interfere with receptor signaling
- promote receptor degradation
- deliver anti-cancer agents to tumour cells
2 ways that mAb can mark cells for destruction
- trigger complement response
- trigger cell-mediated responses
why do tumour-directed mAb interfere with receptor signaling?
prevents it from receiving important signals so it ends up not functional
why do tumour-directed mAb promote receptor degradation?
allows receptor internalization so it can be degraded
what is a tumour antigen?
only expressed on tumour
what is a tumour-associated antigen?
expressed on both tumour and host but higher expression on tumour
what is the general concept of cell therapy?
T cells removed from immunosuppressive environment of cancer patient and manipulated in culture
what is the purpose of manipulating T cells in vitro for cell therapy?
2 ways they accomplish
to make them less “sleepy”/tolerized/anergic
- give growth-promoting cytokines
- genetically modify to be more cytolytic
3 examples of cell therapies
- lymphokine-activated killer-cell therapy (IL2-activated lymphocytes)
- tumour-infiltrating lymphocytes conditioned with IL2
- gene-modified lymphocytes
example of gene-modified lymphocytes
overexpress gene so once TCR is activated it can increase TNFa, IFNy, and IL2 to increase activity
describe development of tumour-infiltrating lymphocyte with IL2 (5 steps)
- excise tumour and plate T cells based on their specificities to endogenous APC
- culture with high dose of IL2 to stimulate growth
- find T cells with best ability to recognize tumour
- select best T cell and cause lots of proliferation
- re-infuse into patient
what do you have to do before re-infusng cell therapy?
patient must undergo preconditioning/lymphodepleting chemotherapy –> wipe out endogenous immunosuppressive and memory mechanisms
patient undergoes the lymphodeletion and adoptive tumour-infiltrating lymphocyte therapy and tumour goes away but in that spot missing melanin
what does this mean?
patient now has self-reactive T cells against melanin
therefore, tolerance is broken!!! has autoimmunity limited to the area where the tumour was
what is active immunotherapy?
act directly on body’s immune system to produce immune system to fight cancer
2 benefits of active immunotherapies
- minimal toxicity
- used in early stage cancer
3 general types of active immunotherapies
- therapeutic cancer vaccines (adjuvants)
- cytokines
- mediators of T cell activation
5 examples of therapeutic cancer vaccines (adjuvants)
- DC vaccines (ex. TLR7)
- tumour cell vaccines
- protein-based vaccines
- recombinant vector vaccines
- BCG
why is HSV-1 a poor recombinant vector vaccine?
it is oncogenic
what type of cancer is BCG vaccine used for?
bladder cancer
5 cytokines used as active immunotherapy
- IL
- IFN
- TNFa
- GM-CSF
- immunocytokines
2 examples of mediators of T cell activation used as active immunotherapy
- immune checkpoints
- co-stimulatory pathways
describe targeting T cell checkpoints
normally, T cell responses are regulated by balance of inhibitory and activating signals BUT tumours dysregulate these pathways to dysregulate the immune system
good to target these pathways to prevent dysregulation
what is ipilimumab?
blocks CTLA4
what does CTLA4 do?
in activated T cell, CTLA4 competes with CD28 for binding to B7 –> BLOCKS T cell activation
how does ipilimumab work?
INHIBITS CTLA4 so prevents the blockade of T cell activation, allowing T cell proliferation
in the stages of T cell development and activity, when and where is CTLA4 pathway blockade most important?
in the priming phase of T cell activation in PERIPHERY
in the stages of T cell development and activity, when and where is PD1 pathway blockade most important?
in the effector phase of T cell activity in TME (i.e. target tissue)
3 past treatments for metastatic melanoma what was wrong with them
- Dacarbazine (DTIC)
- low response rate - Temozolomide
- low response rate - IL-2
- low response rate
- highly toxic
what happens to long-term survival of metastatic melanoma when treated with Ipilimumab?
higher median overall survival (nearly double!!)
which co-inhibitory molecule is associated with tumour evasion?
PD-1
what does PD1 bind? on what type of cell?
PD1 binds PDL1 on tumour cells
what happens when PD1 binds PDL1?
SUPPRESSES cytotoxic T cell responses
why is it important that the tumour expresses PDL1?
so that it can block T cell activity
what are 2 examples of anti-PD1 treatment?
Nivolumab and Pembrolizumab
survival with Nivolumab vs other chemotherapy in melanoma
Nivolumab improved survival in melanoma
survival with Pembrolizumab vs. Ipilimumab
Pembrolizumab (PD1) had better survival than Ipilimumab
side effect of immuno-oncology therapies?
may induce autoimmunity and inflammation
how do Foxp3+ Tregs affect cancer?
having more Foxp3+ Tregs induces a HIGHER metastic potential –> so tumour will try to recruit Tregs and convert other T cells to become Tregs
describe using Foxp3+ Tregs as a target for immunotherapy
creates Ag-specific antitumour immunity
describe co-stimulatory biologics in general
modulate the priming and effector phases of T cell responses by preventing co-inhibition –> i.e. anti-PD1 and anti-CTLA4
8 drugs that are the new “era” of cancer treatment
- cytokines –> non-specific, bad side effects
- allogeneic HSCT –> high dose chemo
- mAb
- oral molecular target drugs –> TK inhibitors, signal transduction inhibitors, “nibs”
- autologous cellular immunotherapy –> activated APC reinfused into patient
- immune checkpoint inhibitors
- immunovirus
- CAR-T therapy
what does CAR T stand for?
chimeric antigen receptor T cell therapy
describe CAR T therapy and the process to make it
engineer T cells from patient to express an engineered receptor with retroviral vector –> then reintroduce into patient to kill tumour cells
how are T cells extracted from patient for CAR T therapy?
leukapheresis
describe chimeric antigen receptors
- has Ag-binding domain specific for a target
- chimeric nature allows molecular recognition directly linked to co-stimulatory pathways
- has CD3 domain that allows TCR signaling
4 advantages and 3 disadvantages to CAR-T therapy
- fast and high response rate
- no HLA typing
- less severe side effects
- can target many types of antigens
- cytokine syndrome (must treat with steroids)
- heavily pretreated patients may not have enough T cells
- long-term sequelae and relapse rates unknown
