Cancer Immunotherapy Flashcards
What are teh 4 major methods of immunotherapy?
stimulate/block components of hte immune system; inject tumour specific immune cells; genetically engineer immmune cells to recognise tumour; deplete immune subsets- Tregs ; MDSC
What are the only 2 cytokine therapies approved?
IFNa and IL-2
What cancers is IL-2 used against?
metastatic melanoma nad renal cell carcinoma
What is the function of IL-2?
activation and expansion of CD4 and CD8 T cells
When is IFNa used in treating cancers?
as an adjuvant therapy of stage III melanoma
What is the function of type I IFNs?
induce expression of MHC-I; mediates maturation of DCs; activates CTLs
What is the efficacy of cytokine therapy?
recent meta-analysis found significant increases in disease free survival and overall survival
Why would IFNa therapy be thought to be particularly good?
many cancers switch off this expression in order to evade the immune repsonse
What makes developing a therapeutic cancer vaccination difficult?
need to find a protein/peptide that specifically expressed in cancers and not normal cells, however most tumour associated antigens are self-antigens and therefore there is tolerance to them; even if generate good responses, cancers create immunosuppressive microenvironment which is notovercome by the vaccine
What makes peptide vaccination difficult?
class I MHC restriction limits relevance of individual peptides to certain HLA types; short peptides may bind directly to MHC on non-professional APCs inducing tolerance; rapidly degraded by proteases
What is the overall response rate for protein/peptide vaccination?
3-5%
How many the efficacy of protein/peptide vaccines be improved?
combinding with otehr treatments e.g checkpoints inhibitors or once finished cancer treatment
What are the most common carcinogenic HPV types?
types 16 and 18
What is the result of HPV infection?
causes cellular transformation and leads to changes to a less differentiated cell type
What proteins does HPV cause the production of ?
E6 and E7
What is the function of E6?
binds and inactivates host p53 which is essential in apoptosis in DNA damaged cells
What is the function of E7?
promotes host and viral DNA replication
What are the two forms of monoclonal antibody?
naked and conjugated
What are naked mAbs?
bind to antigens on tumour cell, other cells in tumour environment or free proteins
What are conjugated mAbs?
act as homing devices to deliver radioactive particle, toxin or chemo drug to tumours
What is the double-edged sword of the specificity of monoclonals ?
reduction in SE profile but antigen identification is important and may differ between cancers
What are the 4 methods by which mAbs work?
block receptor mediated signalling for tumour cell survival and/or growth; mark the tumour cell fro immune mediated destruction; delivering targeted drugs; blocking immunosuppression pathways
What happens when a ligand binds to a growth factor receptor?
triggers a dimerisation event and activation of a signalling casacde leading to cellular proliferation and resistance to cytotoxic agents
How does mAb block signalling?
can occur by blocking the dimerisation event or by interfering with ligand binding
What is herceptin used for?
to treat HER2 positive tumours in breast and gastric cancers
What are the mechanisms of action of herceptin?
triggers HER2 internalisation and degradation; marks cells for NK cell attack and inhibits MAPK and PI3K/Akt pathways
What is a major problem with herceptin?
resistnace develops in virtually all patients
What are the mechanisms of cancer resistance?
altered target expression ( as cancer progresses de-differentiates); altered target (mutation in receptr); overexpression of other receptors and signalling by alternative pathways- bypassing blockade
What are hte 2 benefits of ADCC with mAbs?
causes direct killing or tumour cell whilst creating cell debris that can be presented to other immune cells to stimulate immune response against more tumour cells
What is rituximab used to treat in cancer?
CLL and non-hodgkins
What is the response rate to rituximab?
48%
What are the methods of tumour killingwith rituximab?
complement mediated cytotoxicitiy; direct lysis; FcyR/CR-mediated opsonic phagocytosis or ADCC
Give an example of an antibody-drug conjugate?
Brentuximab vedotin which targets CD30 antigen on lymphocytes attached to a chemotherapy drug
How does antibody-directed enzyme prodrug therapy work?
mAb enzyme conjugate bind to tumour cell-surface antigen and prodrug adminstered binds to mAb-enzyme conjugate on the tumour cell surface releasing prodrug at highest concentrations in the tumour microenvironment
What is the problem with autologous tumour cell vaccine?
low cell numbers and not very efficacious
How does autologous tumour cell vacine work?
remove tumour cells at surgery, treat with radiation to increase immunogenicity and then give back to patietn
How have tumour infiltrating lymphocytes been used in cancer immunotherapy?
select and expand TILs from biopsies which have not been very repsonsive and is very expensive and labour intensive
What are the 2 methods of engineering T cells?
genetically insert a TCR specific for a tumour antigen or insert genes encoding a tumour specific chimeric antigen receptor
What is the benefit of CAR T cells?
they tagret surface antigens in an MHC independent fashion
What is the T body in CAR T cells?
essneitally an antibody with an intracellular signalling domain
Where has there been evidence of CAR persistence?
in immunohistochemistry and PCR of bone marrow
What is the problem with CAR T cells?
can cause cytokine storms and there is no knowledge of the long-term effects
When have CAR T cells been used successfully?
in treating chronic lymphocytic leukaemia and ALL
What solid tumour have CAR T cells been shown to be effective in mice?
ovarian tumours
What type of antigen do yd T cells recognise?
phosphoantigen
What are the benefits of using yd T cells?
very effective at killing tumour cells; don’t rely on MHC
What is the most common subpopulation of yd T cells in humans?
Vy9Vd2 T cells
Waht is hte function of combination therapies?
to increase immune recognition of cancer cells
