Introduction to Tumour Immunology Flashcards
What is ipilimumab?
mAb against CTLA-4
What was the efficacy of ipilimumab for metastatic melanoma with one round of treatment?
more than 20% of patients were alive 10 years later with no evidence of disease vs survival or <10%
What is nivolumab?
mAb against PD-1 receptor
What is the response rate of nivolumab in metastatic melanoma?
50%
what has suggested that the immune system plays a major role in neoplastic development?
patients who are immunsuppressed have a higher risk of cancer and spontaneous regression is rare but well recognised phenomenon- esp. after infectious and/or high febrile episode
What was the first use of modulating hte immune system to treat cancer?
notice of the regression of tumours in cancer patients after erysipelas then intentional infection of cancer patients
How was the the bacterium BCG used in cancer treatment?
effective against superficial bladder cancer
What are Coley’s toxins?
injection of heat-inactivated bacteria into patients with inoperable cancers
What are the non-self antigens that that cells use to recognise cancer cells?
tumour-associated antignes
Give examples of tumour-associated antigens?
products of mutated proto-oncogenes; tumour suppressor genes; overexpressed or aberrantly expressed proteins; tumour antigens produced by oncogenic viruses, altered glycolipids and glycorproteins
What was the first experiment of evidence of immune response to cancer?
a mouse with chemically induced sarcoma had the tumoue resected then retransplanted which resulted in tumour rejection, but if given to naive genetically identical mouse, develops tumour, if give CTLs from original mouse, gets rid of tumour
What demonstrated that immune responses in cancer associated with prognosis to cancer?
presence of tumour infiltrating lymphocytes resulted in better prognosis; with Tregs associated with worse prognosis
What are the hallmarks of cancer?
sustained proliferative signalling; evading growth suppressors; activating invasion and mets; enabling replicative immortality; evasion of cell death and induction of angiogenesis; avoidance of immune destruction
What are the enabling characteristics of cancer?
genome instability and mutation; tumour-promoting inflammation
What are tumour associated antigens?
over-expressed normal genes; products of mutated genes; extopic expression of normal gene products; abnormally glycosylated proteins; viral gene products; novel products of chromosomal instability
What are hte major mechanisms by which CTLs kill target cells?
perforin/granzyme and Fas/FasL
What are the stages of the cancer-immunity cycle?
release of tumour-associated antigens; cancer antigen presenation; priming and activation of T cells; trafficking of T cells to tumours; infiltration of T cells into tumours; reconigiton and killin
What reduces infiltration of t cells into tumours?
VEGF; enfothelin B receptor
What prevents recognition of cancer cells by T cells?
reduced p/MHC on cancer cells
How do traditional cancer drugs contribute to the cancer immunity drugs?
kill tumour cells releasing tumour-associated antigens
What are the stages of cancer immunoediting?
elimination through the cancer-immunity cycle which then provides immune pressure for cells not expressing p/MHC in the equilibrium stage and then escape
Waht si the goal of cancer immunotherapy?
initiate or reinitiate a self-sustaining cycle of cancer immunity enabling it to amplify and propagate but not so as to create n unrestrained autoimmune inflammatory response
Waht can enhance priming and activation in the cancer immunity cycle?
anti-CTLA4
What can enhance infiltration of T cells into tumours?
anti-VEGF
What can enhance recognition of cancer cells by T cells?
CARs
What can enhance immune killing of cancer cells?
anti-PD-1; anti-PD-L1 and IDO inhibitors
What is the cancer immunosurveillance hypothesis?
the immune system is capable of detecting and killing nascent non-self malignant cells
What is the equilibrium phase of cancer immunoediting?
when any tumour cells survive the initial elimination attempt but are not able to progress
How does the immune system regulation contribute to cancer progression?
upregulation of immune checkpoint molecules on their surfaces due to cytokine produced by activated T cells- part of normal negative feedback to control excessive tissue damage from inflammation
What provided the proof that the immune system was capable of seeking and destroying tumour cells and identified the first molecular target?
first human tumour antigen : melanoma antigen-encoding gene encoding an antigen recognised by CTLs
What are the main ways of evasion of the immune destruction by cancer cells?
modulates its own cellular characteristics and creating its own tumour microenvironment by recruiting normal immune cells to shield it from attack
What immune cells do cancers recruit to shield it from the immune repsonse?
macrophages; Tregs; immature myeloid cells (which become myeloid-derived suppressor cells); Th17; Bregs
How do tumours create pre-metastatic niches?
influence the systemic environment through cytokines by altering haematopoiesis and tissue parenchyma of distant organs
What is the cancer immune set point?
intrinsic immunological ability of an individual to comabt cancer
What is the only therapeutic vaccine for cancer licensed?
DC vaccine for prostate carcinoma
How is the prostate cancer vaccin created?
DCs from the patient are exposed to prostatic acid phosphatase and GM-CSF and re-infused into the patietn
What is the goal of all tumour vaccines?
exposure of patients immune system to tumour antigens provoking an anti-tumour immune repsonse
How does BCG vaccination treat bladder carcinoma?
indirectly increases the expression of tumour antigens after the tumour cells internalise the bacteria
What is the function of oncolytic viruses?
genetically modified viruses to lack virulence against normal cells but are able to invade and lyse cancer cells (releasing tumour antigens )which have sacrifieced many anti-viral cellular defnses in order to increase growth potential
What oncolytic virus has been approved?
HSV-1 virus against advanced melanoma
What has allowed a much simpler and efficient method of gene editing for use in adoptive cell therapy?
CRISPR/Casp9 technique
What is a problem with adoptive cell therapy?
deaths due to cytokine storm and cerebral oedema
What is the first disease to receive approval for CAR T cell therapy?
relapsed and refractory B cell ALL
When was T cell exhaustion first observed?
in mice infected with a chronically persistent strain of lymphocytic choriomeningitis virus
Waht is the function of T cell exhaustion?
reversible physiologicaly protective mechanism against autoimmunity
How does the immune checkpoint LAG-3 work ?
structurally homologos to CD4 but has a higher binding affinity to MHC-II than CD4
How can checkpoint molecules be used as markers of T cell exhaustion?
upregulated in suppressed T cells
Why is CTLA-4 considered the leader of the immune checkpoints ?
stops potentially autoreactive T cells at the priming stage of naive T cell activation occuring chiefly in the lymph nodes
When is PD-L1 upregulated on many cell types ?
after exposure to IFNy
Why are immune checkpoint inhibitors an exciting model?
less toxic than conventional therapies and much easier to prepare and administer than other cancer immunotherapeutics
What was the result of a phase I trial of an antibody to the CD28 ligand?
massive cytokine storm associated with multiorgan failure
What is important about the timing of administration of immune checkpoint inhibitors?
to coincide with a high inflammatory microenvironment in the tumoue to ensure presence of many potential tumour-fighting CD8 T cells–tumoue necrosis provoked by chemo; mutational burden of the tumour which has higher antigenicity
Give an example of how increased mutational burden in the tumoue improves response to immune checkpoint inhibitors?
lung cancers in smoker have higher mutation burden and show higher reposnse
How has the gut microbiota been shown to impact immune checkpoint inhibitors?
patients with metastatic renal cell carcinoma shoed faster tumour progression in patietns who had received broad spec antibiotics a month before treatment with ICIs; differences in gut microbiota in melanoma patients between responders and non-responders
Why is cancer immunotherapy particularly active in melanoma?
appears atypically immunogenic
Where do the immunogenic signals resulting in immune activation rather than tolerance to tumour-assocaited antigens?
proinflammatory cytokines and factors released by dying tumour cells or by the gut microbiota
What created a significant problem in stimulating immune responses against cancers?
local immunsuppressive tumour microenvironment
Why are multivalent vaccines more effective than a single antigenic target?
may not generate sufficiently robust T cell repsonses in all patients, if not derived from an inherent oncogenic driver, it will enable resistance by antigenic drift
What are CARs?
a patients T cells are transfected with a construct encoding an antibody against a tumour surface antigen fused to T cell signalling domains
What underlies the significant immune -related toxicities seen with CTLA-4 inhibitors?
lack of selectivity in T cell expansion and the fundamental importance of CTLA4 as a checkpoint
What is the frequency of expression of PD-
L1 across all human cancer?
20-50%
What does the efficicacy of the anti-PD-L1 antibodies suggest about the cancer immunity cycle?
it is intact up until the point of tumour cell killing by T cells which can be potently restrained by PD-L!
What is the signalling pathway of PD-1?
recuits the phosphatase SHP-2 and inactivates PI 3-kinase
Why is the safety profile of PD-L1 inhibitors better than CTLA-4?
many cancer types express PD-L! to inhibit anticancer immune repsonses; most patients do not have underyling autoimmunity inhibited by only DP-L1 expression
Who first suggested that the immune system could repress a potentially overwhelming frequency of carcnomas?
Paul Ehrlich
How does invasive growth cause pro-inflammatory cytokines to be released?
causes minor disruptions within the surrounding tissue
What is the function of CXCL10 and CXCL9 induced by IFNy in the context of tumour growth?
potent angiostatic capacities blocking the formation of new blood vessels in the tumour nad more tumour death
