The Role of immune system in Cancer Flashcards
what can the immune system do in terms of tumour progression
- it can facilitate or inhibit tumour progression
How does the immune system protect us against cancer
via immune surveillance
descirbe how immune surveillance can protect us against cancer
Tumor cells and tumor antigens initiate the release of “danger” cytokines (IFN and heat shock proteins (HSP))
.
Activation and maturation of dendritic cells to present tumor antigens to CD8 and CD4 cells
subsequent T cytotoxic destruction of the tumor
How can cancer evade the immune response
Tumor antigens are weakly immunogenic
Often self antigens, potential tolerance
Cancer cells have evolved mechanisms to prevent immune rejection
name the ways in which the cancer cells have evolved to prevent immune rejection
Secretion of inhibitory cytokines
Creation of unique microenvironment - sits and organises in a way that it can grow and become more malignant and is protected from the immune system
Alteration of host immune system locally and systemically
Induction of inhibitory T cell subsets
describe how cancer can escape from the immune system
- the immune system normally eliminates the cancer and this is effective immune surveillance
- but someones the cancer can escape from the immune system and this leads to rapid proliferation of resistance clones
- this develops over several years
What immune cell is important to have in order for long term survival in cancer
- Many T regs are important to have as these cancers can be controlled fro a longer period of time versus people who have fewer T regs
- if you have fewer T reg cells the cancer is more aggressive
What is progression free survival
The length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse
what family of T cells is T reg from
CD4 positive T cells
what is the role of T reg cells
- regulating the immune response through antigen specific suprpession of effector CD4+ and CD8+ T cells
what are the two molecules that T reg cells express
Most Treg cells express CD4/CD25high and FOXP3
In what cancers in particularly do T reg cells predict survival in
Specific recruitment of regulatory T-cells in ovarian carcinoma and follicular lymphoma fosters immune privilege and predicts survival
Why are T cells in cancer exhausted
T cells in cancer are exhausted due to chronic stimulation by cancer (e.g. CLL).
• Important marker: PD1 (increased on cell surface).
What is cancer immunology
Cancer immunology is the study of how cancer affects the host immune system, focusing on how cancer evades immune destruction
What are the 3Es of immunoediting
o Elimination (immune system eliminated cancer cells) o Equilibrium (cancer cells co-exist with immune system) Immune cells kills of majority of cells, but some of the cells evolve to escape immune system. o Escape (cancer cells escape the immune system).
What are the two types of cancer immunotherapy
- Passive
- Active
Describe passive immunotherapy
- administration of agent for example as a monoclonal antibody, transfer or effector cell, T cells, NK cell, regulatory cells
describe active immunotherapy
- Induction of host immune response for example by a vaccination or adjuvant treatment
describe how monoclonal antibodies are produced
To create mAbs, human cancer cells were injected into mice.
In response, the mouse immune system makes antibodies against these cancer cells.
Mouse plasma cells produce antibodies were fused with laboratory-grown cells to create “hybrid” cells called hybridomas.
Hybridomas indefinitely produced large quantities of these pure antibodies, or mAbs.
what are mouse and human monoclonal antibodies called
chimeric (-imab)
What are fully humanized antibodies called
fully humanized (-umab)
How do you approach using monoclonal antibodies for treatment
o Unconjugated: complement mediated lysis.
o Coupled to toxins: immunotoxins.
o Coupled to radioisotopes: radioimmunoconjugates (radiation theraphy).
o Also to cells surrounding it.
What is the major problem with monoclonal antibodies
Major problem with murine mAbs was that patients developed human anti-mouse antibodies (HAMA) so that these agents could be used only once.
in a mouse and human monoclonal ab what part is human and what part is mouse
Binding site is murine
backbone is human
describe how humanisation of monoclonal abs have taken place
Recent advances to develop recombinant molecules that maintain the antigen binding of the murine mAb coupled to the human Ig backbone, a process known as “humanization” of a mAb has revolutionized this field
What is the ideal target for monoclonal antibody therapy
Expressed on all tumor cells
- Not present on critical host cells
- No significant toxicity if all antigen+ cells eliminated
- High copy number
- No mutations or variant antigens
- Required for critical biologic function or cell survival
- Not shed or secreted
- Not modulated after antibody binding
name three proposed mechanism of action of monoclonal Abs
Antibody-dependent cell-mediated cytotoxicity (ADCC)
Complement-dependent cytotoxicity (CDC)
Apoptosis
Describe how complement dependent cytotoxicity works (CDC)
- uses a membrane attack complex(MAC) and beta cell lysis
- there is a sequential activation of remaining complement components which leads to incorporation into the MAC
- The MAC then forms a pore through the target cell membrane and causes lysis
describe how monoclonal antibodies induced ADCC ( antibody dependence cell mediated cytotoxicity)
Fc region on phagocytic cells e.g. NK cells, macrophages, neutrophils.
Effector cells release mediators that damage and destroy malignant B cells.
Malignant B cells are phagocytosed.
describe how monoclonal abs directly induce B cell apoptosis
mAb binding to CD20 may induce transmission of intracellular signals that trigger cell cycle arrest and apoptosis
What is rituximab used to treat
single agent in patients with relapsed non-Hodgkin’s lymphoma
describe Rituximab as a monoclonal ab
Chimeric MoAb that targets protein called CD20 that is present on the surface of normal and malignant B cells
What is trastuzumab used for
HER2 positive breast cancer
How is trastuzumab afforded
cancer drug fund
What is a bi specific monoclonal ab
MoAb which is designed to bind to two different antigens
E.g. CD19/CD3 bispecific antibodies.
give an example of a bi specific monoclonal ab
blinatumomab
How do Bi specific monoclonal abs work
CD8 positive T cell recognizes an antigen in coordination with MHC 1 which every cell has
tumour antigen is too weak to activate the T cell
if there is a bi specific monoclonal antibodies can grab the T cells and activate it to defend against the antigen
when are prophylactic cancer vaccines given
Prophylactic vaccines are given to healthy individuals before cancer develops.
what are prophylactic cancer vaccines designed to do
These vaccines are usually designed to stimulate the immune system to attack viruses that can cause cancer
what certain cancers are targeted using vaccines
cervix and liver
what are the current types of vaccines
Antigen/adjuvant vaccines
Whole cell tumor vaccines
Dendritic cell (DC) vaccines
Viral vectors and DNA vaccines
Idiotype vaccines.
What is the mechanism of action of immunomodulators
• PD1 is highly expressed in the immune cells of cancer patients.
o These are inhibitory receptors.
• Balance between activing receptors and inhibitory receptors immune response.
o Cancer cells overexpress checkpoint receptors.
Poised to switch immune cells off
What does blocking immune checkpoints promote
Blocking immune checkpoints may promote endogenous antitumor activity
What are PD1 on T cell tumours associated with
PD1 expressed on T-cells when exposed to tumour, and associated with exhaustion.
Blocking these PD1 receptors can restore function
When do PD1 act as inhibitory receptors
PD1: Inhibitory receptor on activated T-cells, B-cells, NK and myeloid cells.
Inhibition of T-cell activation when engaged by ligands (PDL1/2)
How do immune checkpoints inhibitors work and give an example
• Blocking immune checkpoints may promote endogenous antitumor activity
o Eg. Blocking of PD1 can restore function of T-reg cells.
How do you treat Chronic Lymphocytic Leukaemia displaying PD1
by inhibiting PD1
What cancers is PD-L1 expressed in
- Non small cell lung cancer (squamous cell carcinoma)
- Non small cell lung cancer (adenocarcinoma)
- colon
- melanoma
- renal
What two cancer types make up non small cell lung cancer
squamous cell carcinoma
adenocarcinoma
What is the approved treatment used for PD1 (checkpoint inhibitors) today
PD1 inhibitors;
- Nivolumab
- Pembrolizumab
What is a chimeric antigen receptor
The chimeric antigen receptor is then added to immune cells called T cells. This helps the T cells find and kill cancer cells that have the specific protein that the receptor is designed to bind.
Describe the theory behind how chimeric antigen receptors work
= usually T cells cannot recognise an antigen without MCH1
= the chimeric antigen receptor helps the T cell recognise the cancer cell and therefore cause the cancer cell to be killed by the T cell
