Immunotherapy Flashcards
What is the definition of immunotherapy?
Immunotherapy is defined as harnessing the patient’s own immune system to fight disease, by recognising and eradicating diseases.
Overview of immunotherapy
- Immunotherapies are directed at a specific antigen or cluster of antigens that compose the unique signature of a virus or cancer cell that is dissimilar to its host, thus recognising self from non-self.
- Immunotherapies engage and recruit the immune system to combat the disease by inducing an antibody generated response to an antigen (foreign entity) typically present on the cell surface of a virus or cancer cell. These cell surface antigen targets typically evade the immune system and manifest disease within the host.
Success of immunotherapy
The tumour load needs to be reduced, by chemotherapy, irradiation and surgery, for two reasons:
1. Immune system cannot cope with large tumours
2. If there was lots of antigen shedding from the tumour it would result in a stimulation of the regulatory T cells and thus stop an immune response against tumours.
Cancer immunotherapy: Immuno-oncology
Immune checkpoint inhibitors
- The most successful immunotherapeutic approach so far is immune checkpoint inhibitors using agents that block the inhibition of T-cell activation.
- Designed to overcome blockages to T-cell activity medicated by immune checkpoints
- Work by reactivating TILs (tumour infiltrating lymphocytes) particularly CD8+ cytotoxic T cells
- CTLA-4 checkpoint inhibitors: anti-CTLA-4 mAbs are desgined to augment T-cell activation by blocking inhibitor receptors such as CTLA-45
- Checkpoint inhibitors against PD-1 and its ligand PD-L1 release PD-1 pathway mediated inhibition of T-cell activation
Keytruda: Anti-PD-1
- Keytruda PD-1 (programmed cell-death protein-1) inhibitor, blocks PD-1/PD-L1 pathway
- Keytruda approved as first-line treatment for advanced non-small cell lung cancer (NSCLC) whose tumour expresses PD-L1 at 50% and other cancers
- PD-L1 is a useful biomarker for effectiveness of PD-1 inhibitors
- Approved by FDA in May 2017 as the first cancer treatment for any solid tumour with a specific genetic feature (biomarker)
Immune Agonist Therapeutics
- These mainly antibody based drugs target specific cell surface proteins on T-cells causing stimulation on T-cell activity
- CD27 on T-cells interacts with CD70 on antigen presenting cells to deliver second signal
- Varulumab can substitute CD70 by delivering costimulatory signal to CD27 positive T cells with engaged TCRs
Adoptive T-cell transfer
- Involves generating large numbers of T-cells outside the body (ex vivo)
- These isolated T-cells can be genetically engineered si that they produce cytokines such as IL-2 which will boost their activity
- The T-cells are expanded by in vitro stimulation with antigen presenting cells and are then put back into the patient
- By growing these cells in vitro, responses can be generated which are not found in vivo due to tumour derived inhibitory factors, or the presence of T-regulatory cells
METHOD - T cells are isolated from patients and these are then expanded in vitro in high levels of IL-2
- To maximise the chance of expanding rare tumour-reactive T-cell precursors, mature dendritic cells expressing costimulatory signals along with a source of tumour antigen are commonly used
- Over 2 - 3 weeks of cell culture, the T-cells can be increased 1000 fold. The CTLs are transferred back into the patient
- Giving the patient IL-2 in vivo or transferring some T-helper cells not only improves survival of CTLs, but also increases their cytotoxicity function
- There are some risks as the process involves transferring massive numbers of activated T-lymphocytes into a patient - this means that you must select tumour antigens that are not expressed or minimally expressed on tissues other than the tumour, otherwise autoimmunity will be generated
CAR T-cell therapy
- Modified chimeric antigen receptor (CAR) T-cells are designed to redirect T-cell antigen specificity, activation and further enhance T-cell function via costimulation domains in the cytoplasmic tail
Dendritic cell vaccines
- Dendritic cells are a type of antigen presenting cell
- Dendritic cells take up antigen and present this antigen on MHC class II to T-cells, thus inducing an adaptive immune response
- Tumour cells are normal cells that due to mutations divide increasingly. They resemble normal cells and possess normal cell molecules, so are not killed by the immune response. Tumour cells also make factors that down regulate the tumour response. Some tumour cells do express antigens that do initiate an immune response
METHOD - Peripheral blood mononuclear cells (monocytes, NK cells and lymphocytes) are isolated from the blood of a patient
- Dendritic cell progenitors are negatively selected using magnetic beads (CD3, CD11b, CD16)
- These cells are cultured in the presence of growth factors (GM-CSF)
- Tumour cells from the patient or tumour specific antigens are added to the cells and are re-infused back into the patient
- The antigen pulsed dendritic cells will now stimulate an adaptive immune response
Cancer subunit vaccines
A chronic infection with hepatitis B virus increases the risk of developing liver cancer by about 200 fold. Approximately 20% of long term hepatitis B carriers eventually develop liver cancer. Hepatitis B is one of the most infectious of all viruses. A subunit vaccine that protects against Hepatitis B viruses have been given to healthcare professionals who routinely come into contact with blood products and children. This means that if infection with hepatitis B does occur, the immune system is prepared and can quickly eradicate the virus, effectively preventing hepatitis B associated liver cancer.
Human Papilloma Virus (HPV)
Another example is giving HPV vaccines to females and males aged 12 - 13 to prevent them developing cervical, anal, genital cancers and cancers of the head and neck, as HPV is strongly associated with these tumours. The NHS uses a vaccine called Garsadil as it protects against HPV 6, 11, 16 and 18. The vaccine is preventing infection by the virus not stimulating immunity directly against the tumour.
Immunotherapy of cancer
- Passive immunotherapy with monoclonal antibodies (mAb): approved for HER2 in breast cancer, CD20 in lymphoma, EGF in colorectal cancer. Antibodies reacting with antigens on the surface of tumour cells protect the host by complement mediated opsinisation and lysis as well as recruitment of macrophage NK ADCC. The FcR cells not only have cytotoxic functions but cause crosslinking of antibody coated cells which leads to apoptosis or exit from the cell cycle, and makes the cells sensitized to irradiation and DNA damaging chemotherapy. Antibodies alone are sometimes effective; however, a lot of interest has been made into therapeutic immunoconjugates which consist of tumour targeting antibody, linked with a toxic effector component, such as a toxin or small drug molecule
Bispecific T cell engager (BiTE) antibodies
- Designed to bridge cancer cells to CTLs. The construct utilises the binding properties of the variable domains of two monoclonal antibodies. One domain is designed to target an antigen on the surface of a cancer cell, whereas the other is designed to engage CD3 on the surface of a T-cell. With these two different domains, BiTE antibodies aim to engage the endogenous cytotoxic potential of CTLs, bypassing MHC/antigen-dependant activation of T-cells
Immunotherapy of cancer
- Cell-mediated immunity refers to T-cell mediated immune responses. It is T-cells not antibodies that have a role in destroying tumour cells. It is the CD8+ or cytotoxic T-lymphocytes that are important, for particularly expressing processed intracellular antigens on their cell surface, as most are MHC class II negative. However, the T-helper cells are important for persistence of CTLs
- Stimulation of cell-mediated immunity: vaccination with viral antigens from oncogenic viruses. Some cancers are caused by oncogenic viruses, so attempts are being made to isolate the virus and prepare a suitable vaccine from it. Research is currently being undertaken to develop a vaccine to exploit the ability of CTLs to target EBV-related antigens on the cells of all Burkitt Lymphoma’s.
- Immunization of whole tumour cells: Both autologous (from the same individual) whole tumour cell preparations have been given to stimulate an anti-tumour response. The advantage of this approach is that you do not need to have identified the tumour antigen. The disadvantage is that most tumours are weakly immunogenic, and do not present the antigen effectively and so cannot overcome the barrier to activation of resting T-cells. The surface MHC-peptide complex is not enough, costumulation with molecules such as B7 and certain cytokines are needed to activate the T-cells. Once activation is achieved, the activated T-cell no longer requires the accessory costimulation to react with its target, for which it has greatly increased avidity due to upregulation of accessory biding moleculesas CD2 and LFA1.
