Cancer immunotherapy Flashcards
What is immunotherapy
designed to instruct own immune system to kill off patient’s own cancer cells
Characteristics of immunotherapy
- Should recognise specific tumour antigens expressed by cancer cells
- When tumour cells are killed, immune cells exposed to tumour antigens expands and adapts the immune response cascade
- Immunotherapy should lead to prolonged anti-tumour response because it stimulate immunologic memory
What are the types of immunotherapy
Active - cytokine therapy, cancer vaccines
Passive - monoclonal antibody therapy and cell-based therapy
What cytokines can be used in cancer treatments
interferons (type 1,2,3 alb,y,l) subtypes promote B cell proliferation
interleukins stimulate T cell growth and proliferation
chemokine induce movement through chemotaxis
IL-2 • For treatment of metastatic melanoma and renal cell carcinoma
• Target T cells and B cells in adaptive IS
IFN-2α • Stimulate generation of DC and macrophages
• treatment of hairy cell lymphoma and Philadelphia chromosome-positive chronic myelogenous leukaemia
IFN-α2b • Treatment of hairy cell leukaemia, AIDS-related Kaposi’s sarcoma, follicular lymphoma, melanoma, multiple myeloma, genital warts and cervical intraepithelial neoplasms
Drawbacks of cytokine therapy
side effects like flu symptoms, short half life, expressing sufficient amount of cytokines in appropriate target cells is an issue
What are cancer vaccines
• type of vaccines that are designed to boost your immune system to protect you against tumours such as cervical, prostate and bladder cancers.
what are the two types of cancer vaccines
prophylactic which protects from developing tumour, therapeutic which helps immune system
what are the molecular types of vaccines
antigen
tumour cell
DNA/RNA
dendritic cell vaccine
What are prophylactic vaccines
- provide prior immunity so that the body can build up antibodies without contracting the illness
- administrated to people with elevated risk of developing cancers and that may. or may not. have been diagnosed with premalignant changes in tissues.
- specificmemory cellswill be reactivated by the tumour antigen reaching lymph nodes.
What are therapeutic cancer vaccines
- administered after a tumour diagnosis
- used in patients in remission to prevent a likely relapse and the cancer from returning.
can be divided into autologous cancer vaccines which are made from individual’s own cancer cells and allogenic cancer vaccines which are cancer cells taken from different individual
Drawbacks of cancer vaccines
- Hostile tumour microenvironment
○ cancer cells can suppress the immune system
○ The use of adjuvants in vaccines has been implemented to try to fix this problem.- Tumour escape
○ tumour cells can go through antigenic variations or lose the expression of antigens and/or antigen-presenting molecules
§ bypassing the recognition by the immune system. - Older or sick people have weaker immune system
bodies may not be able to produce a strong enough immune response after vaccinatio
- Tumour escape
What are monoclonal antibodies therapy and what antibodies are included ?
• Designed against antigens presented on the surface of tumour cells
Include naked mAbs, Conjugated mABs, Bispecific mAbs
What are naked monoclonal antibodies and their mechanisms
antibodies that are not attached to radioactive material or toxins
- via antibody dependent cell-mediated cytotoxicity by attacking the tumour cells and making them for immune system to kill them with the help of NK cell, oesinophils, macrophages
- By targeting immune checkpoints anti PD-1
blocking the fail-safe mechanisms ensure immune response only occur when needed and are switched of soon - Also to block antigens
negative regulation of PD-1
STAT3 when activated can bind PD-1 and induces it upregulation in cancer hence facilitating tumour escape, it can remove protein expression with roles of apoptosis, metastasis
What are conjugated monoclonal antibodies and examples
- Attached to radioactive particle or to a chemotherapy drug
- Used as a shuttle to deliver these substances directly to cancer
Radio-labelled antibodies such as anti-CD20 antibody used to deliver radioactivity directly to cancerous B cells
chemo-labelled antibodies which are attached to chemotherapeutic drugs
What are bispecific monoclonal antibodies
- designed as an antibody that is composed of two different mAbs, and can thus bind two different proteins (antigens) simultaneously
- bring together, or cluster, the cancer cells and immune cells
What are the drawbacks of monoclonal antibodies therapy
- Allergic reactions
• Hives or itching since antibodies are proteins- Production costs
• Very expensive and a huge effort is required - Tissue penetration
• no more than 20% of the mAbs directed against tumour-specific antigens will interact with the tumour, in murine xenograft models - Mode of action
• mAbs show diverse modes of actions in vitro but what happens once injected in patients is not always clear
- Production costs
How are human monoclonal antibodies
- Technique :
* Transgenic animals (mice or rats)
* Antibody phage display- animals are genetically modified in a way that their own immunoglobulin genes are replaced with the human ones
- they produce human antibodies based on the new inserted human gene sequences.
- Without immunization
- Derived directly from human RNA molecules and entire process is performed in vitro
What are humanised chimeric antibodies
- Derived from non-human immunoglobulins
- protein sequences are then modified using genetic engineering to make them similar to the homologous human ones
- chimeric antibodies are produced when the mouse constant domains (Fc) are replaced with that from human
- humanised antibodies are instead completely similar to the human variant, despite the non-human origin of some of its complementarity determining regions (CDR)
What are cell based therapy
they really on immune cells derived from the patient which are modified to enhance recognition and killing tumour cells
eg. Tumour infiltrating lymphocytes and genetically modified T cells
What are tumour infiltrating lymphocytes
- In adoptive T cell transfer (ATC) therapy
* TILs are isolated from tumours and expanded ex vivo with high dose of IL-2 (growth factor for T cells)- Different cell lines show different tumour reactivity
- Best tumour reactivity are selected and further expanded to be infused
- Chemotherapy before re-inoculation of selection TILs
- Endogenous lymphocytes if not removed could compete for growth factors and decrease the anti-tumour effects
- Different cell lines show different tumour reactivity
What are the two types of genetically modified T cell therapies
• Two classes
• Chimeric antigen receptor (CAR) therapies
§ Recognise tumour antigen on cell surface - external antigens
• Genetically modified T cell receptor (TCR) therapies
§ Recognise cancer peptides presented on HLA molecuels - internal antigens
Describe chimeric antigen receptor therapies
- Utilise receptors that have been engineered to give T cells new ability to target specific tumour protein independably of HLA presentation
- T cells are harvested from patients, genetically modified, and then the resulting CAR-T cells are reinfused
- CAR-T cells can be either derived from the same patient’s T cells (autologous) or from another healthy donor (allogenic)
Describe genetically modified TCR therapies
- modifying the expression of specific TCR α and β chains
* which mediate the recognition of the cancer antigen- tumour-specific TCR α and β chains must be first identified
- genetically engineered to improve specificity and affinity for tumour antigen
- transduced into T cells to become tumour antigen-specific T cells.
