Flashcards in IMI9: Cancer Immunotherapy Deck (106)
What is immunotherapy?
a unique approach aimed at defeating cancer. It is designed to instruct the body’s own immune system to kill off the patient’s own cancer cells in the same way it does with other foreign invaders, such as bacteria
Chronic damage to melanocytes (pigment producing cells in skin) by UV radiation leads to what?
Leads to most cases of melonoma
Can melonoma's spread?
yes e.g. lungs and liver
The cells the immune system can't sense survive and replicate and so the tumour can evade the immune system
What can PDL1 do?
Expressed by tumour cells
Binds to the PD1 receptor on T-cells - inactivating them: this is an immune checkpoint
Tumour cells can attract regulatory T cells and macrophages to do what?
Suppress the activity of other immune cells; thereby supporting tumour growth
What is adoptive cell therapy?
T-cells extracted from patients, tested for their ability to kill cancer cells, replicated and infused back into patients
A therapy where antibodies bind to PD1 receptor does what?
Stops T-cells from switching off
How can you boost the activity of anti-tumour immune cells?
Treating patients with cytokines: interleukin 2 and interferon alpha
Another immune checkpoint that can be targeted is what?
CTLA4: blocking this molecule allows DC to drive anti-tumour cell responses
What does it mean by immune therapy being specific?
- Immunotherapy should recognise specific tumour antigens expressed by cancer cells
- The first key step is identifying a tumour antigen that is found primarily on cancer cells and typically not on normal cells
What does it mean by immune therapy being adaptable?
- Immunotherapy should reinforce the immune system to adapt its attack strategy over time.
- Tumour cells mutate over time, which may make them resistant to traditional anticancer therapies
- When tumour cells are killed, immune cells are exposed to tumour antigens (including the ones that have mutated), which expands and adapts the immune response cascade
What does it mean by immune therapy being durable?
Immunotherapy should lead to a prolonged antitumor response because it should stimulate immunologic memory
What two categories can cancer immunotherapies be listed into?
Active or passive or a combination of the two
What does active immunotherapy mean?
Aims to trigger an anti-tumour response from the immune system of the patient (e.g. vaccination)
What does passive immunotherapy mean?
Requires the use of biological reagents such as mAbs or antigen-specific adaptive immune cells
What does active immunotherapy include?
- Cytokine therapy: stimulation of the patient’s immune system with cytokines;
- Cancer vaccines: stimulation of the patient’s immune system with vaccines.
What does passive immunotherapy include?
- Monoclonal Antibody therapy: therapeutic antibodies are provided to the patient
- Cell-based therapy: immune cells or genetically modified immune cells are provided to the patient
What are interferons?
Interferons (IFNs) are known for their antiviral activity but they also play other key roles in regulating immune activity. They can be divided into three groups
What are the three groups IFNs can be grouped into?
- Type I (these include 13 IFN-α subtypes and IFN-β)
- Type II (IFN-γ)
- Type III (IFN-λ subtypes)
What is the only IFN approved for the treatment of cancer? What does it do?
Interferon alpha. It can promote B cell proliferation, as well as activate natural killer (NK) cells
What are interleukins?
Interleukins work as intercellular signals between leukocytes, our white blood cells
What was the first immunotherapeutic agent to treat cancer in humans?
Interleukin-2 (IL-2). It stimulates T cell growth and proliferation, and is largely produced by CD4+ T cells
What are chemokines? What do they do?
Chemokines induce movement of surrounding cells through a process called chemotaxis. They actually have a double-edged role in tumour formation:
they can either decrease tumour growth by recruiting leukocytes to the tumour site, or
they can stimulate tumour growth by influencing movement of cancer cells
By altering the cytokine milieu at the tumour site using cytokines such as IL-2 or IL-12 what happens?
You can potentially convert an immunosuppressive microenvironment to one that promotes and enhances an immune response
What are the side effects of cytokine therapy?
Some of them can even be unpredictable since cytokine biology is interpreted using mouse models which are not all that similar to the humans despite the many extrapolations done in research setups over the years
What is the half-life of cytokines like?
Short half-life: even if cytokines are tremendously potent, they do have short half-lives. Therefore, to maintain the required blood concentration for biological activity, cancer patients must receive a large amount of the cytokine preparation
Why is there an issue with the amount of cytokine produced for treatment?
Expressing sufficient amounts of cytokines in the appropriate target cells is still an issue and cytokine gene therapy has been explored as a possible approach
The delivery of IL-12 was obtained using what methods?
- Direct infusion of the recombinant protein
- gene therapy using viral and non-viral vectors
- IL-12-containing microspheres
- the transfer of IL-12-overexpressing stromal and immune cell types