IMI 10: Cancer Immunotherapy Flashcards
1
Q
Observe the learning outcomes of this session
A
2
Q
What is immunotherapy?
A
- Immunotherapy is 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.
3
Q
Describe the different antigens of cancer cells
A
- Self-antigens:
- all nucleated cells in our body present self antigens or self-peptide on MHC Class I
- the immune system recognises these peptides as self and does not mount a response (tolerance) - Tumour specific antigen (TSA)
- mutated genes can be transcribed and translated and the resulting altered protein is a tumour-specific antigen (TSA)
- they are present only in cancer cells but not normal
- the immune system will mount a response against TSA because these antigens are new to the immune system - Tumour-associated antigens (TAA):
- cancer cells can increase the expression of some proteins that make them thrive
- e.g. some growth factors
- the immune system is tolerance to these proteins because they are also present in normal cells
- however, some TAAs are expressed at a very low level in normal cells and when expressed in higher levels within cancer cells, they cna trigger an immune response
- they can also be used to develop some immune therapies - Embryonic antigens (TAA):
- some proteins are expressed during early embryonic development and are switched off in adult life
- some of these proteins are expressed before the immune system fully develops and acquires self-tolerance
- cancer cells have the ability to activate the transcription and translation of embryonic genes that make them thrive
- once these are active, the immune system encounters them for the first time and is able to mount a response
- embryonic antigens are considered tumour-associated antigens because at a stage of development they were expressed in normal cells
4
Q
Describe immune surveillance, equilibrium and escape
A
- Immune surveillance:
- the immune response cells of the innate and adaptive immune system are able to identify cancerous cells and eliminate them
- these include dendritic cells, inflammatory macrophages, T helper cells, CTLs and NK cells
- the immune response to cancer cells is very similar to that of virus infected cells - Equilibrium:
- if cancer cell are not completely eradicated during the tumour elimination phase, another transitory phase kicks in, called the equilibrium phase
- when the immune system and the developing tumour are in a balanced state
- tumour cells can remain dormant or keep on acquiring genome modifications
- this can result in the alteration of tumour-specific antigens which may no longer be recognised by the immune system
- there is also equilibrium between tumour-promoting cytokines (e.g. IL-10, IL_23) and anti-tumour cytokines (e.g. IL_12, IFN-gamma) - Escape
- see future flashcard
5
Q
Describe the escape stage of the immune response in cancer
A
- Escape: cancer cells subverting the immune response
- Mutations:
- cancer cells mutate continuously and a new set of cells of the adaptive immunity are able to recognise the new mutated antigens need to be activated
- this prolonged stimulation can lead to immune cell exhaustion
- Low MHC molecule expression:
- viruses can repress the expression of MHC molecules
- in cancer caused by oncoviruses, loss of MHC is not uncommon
- cancer with a high rate of mutation may have aberrant MHC proteins
- lack of MHC will halt the recruitment and activations of T cells
- in this instance, NK cells should be more active, but often activating factors on target cells have also reduced expression
- Lack of co-stimulatory signals:
- tumour cells lack co-stimulatory signals
- complete activation of cytotoxic T cells requires support from helper T cells and professional antigen-presenting cells in antigen cross-presentation
- if such support is missing, T cells cannot be activated
- Immunosuppressive environment:
- cancer cells induce the production of anti-inflammatory cytokines such as IL_10 and TGF-beta
- these dampen the immune repsonse inducing helper T cells to acquire a regulatory phenotype expressing CTLA-4
- CTLA-4 compete with CD28 for CD80/86
- this further leads to T cell anergy rather than activation
- similarly, inflammatory macrophages can acquire an alternatively activated (or M2) phenotype and will become unable of antibody-dependent cellular cytotoxicity (ADCC)
- moreover, cancer cells can exploit immune checkpoints by expressing PD-1L and directly inducing T cells anergy
- resistance to apoptosis:
- one of the main mechanisms of tumour cell eradication consists of apoptosis caused by cytotoxic T lymphocytes and NK cells
- as part of the tumour/immune system co-evolution, tumour cells activate signalling pathways that lead to resistance to apoptotic signals
6
Q
What is tumour immune editing?
A
- During immune surveillance, the immune system is capable of eliminating cancer cells.
- However, some cells are able to enter a dormant state which enables them, with time, to evolve strategies to escape and/or weaken the immune response.
- This phase is called tumour immune editing.
7
Q
Observe this diagram of the location and steps required for the activation of T cells in response to tumour cells
A
8
Q
How can immunotherapy improve such response(s) so that the immune system can fight cancer progression more effectively?
A
- 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.
- 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.
- Durable
- Immunotherapy should lead to a prolonged antitumor response because it should stimulate immunologic memory.
9
Q
What are the types of cancer immunotherapies?
A
- active:
- aims to trigger an anti-tumour response from the immune system of the patient (e.g. vaccination)
- passive:
- requires the use of biological reagents such as mAbs or antigen-specific adaptive immune cells
- or a combination
10
Q
Give examples of active immunotherapy
A
- Cytokine therapy: stimulation of the patient’s immune system with cytokines.
- Cancer vaccines: stimulation of the patient’s immune system with vaccines.
11
Q
Give examples of passive immunotherapy
A
- 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.
12
Q
Briefly recap interferons (IFNs)
A
- 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:
Type I (these include 13 IFN-α subtypes and IFN-β)
Type II (IFN-γ)
Type III (IFN-λ subtypes)
- To date, only interferon alpha has been approved for the treatment of cancer. It can promote B cell proliferation, as well as activate T cells and natural killer (NK) cells.
13
Q
Recap interleukins
A
- As their name suggests, interleukins work as intercellular signals between leukocytes, our white blood cells.
- The first immunotherapeutic agent to treat cancer in humans was interleukin-2 (IL-2). It stimulates T cell proliferation, and is largely produced by CD4+ T cells.
14
Q
Recap chemokines
A
- 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.
15
Q
Observe this figure and describe it
A
- Note that the tumour microenvironment contains many different cells and cytokines, some with opposing functions.
- By altering the cytokine milieu at the tumour site using cytokines such as IL-2 or IL-12 we can potentially convert an immunosuppressive microenvironment to one that promotes and enhances an immune response
16
Q
Describe the drawbacks and limitations of cytokine therapy
A
- Side effects: cytokine therapy may cause side effects such as flu-like symptoms, depression, and fatigue.
- Some of them can even be unpredictable since cytokine biology is interpreted using mouse models, which are not always similar to the humans despite the many extrapolations done from research over the years.
- 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.
- Amount of cytokines: 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.
17
Q
What is the current status of cytokine therapy?
A
To date, to the best of our knowledge, only three cytokines have been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for use in cancer patients (sources www.fda.gov and www.ema.europa.eu/ema/).
- IL-2 targets cells of the adaptive immune system, such as T cells and B cells, to respond to tumours. IL-2 has been approved for the treatment of some forms of metastatic melanoma and renal cell carcinoma (RCC).
- IFN-α activates innate immune cells, such as dendritic cells (DCs) and macrophages to help the fight against cancer.
- IFN-α2a has been licensed for the treatment of hairy cell lymphoma and Philadelphia chromosome-positive [Ph+, t(9;22)] chronic myelogenous leukaemia (CML);
- IFN-α2b has been approved for the treatment of hairy cell leukaemia, AIDS-related Kaposi’s sarcoma, follicular lymphoma, melanoma, multiple myeloma, genital warts (Condyloma acuminata) and cervical intraepithelial neoplasms.
18
Q
What are cancer vaccines
A
- Cancer vaccines are a type of vaccines that are designed to boost your immune system to protect you against tumours such as cervical, prostate and bladder cancers.
19
Q
What response do you think would be the most important one to elicit with an anti-cancer vaccine?
A
- cytotoxic T cell response
There will be more potential antigens available for presentation to T cells (and vaccination uses antigens to educate the immune system).
- The most effective response to killing cancer cells is CD8+ T cells and NK cells, so educating these is the most crucial, although B cell and T helper cell responses are also useful.
- NK cells do not recognise antigen, so cannot be induced by a vaccination strategy, although antibodies against surface antigens can provoke NK cells to kill.
20
Q
Look at this figure and describe how cancer vaccines work
A
- all rely on generating an antigen that is presented on MHC class I molecules by dendritic cells (DCs).
- This is shown using an mRNA molecule (but DNA can be also used) or tumour antigens (proteins) extracted from the cancer cells.
23
Q
Describe therapeutic cancer vaccines
types
A
- These type of vaccines are administered after a tumour diagnosis and the tumour is already likely interacting with the immune system.
- they are more commonly used in patients in remission to prevent a potential relapse and the cancer from returning.
- Therapeutic vaccines can be classified in two groups, namely autologous and allogenic vaccines.
- Autologous cancer vaccines: they are vaccines made from an individual’s own cancer cells and, therefore, can defined effectively as personalised vaccines. You can revise this concept in the figure:
- Allogeneic cancer vaccines: they are made from cancer cells taken from a different individual and then grown in the laboratory before being introduced into the cancer patient undergoing the treatment.
27
Q
Describe monoclonal antibodies (mAbs)
A
- Monoclonal antibodies (mAbs) are designed against antigens presented on the surface of tumour cells.
- As you can see from this image, distinct types of monoclonal antibodies (mAbs for short) are used in cancer treatment:
- Naked mAbs, which can trigger, for instance, antibody-dependent cell-mediated cytotoxicity (ADCC), or simply block cancer growth factor receptors
- Conjugated mAbs with, for example, a toxin, a chemotherapeutic agent or a radioisotope
- Bispecific mAbs bridge (connect) the target cells with cells of the immune system bringing them closer together:
29
Q
What are the different ways naked mAbs can work?
A
- They can improve the immune response against cancer cells by attaching to the tumour cells and marking them for the immune system to kill them through antibody-dependent cell cytotoxicity (ADCC), which we also encountered as type II hypersensitivity in IMI9.
- ADCC leads to cell lysis via effector immune cells such as NK cells, eosinophils, macrophages or neutrophils.
- They can bind to and inhibit proteins on cancer cells, or on other nearby cells, that are necessary for the cancer cells to grow or spread (e.g. growth factor receptors).
- They can increase the immune response by targeting immune checkpoints such as anti-PD-1/ anti-PD-L1.
- Immune checkpoint inhibitors work by targeting and disabling the fail-safe mechanisms that have evolved to prevent unwanted immune responses.
- These checkpoints ensure that responses only occur when needed and that they are switched off as soon as the issue has been resolved (be it an infection, or injury).
- As shown in the right-hand figure below, they can bind and block either the receptor (PD-1) on the immune cell or the ligand (PD-L1) on the tumour cell.
32
Q
What are bispecific monoclonal antibodies
A
- Bispecific mABs are named in this way because they are designed as an antibody that is composed of two different mAbs, and can thus bind two different proteins (antigens) simultaneously.
- This allows them to bring together, or cluster, the cancer cells and immune cells, which makes it easier for the immune cells to attack the cancer cells.
- The image below shows an antibody bringing the tumour cell and T cell together, with a third innate cell such as a macrophage, dendritic cell (DC) or innate lymphoid cell/ NK cell, binding the Fc region of the antibody.
34
Q
What is the current status of monoclonal antibody therapy?
A
- Even with these drawbacks, many mAbs have been approved for cancer treatment in the last years and many patients have benefited from their use
38
Q
Describe adoptive T cells transfer (ATC) therapy and how tumour infiltrating lymphocytes (TILs) are utilised
A
- The name of tumour infiltrating lymphocytes (TILs) derives from the fact that they are found in the tumour, where they migrate to in order to kill it.
- In adoptive T cell transfer (ATC) therapy, TILs are isolated from tumours and expanded ex vivo (i.e. outside the patient) with a high dose of IL-2, well-known for driving the proliferation of T cells
- note that despite this function, IL-2 is not classified as a growth factor but rather as a cytokine).
- Not all TILs will be the same or show the same killing efficiency and thus different cells of that population of lymphocytes are grown.
- TILs that show the best tumour reactivity are then selected and further expanded to be infused back into the patient, as depicted in the figure.
41
Q
Describe CAR-T cell therapy
A
- Chimeric antigen receptor therapies utilise receptors that have been engineered to give T cells the new ability to target a specific tumour protein independently of the MHC presentation.
- T cells are harvested from patients, genetically modified, and then the resulting CAR-T cells are re-infused into patients to fight their tumours.
- CAR-T cells can be either derived from the same patient’s T cells (autologous) or from another healthy donor (allogenic), and the receptors are called chimeric because they are a mixture of various proteins, as you can see in this figure.
42
Q
Describe modified TCR therapies
A
- Genetically modified TCR therapies are based on modifying the expression of specific TCR α and β chains, which mediate the recognition of the cancer antigen.
- This means that the tumour-specific TCR α and β chains must be first identified, then genetically engineered to improve specificity and affinity for a tumour antigen and, finally, transferred into T cells to become tumour antigen-specific T cells.
43
Q
Observe this diagram for an overview of CAR-T and modified TCR cell therapy
A
47
Q
What is the current status of cell-based therapy?
A
Five CAR-T cell therapies have thus far received FDA approval:
- Tisagenlecleucel (KymriahTM) for the treatment of diffuse large B cell lymphoma and B cell acute lymphoblastic leukaemia (ALL);
- Axicabtagene ciloleucel (YescartaTM), for the treatment of relapsed/refractory large B cell lymphoma in adult patients.
- Brexucabtagene autoleucel (TecartusTM), for treatment of mantle cell lymphoma (MCL) or acute lymphoblastic leukemia (AML)
- Lisocabtagene maraleucel (Breyanzi®), for treatment of large B-cell lymphoma in patients that have had at least 2 previous failed treatments.
- Idecabtagene vicleucel (Abecma®), for treatment of multiple myeloma (MM) in patients who have received at least four kinds of treatment that have failed.
48
Q
Which cells are therapeutic cancer vaccine therapies normally relying on for generating an immune response?
A
- dendritic cells
- The vaccine may be made of material from tumour cells, but it is dendritic cells that we rely on to make or process the antigen for presentation on class I MHC molecules.
49
Q
Which of the following cytokines is used to expand TILs in vitro?
A
- IL-2
52
Q
Observe this diagram of how tumours evade the immune system
A
