L16 - Cancer Immunology Lecture 2 - Christoph Wuelfing Flashcards
In general: Start with the key questions and principles - then add examples and detail Key mechanisms of suppression Key metabolites and cells using them Cells that generate adenosine and how they do it, one example of escape Key mechanisms of inhibitory receptor function For CTLA-4, PD-1 and TIM-3: Which cells express them and their ligands, when and where in an immune response, examples of their function
1
Q
What is one of the key soluble mediators of tumor immunity?
A
🧪 Prostaglandin E2 is produced by tumor cells and plays a role in immune suppression. It is generated by cyclooxygenase (COX), and drugs like aspirin and ibuprofen can inhibit its synthesis.
2
Q
What is the role of the enzyme indoleamine 2,3-dioxygenase (IDO) in immune suppression?
A
🧬 IDO depletes tryptophan, an essential amino acid, from the extracellular space. This deprives immune cells like T cells of critical resources, contributing to immune suppression in the tumor microenvironment.
3
Q
How does adenosine contribute to immune suppression in tumors?
A
🛑 Adenosine is generated when ATP is broken down by CD39 and CD73 enzymes. It binds to adenosine receptors on T cells, inhibiting their function and promoting an immunosuppressive environment.
4
Q
What role do damage-associated molecular patterns (DAMPs) like ATP play in tumor immunity?
A
🔥 ATP, released during necrotic cell death, acts as a DAMP and activates inflammatory pathways, which are typically pro-inflammatory. In tumors, this process can be suppressed by the breakdown of ATP into adenosine, leading to immune suppression.
5
Q
What happens when CD73 or adenosine A2A receptor is targeted for therapy in tumor models?
A
🔬 When CD73 is inhibited, there is a compensatory increase in suppressive myeloid cells, and minimal effect on tumor growth. However, targeting both CD73 and adenosine A2A receptor together yields a more significant effect on tumor growth.
6
Q
What therapeutic challenge does the adenosine pathway present in tumor immunotherapy?
A
⚠️ Compensatory mechanisms can reduce the effectiveness of treatments targeting just one part of the pathway, such as CD73 or adenosine receptors. This highlights the importance of combining therapies to achieve more effective outcomes.
7
Q
Why is a combination therapy targeting both CD73 and the adenosine A2A receptor effective?
A
💡 Using both treatments together overcomes compensatory mechanisms and significantly reduces tumor growth, demonstrating the need for dynamic, multi-targeted approaches in cancer therapy.
8
Q
What role do regulatory T cells (Tregs) play in immune suppression in tumors?
A
🛡️ Tregs are major suppressive cells in the tumor microenvironment. They can generate adenosine by expressing CD39 and CD73, which contributes to immune suppression by inhibiting T cell activity.
9
Q
How do myeloid-derived suppressor cells (MDSCs) contribute to tumor immune suppression?
A
⚔️ MDSCs are enhanced by prostaglandin E2 (PGE2), which is produced by tumor cells. These cells suppress T cell activity and promote an immunosuppressive microenvironment, aiding tumor progression.
10
Q
What role do cytokines play in Treg-mediated immune suppression?
A
Tregs secrete immunosuppressive cytokines such as TGF-β, IL-10, and IL-35, which inhibit the activation, proliferation, and differentiation of effector T cells, thereby dampening immune responses.
11
Q
How do Tregs influence the metabolic environment to suppress immune responses?
A
Tregs consume essential metabolites like IL-2, creating a competitive environment that limits the resources available to effector T cells, thereby suppressing their activity.
12
Q
What is the role of adenosine in Treg-mediated immune suppression?
A
Tregs produce adenosine through the ectoenzymes CD39 and CD73, which binds to A2A receptors on effector T cells, leading to immunosuppression via cAMP-mediated pathways.
13
Q
How does Granzyme B contribute to Treg-mediated suppression?
A
Tregs secrete Granzyme B, which induces apoptosis in effector T cells, thereby reducing immune responses.
14
Q
In what ways does direct interaction between Tregs and other immune cells facilitate suppression?
A
Through direct contact, Tregs can modulate the function of antigen-presenting cells like dendritic cells, reducing their ability to activate effector T cells.
15
Q
What is the effect of immunosuppressive cytokines secreted by Tregs?
A
Cytokines such as TGF-β, IL-10, and IL-35 secreted by Tregs inhibit the differentiation, proliferation, and activation of effector T cells, suppressing cytokine production and promoting the conversion of conventional T cells to immunosuppressive phenotypes
16
Q
What is the role of MHC Class 1 in tumor immunity?
A
💡 MHC Class 1 is crucial for presenting cytoplasmic proteins (antigens) on the cell surface, allowing CD8+ T cells (Cytotoxic T cells) to recognize and kill tumor cells. Without it, the immune system cannot effectively target and destroy tumor cells.
17
Q
How does MHC Class 1 upregulation help in immune responses?
A
💥 MHC Class 1 is upregulated by pro-inflammatory signals like Type I interferons and interferon-gamma. This boosts antigen presentation, making it easier for CD8+ T cells to detect and kill infected or tumor cells.
18
Q
How do tumours evade CD8+ T cell killing using MHC class I
A
🔽 Tumours often downregulate or lose MHC class I expression, making it harder for CD8+ T cells to recognise and kill them. This is a common immune escape mechanism for tumours and helps them survive in the immune system
19
Q
What happens to NK cells when MHC class I is downregulated
A
⚔️ Natural Killer (NK) cells are less sensitive to MHC Class 1 loss. When MHC Class 1 is downregulated, NK cells become more effective at killing the tumor cells, since MHC Class 1 normally acts as an inhibitory signal for NK cells.
20
Q
Why do tumours prefer to downregulated MHC class I rather than evade NK cells?
A
🌿While downregulating T cells are a greater threating MHC class I reduces CD8+ T cell killing, the tumour seems to favour this because CD8+ T cells are a greater threat. Additionally, tumours often lack the ability to compensate for MHC class I loss, and escape NK cell recognition effectively
21
Q
How does the evolution of tumour immune evasion favour MHC class I downregulation?
A
⚖️ Evolution favours tumours that can escape the stronger immune threat from CD8+ T cells. Tumors that downregulate MHC Class 1 can avoid this specific immune surveillance, even if they become more vulnerable to NK cells.
22
Q
What is the relationship between MHC Class 1 expression and cancer prognosis?
A
Loss of MHC Class 1 expression is common in many cancers and correlates with poorer prognosis. This is because it reduces the ability of the immune system to recognize and attack tumor cells, allowing the tumor to grow unchecked.
23
Q
What is the role of MHC class I loading molecules like Tapasin in cancer immune evasion?
A
🔧Tapasin is involved in loading peptides onto MHC Class 1 molecules. Loss of Tapasin can further reduce MHC Class 1 function and antigen presentation, helping tumors evade immune detection.
24
Q
What are inhibitory receptors in the context of immunology
A
🚫 Inhibitory receptors are molecules found on immune cells (including T cells) that help regulate or “brake” the immune response. They prevent excessive or prolonged immune activity, thereby maintaining immune homeostasis.
25
Why are inhibitory receptors important in cancer therapy
🚫 Blocking inhibitory receptors (e.g., with checkpoint inhibitors like anti-PD-1 or anti-CTLA-4 antibodies) can reinvigorate immune cells to attack cancer cells. This approach has revolutionized cancer treatment.
26
Are inhibitory receptors found only on T cells?
🚫 No. While they are often studied in T cells, many inhibitory receptors are widely expressed on multiple immune cells, such as NK cells, B cells, and some myeloid cells.
27
Why is it important to consider inhibitory receptor expression on multiple cell types
🚫 Because the function and therapeutic targeting of these receptors can affect various immune cells differently. Understanding their expression beyond T cells helps explain how checkpoint-blocking antibodies actually work in the clinic
28
How do inhibitory receptors function in normal T cell biology?
🆙 They are upregulated when T cells are activated and serve as a natural mechanism to limit the duration and intensity of immune responses, preventing potential tissue damage and autoimmunity.
29
What happens in mice lacking certain inhibitory receptors?
🐭 Mice deficient in CTLA-4 die from severe inflammatory disease around four weeks old, and PD-1 knockout mice develop autoimmune symptoms. This demonstrates the critical role these receptors play in immune regulation.
30
Why are inhibitory receptors upregulated in persistent immune responses?
🚫 In chronic or persistent infections (and in tumors), these receptors become highly expressed to curb ongoing inflammation. While beneficial for limiting damage, this can also dampen anti-tumor immunity.
31
Which five key inhibitory receptors should I remember?
1. PD-1
2.LAG-3
3.TIM-3
4.CTLA-4
5.TIGIT
32
What is PD-1 and why is it notable?
💀 Programmed cell death protein 1 (PD-1) is widely expressed on T, B, and NK cells. It’s a major target in cancer immunotherapy; blocking PD-1 can restore T cell function against tumors.
33
What is LAG-3 and where is it found?
💥 Lymphocyte-activation gene 3 (LAG-3) is an inhibitory receptor on T cells, NK cells, and other immune cells. Its ligands include MHC II and a newly identified FGL1. It modulates T cell activation and helps maintain tolerance.
34
What is TIM-3 and why is it significant?
🎯T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) is expressed on T cells, NK cells, and other cells. It binds ligands like Galectin-9, CEACAM-1, and HMGB-1, regulating immune responses. It is being explored as a cancer therapy target.
35
What is CTLA-4 and what does it do?
🥊Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is primarily expressed on T cells (including regulatory T cells). It competes with the costimulatory molecule CD28 for binding to B7 ligands (CD80/CD86), thereby dampening T cell activation.
36
What is TIGIT and how does it function?
🛑T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory receptor expressed on T cells, NK cells, and other immune cells. It binds ligands like PVR (CD155), reducing T cell and NK cell activity.
37
How do inhibitory receptors contribute to immune homeostasis?
📛By limiting T cell activation and preventing autoimmunity. Their absence or dysfunction often results in excessive inflammation or autoimmune disorders, underscoring their role in balancing immune responses.
38
In summary, why must we keep context in mind when targeting inhibitory receptors in cancer?
🚫 Because blocking these receptors can enhance tumor-specific immune responses but may also disrupt normal immune regulation. This balance is critical to avoid autoimmunity and other adverse effects.
39
What are the two key principles by which inhibitory receptors function?
They work by (1) triggering inhibitory signaling—recruiting phosphatases to downregulate activation signals—and (2) receptor competition—binding ligands more effectively than their costimulatory counterparts.
40
What are the four main mechanisms by which inhibitory receptors can function?
ITIM/ITSM-based inhibitory signaling (A)
Receptor competition (B)
Unconventional signaling (C)
Mixed inhibition (D)
41
How does ITIM/ITSM-based inhibition (mechanism A) work?
Receptors like PD-1 recruit phosphatases (tyrosine, serine/threonine, and lipid) to their ITIM/ITSM motifs, counteracting activating signals at a proximal step.
42
How does the inhibitory signaling mechanism operate in receptors like PD-1?
It involves recruiting phosphatases (tyrosine, serine/threonine, and lipid phosphatases) to the receptor's cytoplasmic domains (ITIMs/ITSMs), which counteracts the signaling pathways mediated by tyrosine kinases.
43
What is an example of a receptor that employs classical inhibitory signal transduction?
PD-1 is a prime example, using the recruitment of phosphatases to dampen T cell activation signals.
44
Why is the recruitment of phosphatases important in inhibitory signaling?
It counterbalances the activation signals from tyrosine kinases, ensuring that immune responses are properly regulated and preventing excessive activation that could lead to tissue damage.
45
What is receptor competition (mechanism B), and which receptor is a classic example?
Receptor competition happens when an inhibitory receptor binds ligands more effectively than a costimulatory receptor. CTLA-4 is a prime example, outcompeting CD28 for CD80/CD86.
46
What is unconventional signaling (mechanism C) in the context of inhibitory receptors?
It refers to inhibitory signaling through motifs that do not share homology with known inhibitory domains. TIM-3 is an example, using unique pathways to modulate T cell responses.
47
What does mixed inhibition (mechanism D) involve?
It can include both receptor competition and intracellular inhibitory signaling. This dual approach further dampens T cell activation.
48
Why are ITIM and ITSM motifs crucial in inhibitory receptors?
They serve as docking sites for phosphatases, which remove phosphate groups from signaling molecules, thereby inhibiting T cell activation.
49
How does CTLA-4 use receptor competition to inhibit T cell activation?
By binding CD80/CD86 more effectively than CD28, CTLA-4 sequesters the ligands, preventing CD28 from delivering its costimulatory signal.
50
Where is CTLA-4 highly expressed besides activated T cells?
CTLA-4 is consistently and highly expressed on regulatory T cells (Tregd) playing a major role in their suppressive function
51
How do regulatory T cells use CTLA-4 to inhibit costimulation?
By binding CD80/CD86 on antigen-presenting cells (APCs) more effectively than CD28, Tregs deprive other T cells of costimulatory signals
52
What is trans-endocytosis in the context of CTLA-4?
Tregs can physically "pull in" (internalise) CD80/CD86 from the APC membrane further limiting availability to other T cells
53
Why does blocking CTLA-4 affect both effector T cells and Tregs?
Because CTLA-4 is expressed on both cell types. inhibiting CTLA-4 can enhance effector T cell responses but also disrupt Treg-mediated immune regulation
54
Why is high CTLA-4 expression on Tregs critical in a tumour draining lymph node?
It enables Tregs to outcompete and suppress tumor-specific T cells, helping tumors evade immune destruction.
55
What is the overall effect of CTLA-4 on immune activation?
CTLA-4 reduces T cell activation by limiting costimulatory signals, maintaining immune homeostasis but also potentially impairing anti-tumor immunity.
56
Why is PD-1 considered a default part of T cell activation?
Because PD-1 is upregulated on T cells as they become activated, much like other activation markers e.g. CD25, CD69
57
On which T cell subsets is PD-1 expressed?
PD-1 is found on CD8+ T cells, CD4+ effector T cells, and CD4+ regulatory T cells (Tregs)
58
What is the significance of blocking PD-1 in terms of different T cell subsets?
blocking PD-1 affects not onlt CD8+ T cells and CD4+ effector T cells but also CD4+ Tregs, potentially altering multiple arms of the immune response
59
How is PD-1 related to T cell exhaustion?
PD-1 becomes further upregulated in chronically stimulated T cells (E.g. persistent viral infection or in tumours), marking T cell exhaustion
60
Aside from T cells, which other immune cells express PD-1 and why is that important?
Myeloid cells also express PD-1. Research indicates that deleting PD-1 in myeloid cells can have a greater impact on anti-tumour immunity than deleting it in T cells
61
What are the two known ligands for PD-1 and where are they typically expressed?
PD-L1 (PD-Ligand 1), often found on tumour cells (frequently upregulated to evade immunity) and PD-L2, mainly on immune cells involved in regulation.
62
Why has PD-1 become an important target in cancer therapy?
Because blocking PD-1 (or its ligands) can reverse T cell exhaustion, allowing the immune system to more effectively attack tumour cells
63
What are some of the different actions of TIM-3 on various cell types?
TIM-3 has multiple roles: it limits the cGAS-STING pathway in dendritic cells by suppressing extracellular DNA uptake, regulates inflammasome activation in migratory DCs, mediates recognition and phagocytosis of apoptotic bodies via phosphatidylserine, and is highly expressed on exhausted CTLs where it inhibits tumor cell cytolysis
64
How does TIM-3 limit cGAS-SING pathway in intra-tumoral dendritic cells?
TIM-3 suppresses the uptake of extracellular DNA, which limits activation of the cGAS-STING pathway
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65
What is the role of TIM-3 in migratory dendritic cells (DCs)?
TIM-3 restrains anti-tumour immunity by regulating inflammasome activation in migratory DCs affecting how these cells process and present antigens
66
How does TIM-3 contribute to the recognition and phagocytosis of apoptotic bodies?
TIM-3 binds to phosphatidylserine on apoptotic cells, facilitating their recognition and subsequent phagocytosis
67
What is the significance of TIM-3 expression on exhausted cytotoxic T lymphocytes (CTLs)
TIM-3 is highly expressed on exhausted CTLs where it inhibits the cytolytic activity against tumour target cells, contributing to immune dysfunction in chronic settings
68
How is TIM-3 expression regulated on T cells compared to other inhibitory receptors?
Unlike some inhibitory receptors that are upregulated during normal T cell activation, TIM-3 is only significantly upregulated after persistent T cell stimulation, marking a state of chronic activation or exhaustion
69
Why is TIM-3 considered a challenging target for drug development?
TIM-3 acts on multiple cell types : T-cells, dendritic cells and macrophages, with distinct functions, making it difficult to target without affecting normal immune regulation
70
What additional role does TIM-3 play on macrophages?
On macrophages, TIM-3 binds to phosphatidylserines on apoptotic cells, which can inhibit macrophage function and alter inflammatory responses
71
Are there currently any Tim-3 blocking antibodies in clinical use?
While TIM-3 is an area of interest, there are no blocking TIM-3 antibodies approved for clinical practice at this time
72
How does TIM-3 affect the handling of damage-associated molecular patterns (DAMPs) in the tumour microenvironment?
TIM-3 on dendritic cells can sequester high mobility group binding protein 1 (HMGB1) on the cell surface, which prevents the uptake of cytoplasmic DNA fragments and limits cGAS-STING pathway activation, thereby reducing inflammatory signaling.
73
What are the key types of tumour immunotherapies
They include :
- Antibody drug conjugates
- Cytokines
- Vaccination
- Checkpoint blockade
- T cell therapies ( Linda Woolridge)
74
How do Antibody Drug Conjugates (ADCs) work in cancer treatment?
ADCs use antibodies that specifically target a tumour-associated protein to deliver a cytotoxic payload (like DNA-targeting agents or tubulin inhibitors) directly to tumour cells, aiming to minimise side effects
75
What is the major challenge with using antibody drug conjugates?
The challenge is finding proteins that are exclusively expressed on tumour cells; targeting common proteins can lead to side effects and allows tumour cells to escape by downregulating the target
76
What is the current status of cytokine-based immunotherapies in cancer?
Cytokine therapies have a long history and high hopes, but they have yielded limited success in clinical practice so far
77
What effors are being made with vaccination strategies in tumour immunotherapy?
Researchers are working on personalised tumour vaccines, though success has been limited despite significant efforts and investment
78
Why is checkpoint blockade considered a breakthrough in cancer care?
Checpoint blockade targtes inhibitory receptors on immune cells, reinvigorating them to attack tumour cells, this approach has significantly transformed cancer treatment
79
What are T cell therapies
T cell therapies involve engineering or harnessing T cells to target tumors
80
What potential issue arises when targeting tumor cells with antibodies?
Tumor cells may downregulate the targeted molecule, leading to immune escape and reducing the therapy's effectiveness.
81
Why is it difficult to find ideal targets for ADCs?
It’s challenging to identify proteins that are exclusively expressed on tumor cells; without this specificity, there is a risk of harming normal cells and reducing the treatment’s precision.
82
What is the theoretical advantage of using antibody-drug conjugates?
The advantage is that they combine the specificity of antibodies with the potency of chemotherapeutic payloads, potentially reducing systemic toxicity by focusing the drug on tumor cells
83
How do ADCs, carrying drugs that interfere with DNA replication or tubulin, enter the cell?
When the ADC’s antibody binds its target receptor on a tumor cell, the receptor–ligand complex is internalized (a classic receptor-mediated endocytosis), allowing the drug payload to be released from the endolysosomal compartment into the cell.
84
What is the similarity between ADC internalization and trans-endocytosis seen with CTLA-4 on regulatory T cells?
Both processes involve the receptor binding its ligand and then being internalized. In trans-endocytosis, CTLA-4 on T cells “rips” CD80/CD86 from dendritic cells; similarly, ADC binding leads to the internalization of the conjugate.
85
What is one key mechanism of resistance to ADC therapy?
Tumour cells can downregulate or lose the expression of the targeted antigen. This antigen downregulation allows resistant tumour cells to acoid ADC binding, giving them a growth advantage
86
Besides antigen downregulation, what other resistance mechanism is mentioned?
There can be drug-specific resistance mechanisms, where the tumor cell adapts to counteract the cytotoxic payload, though the transcript emphasizes antigen loss as the major factor.
87
What does the lecture mention about cytokines in the context of immunotherapy?
Cytokine therapy is noted as the oldest form of immunotherapy, with a long history and high hopes, though it has generally shown limited clinical success compared to newer approaches.
88
What are the sequential steps involved in the mechanism of action of ADCs?
1.Antigen Binding: The ADC binds specifically to a tumor-associated antigen on the cancer cell surface.
2.Antigen Internalization: The antigen-ADC complex is internalized into the cancer cell via endocytosis.
3.Lysosomal Delivery: The internalized complex is transported to lysosomes.
4.Lysosomal Release: The cytotoxic payload is released within the lysosome through linker cleavage or proteolytic degradation.
5.Drug Action: The released cytotoxic agent exerts its effect, such as inducing DNA damage, leading to cancer cell death.
89
Why is antigen binding crucial for the efficacy of ADCs?
Antigen binding ensures that the ADC specifically targets and attaches to cancer cells expressing the tumor-associated antigen, minimizing effects on healthy cells.
90
What are key mechanisms by which cancer cells develop resistance to ADCs?
Antigen Downregulation: Cancer cells reduce or lose expression of the target antigen, decreasing ADC binding and efficacy.
Efflux Pump Activation: Upregulation of efflux pumps expels the cytotoxic payload from cancer cells, reducing drug accumulation.
Drug-Specific Resistance: Genetic or epigenetic changes in cancer cells confer resistance to the specific cytotoxic agent used in the ADC.
91
What is the primary function of IL-2 in the immune system?
IL-2 drives the proliferation of activated T cells
92
Which cells constututively express the IL-2 receptor alpha chain (CD25?)
Regulatory T cells (Tregs)
93
Wen is the IL-2 receptor alpha chain (CD25) expressed on effector T cells
CD25 is expressed on effector T cells upon activation
94
Why are Tregs highly dependent on IL-2
IL-2 is crucial for the survival and function of Tregs, which maintain immune tolerance
95
What percentage of tumour regression is observed with high dose IL-2 therapy in mRCC patients?
~20% of patients experience tumour regression
96
What is the complete response rate for mRCC patients treated with high dose IL-2 therapy?
Around 9% of patients achieve a complete response
97
List some key toxicities associated with high dose IL-2 therapy
Leukopenia, nausea, hypotension and fatugye
98
What is a significant challenge in IL-2 therapy for tumours?
Achieving local and time-limited delivery of IL-2 within the tumour microenvironment
99
What is the primary goal of cancer vaccines?
To enhance the overall immune response against tumours
100
Why is vaccination a promising approach for cancer treatment?
Vaccination strengthens immunity by activating dendritic cells, similar to how cGAS-sTING agonsists enhance immune responses
101
What are the two main strategies for antigen selection in cancer vaccines?
Targeting conserved tumour-associated antigens or patient-specific neoantigens
102
What are common delivery platforms for cancer vaccines?
Peptide-based vaccines and mRNA vaccines
103
What is a significant challenge faced by cancer vaccines?
Overcoming tumour-mediated immune suppression to maintain a lasting immune response
104
What is a key decision in cancer vaccine development?
Whether to target a single protein or multiple proteins in the immune response against cancer.
105
Why might targeting multiple proteins be beneficial
Most studies target multiple proteins to increase the chances of mounting a strong and effective immune response
106
What are the two main antigen strategies in cancer vaccines?
🔹 Conserved tumor-associated antigens (common across patients)
🔸 Patient-specific neoantigens (unique mutations in individual tumors)
107
What are the drawbacks of using conserved tumour-associated antigens?
🚧 There is partial immune tolerance, meaning the body might not fully recognize these antigens as threats.
108
How are patient specific neoantigens identified
🧬 By sequencing the patient’s exome and detecting unique mutations, which are then used to create a personalized vaccine.
109
Which company has invested heavily in patient specific neoantigen vaccines?
💵 BioNTech has redirected profits from its COVID-19 vaccine into developing personalized cancer vaccines.
110
What are the main platforms used to deliver cancer vaccines
💉 Peptide-based vaccines (fragments of tumor proteins)
🧬 mRNA vaccines (used to encode tumor antigens)
111
What is a key challenge in making cancer vaccines effective?
Ensuring that the immune response lasts for weeks or months rather than fading too quickly
112
Why is generating an immune response alone not enough
The response must persist over time, otherwise, the tumour can continue to grow despite an initial reaction
113
What is a major barrier to sustained immunity to cancer vaccines
Tumour-mediated immune suppression, where tumours create an environment that inhibits the immune system's response
114
What strategy was used for the melanoma vaccine
🏹 The tumor-associated antigen (TAA) strategy was used, selecting four specific antigens commonly found in melanoma.
115
What tumour associated antigens were targetd in the melanoma vaccine?
🎯 The vaccine targeted:
NY-ESO-1
MAGE-A3
MART-1
Tyrosinase
TPTE
116
What type of vaccine platform was used for melanoma?
An RNA-based vaccine was used to stimulate an immune response
117
How was the immune response boosted in the melanoma vaccine study?
The vaccine was administered with cytokines to enhance immune activation
118
What additional therapy was combined with the melanoma vaccine
Some patients also recieved an anti-PD-1 antibody to counteract immune suppression by tumours
119
What were the overall results of the melanoma vaccine study?
Only a small fraction of patients responses, with slightly better results when combined with anti PD-1 therapy
120
What was the key takeaway from the melanoma vaccine study?
✅ Even partial responses are valuable, but many patients showed no benefit from the vaccine.
121
What type of cancer was targeted in the second study?
🎯 Glioblastoma, an immune-cold tumor with little natural immune response.
122
What antigen strategy was used in the glioblastoma vaccine?
🏗️ A patient-specific neoantigen approach—sequencing each patient’s tumor to identify unique mutations.
123
How many neoantigens were included in each glioblastoma vaccine?
🧩 Each vaccine contained an average of 12 peptides, tailored to the patient's specific tumor.
124
What were the results of th eglioblastoma vaccine study?
All patients required secondary treatment, and sadly, all died relatively quickly despite vaccination
125
What does this study reveal about cancer vaccine challenges?
While promising, cancer vaccines face real world obstacles, including weak immune responses and tumour resistance
126
Why continue researching cancer vaccines despite setbacks?
Any improvement over existing treatments is valuable, and researchers are still refining strategies
127
What is checkpoint blockade therapy?
Checkpoint blockade uses antibodies to block inhibitory immune checkpoints, allowing T cells to attack tumours more effectively
128
What are the two main checkpoint molecules targeted in therapy?
⚔️ The two widely used checkpoint inhibitors are:
PD-1 (Programmed Death-1)
CTLA-4 (Cytotoxic T-Lymphocyte Antigen-4)
129
What is the recently approved third checkpoint inhibitor?
🔬 LAG-3 (Lymphocyte-activation gene 3)—approved in combination with anti-PD-1 therapy.
130
What are some example of checkpoint inhibitor drugs?
💉 Examples include:
PD-1 inhibitors: Nivolumab, Pembrolizumab
CTLA-4 inhibitor: Ipilimumab
131
When were checkpoint inhibitors approved for clinical use?
✅ Anti-CTLA-4 therapy was approved about 15 years ago.
✅ Anti-PD-1 therapy has been in the clinic for over 10 years.q
132
How have PD-1 inhibitors been integrated into cancer treatment over time?
🔬 Initially used as a last-line treatment, they are now first-line therapies for many cancers.
133
What type of cancers are treated with PD-1 inhibitors?
📋 PD-1 blockade is used in a large number of tumors, originally starting with melanoma and now covering many cancer types.
134
How are PD-1 inhibitors used in cancer research?
🔍 They are now routinely included in clinical trials for new therapies, often combined with other treatments.
135
Why are PD-1 inhibitors often combined with other therapies?
🔗 Combination therapies can enhance efficacy by attacking cancer from multiple angles.
136
What is the significance of FDA approvals for PD-1 inhibitors?
🏛️ The FDA has approved PD-1 blockade for an extensive list of cancers, showing its widespread clinical use.
137
What are the main checkpoint blockade targets used in the clinic?
🧬 The main targets are PD-1, CTLA-4, and more recently, LAG-3. Anti-PD-1 and anti-CTLA-4 antibodies are widely used in cancer treatment, while anti-LAG-3 antibodies have recently been approved.
138
What are some examples of checkpoint blockade drugs
💊 Examples include Nivolumab (anti-PD-1), Pembrolizumab (anti-PD-1), and Ipilimumab (anti-CTLA-4). However, remembering the drug names is less important than knowing their targets.
139
How did checkpoint inhibitors initially enter clinical use?
🏥 They were first used as last-line treatments for specific cancers like melanoma. Over time, as their effectiveness was proven, they became first-line treatments for many cancer types.
140
What is the mechanism of activation of PD-1 blockade
Instead of reactivating exhausted T cells, PD-1 blockade allows for the continuous priming of new T cell clones. This process enables wave after wave of new immune responses against tumors.
141
What is the significance of clonal replacement in checkpoint blockade therapy?
🔄 Clonal replacement means that new T cell clones, rather than pre-existing exhausted T cells, become activated and attack the tumor. This ensures a sustained immune response.
142
What was a key finding from T cell receptor sequencing in checkpoint blockade studies?
🧪 Studies showed that T cells present in the tumor before treatment did not expand after PD-1 blockade. Instead, new T cell clones appeared, suggesting that the therapy works by generating new immune responses.
143
How effective is combination therapy with anti-PD-1 and anti-CTLA-4?
📊 A landmark study showed that in melanoma patients who had failed other treatments, 30% experienced over 80% tumor reduction after 12 weeks of combined anti-PD-1 and anti-CTLA-4 therapy
144
Why do checkpoint inhibitors not work for all patients?
❌ While highly effective for some, checkpoint inhibitors still fail in about 70% of patients. Factors like immune suppression, tumor microenvironment, and lack of T cell priming can limit their success.
145
What are common side effects of checkpoint blockade therapy?
⚠️ Autoimmune-related side effects are common since blocking PD-1 or CTLA-4 can lead to excessive immune activation, resulting in inflammation and autoimmunity.
146
How has PD-1 blockade changed cancer treatment?
🌍 PD-1 inhibitors have become a standard treatment for many cancers. They are now commonly combined with other therapies, and most new cancer treatments are tested alongside PD-1 blockade.
147
What is the key side effect of PD-1 blockade therapy?
⚠️ The main side effect is autoimmunity. PD-1 plays a key role in immune homeostasis, so blocking it can lead to excessive immune activation, resulting in autoimmune diseases.
148
Why does PD-1 blockade cause autoimmune side effects?
🔬 PD-1 helps regulate immune homeostasis. In PD-1 knockout mice, autoimmune diseases develop. Similarly, when patients receive anti-PD-1 therapy over months, they can experience autoimmune-related side effects.
149
How are autoimmune side effects managed in patients receiving checkpoint inhibitors?
💊 Patients often require steroids or other immunosuppressants to control autoimmunity. While not ideal, many patients accept this trade-off if the alternative is rapid disease progression.
150
Why is reducing autoimmune side effects in checkpoint therapy challenging?
🧩 Since PD-1 and CTLA-4 are crucial for maintaining immune balance, it is very difficult to block them without causing excessive immune activation.
151
Does checkpoint blockade therapy always work?
❌ No. Response rates vary by cancer type, and about 50% of patients develop resistance over time.
152
What are the main reasons for checkpoint blockade failure?
📉 Two key mechanisms:
Downregulation of MHC class I – Tumors stop presenting antigens, making them invisible to T cells.
Upregulation of other inhibitory receptors – Blocking PD-1 can lead to increased expression of TIM-3, LAG-3, and others, which continue suppressing immune responses.
153
What is compensatory inhibition in checkpoint blockade failure?
🔄 When PD-1 is blocked, tumors upregulate other immune checkpoints (e.g., TIM-3, LAG-3) to continue suppressing the immune system. This adaptation is commonly observed in both mouse models and patients.
154
What are the four main types of tumor immunotherapy?
🏥
Checkpoint inhibitors (e.g., anti-PD-1, anti-CTLA-4)
Antibody-drug conjugates
Cancer vaccines
Cellular therapies (e.g., CAR-T cells)
155
What is a major challenge with IL-2 therapy in immunotherapy?
🧬 IL-2 therapy has systemic vs. local effects, where systemic administration can cause severe toxicity, making it difficult to use effectively.
156
Why is understanding immunotherapy failures important for drug design?
🧠 It helps in refining therapies, improving combination treatments, and designing new drugs that minimize resistance and side effects.
