1
Q
Overview of lymphocytes in immune response
B Cells
A
Recognition: Antigen on pathogens or soluble antigen
Functions:
Production of antibodies
Neutralization of pathogens
Phagocytosis (via opsonization)
Complement activation
2
Q
Overview of lymphocytes in immune response
Helper T Cells (CD4⁺)
A
Recognition: Antigen presented by professional APCs (via MHC II)
Functions:
Secretion of cytokines
Activation of macrophages
Activation of B cells
Activation of other T cells
Promotion of inflammation
3
Q
Overview of lymphocytes in immune response
Cytotoxic T Cells (CD8⁺)
A
Recognition: Antigen presented by infected or malignant cells (via MHC I)
Function:
Elimination (killing) of infected or malignant cells
4
Q
Overview of lymphocytes in immune response
Regulatory T Cells (Treg)
A
Recognition: Not antigen-specific in the same effector way
Function:
Regulate and suppress immune responses
Maintain immune tolerance
5
Q
Overview of lymphocytes in immune response
Natural Killer (NK) Cells
A
Recognition:
Self-antigen
Foreign antigen on host cells (e.g. missing MHC I)
Function:
Elimination of infected or malignant cells
6
Q
Overview of lymphocytes in immune response
Key Comparison
Q: Which lymphocytes are part of adaptive vs innate immunity?
A
Adaptive: B cells, Helper T cells, Cytotoxic T cells, Regulatory T cells
Innate: Natural Killer (NK) cells
7
Q
Overview of t cell types and their roles in immune response
Overview of T Cell Roles
Q: What are the main roles of different T cell types in the immune response?
A
Helper T cells (CD4⁺): Coordinate immune response via cytokines
Cytotoxic T cells (CD8⁺): Kill infected or malignant cells
Regulatory T cells: Suppress immune responses and maintain tolerance
8
Q
Overview of t cell types and their roles in immune response
How CD8⁺ T Cells Kill Target Cells
Q: How do cytotoxic T cells eliminate infected cells?
A
Recognise antigen on MHC class I of infected cells
Release perforin → forms pores in target cell membrane
Release granzymes → enter through pores
Granzymes activate caspases → apoptosis
Result: dying infected cell
9
Q
Overview of t cell types and their roles in immune response
Key Molecules in CD8⁺ Killing
Q: What are perforin and granzymes?
A
Perforin: Creates pores in target cell membrane
Granzymes: Proteases that trigger apoptosis inside the cell
10
Q
Overview of t cell types and their roles in immune response
Challenges in Treating Solid Tumours
Q: Why is CAR T-cell therapy less successful in solid tumours?
A
Lack of ideal tumour-specific antigens
Poor trafficking of T cells to tumour site
Hostile tumour microenvironment (immunosuppressive)
11
Q
Overview of t cell types and their roles in immune response
What is CAR T-cell Therapy?
Q: What is CAR T-cell therapy?
A
A treatment where a patient’s T cells are genetically engineered to recognise and kill cancer cells
12
Q
Overview of t cell types and their roles in immune response
Steps of CAR T-cell Therapy
Q: What are the steps involved in CAR T-cell therapy?
A
- Extract T cells from patient
- Genetically modify them to express CAR (chimeric antigen receptor)
- Expand (grow millions of cells) in the lab
- Infuse modified T cells back into patient
12
Q
Overview of t cell types and their roles in immune response
How CAR T Cells Work
Q: How do CAR T cells kill cancer cells?
A
CAR allows direct recognition of tumour antigens (no MHC required)
Bind to cancer cells
Activate cytotoxic response
Kill cancer cells (similar to CD8⁺ mechanism)
13
Q
Overview of t cell types and their roles in immune response
Flashcard 8: Why CAR T Cells Are Powerful
Q: What is a key advantage of CAR T cells over normal T cells?
A
MHC-independent recognition → can target tumours that evade normal T cell detection
14
Q
Tumour Microenvironment (TME)
Q: What is the tumour microenvironment (TME)?
A
The environment surrounding a tumour
Composed of:
Immune cells
Non-immune stromal cells
Extracellular matrix (ECM) proteins
15
Q
Tumour Microenvironment (TME)
Q: What roles does the tumour microenvironment play?
A
Regulates tumour growth
Promotes progression and metastasis
Influences anti-tumour immune responses
16
Q
Tumour Microenvironment (TME)
Q: How do cancer cells interact with immune cells in the TME?
A
Recruit immune cells that support tumour growth
Suppress inflammatory immune responses
Create an immunosuppressive environment
17
Q
Tumour Microenvironment (TME)
Q: Why does a hypoxic core develop in tumours?
A
Due to diffusion limitations of oxygen
Leads to:
Low oxygen (hypoxia)
Necrosis
Increased tumour aggressiveness
18
Q
Tumour Microenvironment (TME)
Q: What are key features of tumour organisation?
A
Core: hypoxia, necrosis, inflammation
Periphery: actively proliferating cells
Cancer cells at edges invade surrounding tissues
19
Q
Tumour Microenvironment (TME)
Q: What is the role of extracellular matrix (ECM) in tumours?
A
Accumulates around tumour
Provides structural support
Can act as a barrier to immune cell infiltration
20
Q
Tumour Microenvironment (TME)
Q: What is tumour immune evasion?
A
Mechanisms that prevent immune-mediated tumour killing
21
Q
Tumour Microenvironment (TME)
Q: How do tumours evade the immune system?
A
Suppress lymphocyte activation and function
Direct tumour–immune cell interactions
Recruit immunosuppressive cells (e.g. Tregs, TAMs)
Alter antigen presentation
22
Q
Tumour Microenvironment (TME)
Q: How does immunotherapy differ from chemotherapy?
A
Immunotherapy: reactivates immune system to attack cancer
Chemotherapy: directly targets tumour cell growth
Highlights importance of the TME and immune cells
23
Q
Tumour Microenvironment (TME)
Q: What role do CD8⁺ T cells play in anti-tumour immunity?
A
Primary cells responsible for killing tumour cells
Recognise tumour antigens via TCR–MHC I interaction
24
Tumour Microenvironment (TME)
Q: How do CD8⁺ T cells recognise tumour cells?
Tumour antigens presented on MHC class I molecules
Recognised by T cell receptor (TCR)
25
Tumour Microenvironment (TME)
Q: What happens after CD8⁺ T cell activation?
Release cytotoxic molecules → kill tumour cells
Secrete cytokines:
IFN-γ
TNF-α
26
Tumour Microenvironment (TME)
Q: Why is the tumour microenvironment important in cancer therapy?
It can block immune responses
Determines success of immunotherapy
Targeting the TME can improve treatment outcomes
27
TME infiltration
T Cell Infiltration Overview
Q: Why is T cell infiltration into solid tumours difficult?
Due to multiple barriers created by the tumour microenvironment (TME)
Includes physical, immunological, and tumour-specific challenges
28
TME infiltration
Physical Barriers in the TME
Q: How does the tumour stroma block T cell infiltration?
Dense fibrotic stroma and extracellular matrix (ECM)
Acts as a physical barrier preventing T cell entry
29
TME infiltration
Hypoxia and Ischemia
Q: How do hypoxia and poor blood supply affect T cells?
Tumours have low oxygen (hypoxia) and poor perfusion
Leads to reduced T cell survival and function
30
TME infiltration
Tumour Vasculature
Q: Why is tumour vasculature a problem for T cell infiltration?
Blood vessels are abnormal, leaky, and disorganised
Impairs efficient T cell trafficking into tumours
31
TME infiltration
Immunosuppressive TME
Q: How does the TME suppress T cell activity?
High expression of immune checkpoint molecules (e.g. PD-1, CTLA-4)
Presence of regulatory T cells (Tregs)
Overall suppression of immune responses
32
TME infiltration
Chemokine Deficiency
Q: Why is chemokine expression important for T cell infiltration?
Chemokines guide T cells to tumours
Lack of chemokines → poor T cell recruitment
33
TME infiltration
T Cell Exhaustion
Q: What is T cell exhaustion in the TME?
Caused by chronic antigen exposure + suppressive signals
Leads to reduced cytotoxic function and cytokine production
34
TME infiltration
Metabolic Suppression
Q: How does the tumour metabolic environment affect T cells?
Acidic, nutrient-poor conditions
Impairs T cell survival and function
35
TME infiltration
T Cell Anergy
Q: What is T cell anergy?
State of functional unresponsiveness
T cells fail to respond to tumour antigens
36
TME infiltration
Immunosuppressive Cells
Q: Which cells in the TME suppress T cell function?
Myeloid-derived suppressor cells (MDSCs)
Tumour-associated macrophages (TAMs)
Regulatory T cells (Tregs)
Tumour-associated dendritic cells
37
TME infiltration
Tumour Antigen Heterogeneity
Q: Why is antigen heterogeneity a problem for T cell therapy?
Different tumour cells express different antigens
Difficult to target all tumour cells with one therapy
38
TME infiltration
Antigen Escape
Q: What is antigen escape?
Tumour cells lose or alter antigen expression
Avoid recognition by T cells
39
TME infiltration
Antigen Shedding
Q: How does antigen shedding impair T cell recognition?
Tumour releases antigens into environment
Reduces antigen availability on tumour surface
Interferes with CAR T cell targeting
40
TME infiltration
Q: What are the three major categories limiting T cell infiltration in tumours?
1. Physical barriers (stroma, hypoxia, vasculature)
2. T cell dysfunction (exhaustion, anergy, suppression)
3. Tumour factors (heterogeneity, antigen escape)
41
TME infiltration
1) Physical Barriers and Tumor Microenvironment (TME):
o Dense fibrotic stroma:
The dense extracellular matrix and fibrotic stroma surrounding can act as physical barriers
o Hypoxia and ischemia:
Tumours often have poor blood supply and can experience lack of oxygen and blood flow
o Tumour vasculatrure:
The vasculature in tumours is often abnormal, with leaky and irregular blood vessels
o Immunosuppressive TME
Solid tumours create a TME that is often immunosuppressive, with high levels of immune checkpoint molecules (like PD-1, CTLA-4) and regulatory T cells
o Lack of chemokine expression
The lack of chemokine expression, which are signalling molecules that attract T cells to the tumor site
42
TME infiltration
2) T cell Dysfunction and Exhaustion
o T cell exhaustion
Prolonged exposure to tumor antigens and the immunosuppressive TME can lead to T-cell exhaustion, where T cells become dysfunctional and lose their ability to effectively target tumor cells.
o Altered metabolic microenvironment
The altered metabolic environment within the TME can also negatively impact T-cell function and survival. (acidic environment)
o T-cell anergy:
a state of functional unresponsiveness, can also occur in the TME, further hindering T-cell activity.
o Immunosuppressive cells
Myeloid-derived suppressor cells, tumour-associated macrophages, regulatory T cells (Tregs), and tumour-associated dendritic cells
43
TME infiltration
3) Tumour antigen heterogeneity
o Lack of specific taregts:
Solid tumours often exhibit high antigen heterogeneity, meaning that different tumor cells express different antigens, making it difficult to identify a single, effective target for T-cell therapy.
44
TME infiltration
- Antigen escape:
o Tumour cells can evolve mechanisms to evade immune recognition, such as losing the expression of target antigens or expressing inhibitory molecules.
o Some tumor cells may shed or release the target antigen from their surface into the surrounding microenvironment. Shed antigens can bind to soluble factors or be taken up by antigen-presenting cells, effectively reducing the amount of antigen available for CAR-T cell recognition.22 Antigen shedding can be a result of protease activity, tumor microenvironment factors, or cellular processes within cancer cells.
45
Tumour immunosuppression
Q: What is tumour immunosuppression?
Mechanisms by which cancer cells inhibit immune responses
Achieved through cell signalling, cytokines, and checkpoint pathways
46
Tumour Immunosuppression
Key Immune Checkpoint Proteins
Q: Which immune checkpoint proteins are involved in tumour immunosuppression?
PD-L1 (on tumour cells) → binds PD-1 on T cells
CTLA-4 (on T cells) → inhibits activation
RAGE (on immune cells) → binds S100B
47
Tumour Immunosuppression
PD-1 / PD-L1 Pathway
Q: How does PD-L1 suppress T cell function?
PD-L1 on tumour cells binds PD-1 on T cells
Leads to:
T cell inhibition
T helper cell apoptosis
Increased Treg immunosuppressive activity
48
Tumour Immunosuppression
CTLA-4 Function
Q: What is the role of CTLA-4 in T cell suppression?
CTLA-4 binding downregulates T cell activation
Acts as a key immune checkpoint
49
Tumour Immunosuppression
RAGE–S100B Pathway
Q: How does RAGE contribute to immunosuppression?
RAGE binds S100B
Inhibits TAM and microglia production of immunostimulatory cytokines
50
Tumour Immunosuppression
Tumour-Derived Immunosuppressive Factors
Q: What factors do tumour cells release to suppress immunity?
CSF-1 → recruits TAMs and microglia
IL-10 → anti-inflammatory
TGF-β → immunosuppressive cytokine
51
Tumour Immunosuppression
Recruitment of Immunosuppressive Cells
Q: How do tumours recruit suppressive immune cells?
Via CSF-1 signalling
Recruits:
Tumour-associated macrophages (TAMs)
Microglia
52
Tumour Immunosuppression
Role of Hypoxia in Immunosuppression
Q: How does hypoxia promote tumour immunosuppression?
Increases VEGF expression
Activates STAT3 pathway in TAMs/microglia
Promotes release of IL-10 and TGF-β
53
Tumour Immunosuppression
Effects of TAM/Microglia Activation
Q: What happens after TAMs and microglia are activated?
Increased immunosuppressive cytokines (IL-10, TGF-β)
Enhanced tumour support and immune evasion
54
Tumour Immunosuppression
Impact on Antigen Presentation
Q: How do tumours impair antigen presentation?
Downregulate MHC expression
Reduce MHC–TCR interactions
Impair immune recognition of tumour cells
55
Tumour Immunosuppression
Effects on Tumour Progression
Q: What are the outcomes of tumour immunosuppression?
Increased tumour invasiveness
Reduced immune clearance
Enhanced tumour survival and growth
56
Tumour Immunosuppression
What are Immune Checkpoint Inhibitors (ICIs)?
Q: What are ICIs and how do they work?
Drugs that block checkpoint protein interactions
Restore T cell activation and tumour killing
57
Tumour Immunosuppression
Mechanism of ICIs
Q: How do ICIs enhance anti-tumour immunity?
Prevent binding of:
PD-1 ↔ PD-L1
CTLA-4 interactions
Result: T cells remain active and kill tumour cells
58
Tumour Immunosuppression
Approved ICIs
Q: Which immune checkpoint inhibitors are FDA-approved?
Anti-CTLA-4
Anti-PD-1
Anti-PD-L1
59
Tumour Immunosuppression
Physiological Role of Checkpoints
Q: Why do immune checkpoints exist normally?
Prevent autoimmunity
Ensure T cells do not attack healthy tissues
60
Tumour Immunosuppression
Tumour Exploitation of Checkpoints
Q: How do tumours exploit immune checkpoints?
Overexpress checkpoint ligands (e.g. PD-L1)
Turn off T cell responses
Avoid immune destruction
61
Tumour Immunosuppression
Limitations of ICIs
Q: What are the limitations of immune checkpoint inhibitors?
Not effective in all cancers
Tumour microenvironment can still suppress immunity
Resistance mechanisms exist
62
Tumour Immunosuppression
Big Picture
Q: What is the overall strategy of tumour immunosuppression?
Recruit suppressive cells
Release inhibitory cytokines
Block antigen presentation
Activate checkpoint pathways
→ Result: immune evasion and tumour survival
63
Immune evasion by tumours
Overview of Tumour Immune Evasion
Q: What is tumour immune evasion?
Mechanisms by which tumours avoid detection and destruction by CD8⁺ T cells
Includes:
Loss of antigen presentation
Inhibition of T cell function
Immunosuppressive environment
64
Immune evasion by tumours
Loss of MHC Class I (Diagram B)
Q: How does loss of MHC class I help tumours evade CD8⁺ T cells?
CD8⁺ T cells require MHC I to recognise tumour antigens
Downregulation of MHC I → T cells cannot detect tumour cells
65
Immune evasion by tumours
Loss of Tumour Antigens
Q: What is a loss-antigen variant in tumours?
Tumour cells stop expressing target antigens
Leads to failure of T cell recognition
66
Immune evasion by tumours
Non-Classical HLA Molecules
Q: How do non-classical HLA molecules contribute to immune evasion?
Expression of molecules like HLA-E/F/G
Alters immune recognition and inhibits T cell responses
67
Immune evasion by tumours
T Cell Inhibition (Diagram C)
Q: How are T cells directly inhibited by tumour cells?
Tumour cells express inhibitory ligands
Bind to inhibitory receptors on T cells
Result: T cell activation is blocked
68
Immune evasion by tumours
Immunosuppressive Cytokines
Q: How do cytokines suppress anti-tumour immunity?
Tumours release cytokines (e.g. IL-10, TGF-β)
Suppress T cell activation and function
69
Immune evasion by tumours
Regulatory T Cells (Diagram D)
Q: What role do Tregs play in tumour immune evasion?
Suppress effector T cell responses
Inhibit anti-tumour immunity
70
Immune evasion by tumours
Myeloid-Derived Suppressor Cells (MDSCs)
Q: How do MDSCs contribute to immune evasion?
Accumulate in tumour microenvironment
Suppress CD8⁺ T cell responses
71
Immune evasion by tumours
Effect on T Cell Differentiation
Q: How does the tumour microenvironment affect T cell differentiation?
Inhibits differentiation into:
Th1 cells
CD8⁺ cytotoxic T cells
72
Immune evasion by tumours
Combined Effect
Q: What is the overall effect of these immune evasion mechanisms?
Reduced tumour recognition
Inhibited T cell activation
Suppressed immune response
→ Tumour survival and progression
73
Immune evasion by tumours
Q: List three major mechanisms of tumour immune evasion.
1. Loss of antigen presentation (↓ MHC I, antigen loss)
2. T cell inhibition (checkpoint ligands, cytokines)
3. Immunosuppressive cells (Tregs, MDSCs)
74
Modulation of T cell functions (how can we solve these issues for treatment)
Overall Strategy – Modulating T Cell Function
Q: What are the main strategies to improve T cell function in cancer therapy?
CAR-T cell therapy
Modifying CAR-T cells
Modulating the tumour microenvironment (TME)
Combination therapies
Targeting tumour-specific antigens
Activating general inflammatory pathways
75
Modulation of T cell functions (how can we solve these issues for treatment)
Engineering CAR-T Cells
Q: How can CAR-T cells be engineered to improve efficacy?
Add molecules to overcome immunosuppression
Enhance T cell trafficking to tumours
Improve survival and persistence in the TME
76
Modulation of T cell functions (how can we solve these issues for treatment)
Modulating the TME
Q: How can the tumour microenvironment be modified to support T cells?
Block immunosuppressive signals (e.g. cytokines, checkpoints)
Promote T cell infiltration
Make environment more immune-supportive
77
Modulation of T cell functions (how can we solve these issues for treatment)
Combination Therapies
Q: Why combine CAR-T therapy with other treatments?
Overcome immunosuppression
Enhance T cell activation
Examples:
Checkpoint inhibitors
Other immunotherapies
78
Modulation of T cell functions (how can we solve these issues for treatment)
Targeting Tumour Antigens
Q: Why is identifying tumour antigens important?
Enables specific targeting of cancer cells
Must identify shared or key tumour antigens
Helps overcome tumour heterogeneity
79
Modulation of T cell functions (how can we solve these issues for treatment)
CCR5 + IL-12 Strategy
Q: How does CCR5 and IL-12 co-expression improve therapy?
Reprograms the TME
Enhances anti-tumour immune responses
Improves CAR-T cell effectiveness
80
Modulation of T cell functions (how can we solve these issues for treatment)
IL-15 in CAR-T Therapy
Q: What is the role of IL-15 in CAR-T therapy?
Enhances T cell survival and proliferation
Improves effectiveness in solid tumours
81
Modulation of T cell functions (how can we solve these issues for treatment)
General Inflammation Pathways
Q: How can inflammation be used therapeutically against tumours?
Activate immune signalling pathways
Deliver cytokines or antibodies
Promote immune-mediated tumour killing
82
Modulation of T cell functions (how can we solve these issues for treatment)
Antibody-Based Approaches
Q: How do antibodies promote tumour killing?
Bind tumour antigens (e.g. EGFR)
Trigger ADCC (antibody-dependent cell-mediated cytotoxicity)
Activate immune cells
83
Modulation of T cell functions (how can we solve these issues for treatment)
Cytokine Therapy (CCL21 Example)
Q: How does CCL21 enhance anti-tumour immunity?
Recruits:
Lymphocytes
Dendritic cells
NK cells
Enhances immune infiltration into tumour
84
Modulation of T cell functions (how can we solve these issues for treatment)
Nanoparticle Delivery (Diagram-Based)
Q: Why use nanoparticles (e.g. vault proteins) for cytokine delivery?
Improve stability and bioavailability
Enable delivery across barriers (e.g. blood-brain barrier)
Protect cytokines until release
85
Modulation of T cell functions (how can we solve these issues for treatment)
Challenges of Cytokine Delivery
Q: What are the risks of cytokine therapy?
Off-target inflammation
Systemic toxicity (“cytokine bomb”)
Need for targeted delivery to tumour site
86
Modulation of T cell functions (how can we solve these issues for treatment)
Targeted Cytokine Delivery
Q: How can cytokine therapy be safely delivered?
Intratumoral injection
Encapsulation in particles/vesicles
Controlled release within tumour
87
Modulation of T cell functions (how can we solve these issues for treatment)
Blood-Brain Barrier Challenge
Q: Why is delivery difficult in brain tumours (e.g. GBM)?
Blood-brain barrier limits access
Direct injection is invasive
Requires specialised delivery systems
88
Modulation of T cell functions (how can we solve these issues for treatment)
Big Picture
Q: What is the overall goal of modulating T cell function in cancer therapy?
Enhance T cell infiltration, survival, and activity
Overcome tumour immunosuppression
Improve tumour clearance
89
TILs and CAR T cell therapies
Overview of TIL vs CAR-T Therapy
Q: What are TIL and CAR-T therapies?
Both are adoptive T cell therapies
TILs: use naturally tumour-infiltrating T cells
CAR-T: genetically engineered T cells targeting specific antigens
90
TILs and CAR T cell therapies
What are TILs?
Q: What are tumour-infiltrating lymphocytes (TILs)?
T cells naturally found within tumour tissue
Already recognise tumour antigens
91
TILs and CAR T cell therapies
Steps of TIL Therapy
Q: What are the steps in TIL therapy?
1. Partial tumour excision
2. Isolation of TILs
3. Expansion of TILs in vitro
4. Lymphodepleting chemotherapy
5. Infusion of TILs back into patient
6. Administration of IL-2
92
TILs and CAR T cell therapies
Role of Lymphodepletion
Q: Why is lymphodepleting conditioning used before TIL infusion?
Removes endogenous lymphocytes
Reduces competition
Enhances proliferation and activity of infused TILs
93
TILs and CAR T cell therapies
Role of IL-2 in TIL Therapy
Q: Why is IL-2 given in TIL therapy?
Promotes T cell growth and survival
Enhances anti-tumour activity
94
TILs and CAR T cell therapies
What is CAR-T Cell Therapy?
Q: What is CAR-T cell therapy?
Patient T cells are genetically engineered to express CARs
Enables targeting of specific tumour antigens
95
TILs and CAR T cell therapies
Steps of CAR-T Therapy
Q: What are the steps in CAR-T therapy?
1. Extract T cells from blood
2. Insert gene encoding CAR
3. Expand modified T cells
4. Infuse CAR-T cells into patient
96
TILs and CAR T cell therapies
Structure of CAR
Q: What is the structure of a chimeric antigen receptor (CAR)?
Extracellular domain: antibody-derived antigen recognition
Intracellular domain: T cell activation signalling
97
TILs and CAR T cell therapies
CAR-T Targeting Example
Q: What antigen is targeted in GBM CAR-T therapy?
EGFRvIII (tumour-specific variant)
98
TILs and CAR T cell therapies
Clinical Success of CAR-T
Q: Where has CAR-T therapy been most successfu
Blood cancers (e.g. chronic lymphocytic leukaemia)
FDA-approved for leukaemia and lymphoma
99
TILs and CAR T cell therapies
Challenges in Solid Tumours
Q: What limits CAR-T therapy in solid tumours?
Tumour microenvironment (TME) suppression
Poor T cell infiltration
Antigen heterogeneity
Off-tumour toxicity
100
TILs and CAR T cell therapies
Off-Tumour Toxicity
Q: What is off-tumour toxicity in CAR-T therapy?
CAR-T cells attack healthy tissues expressing similar antigens
101
TILs and CAR T cell therapies
Antigen Heterogeneity Problem
Q: Why is antigen heterogeneity a challenge?
Tumour cells express different antigens
Some cells escape CAR-T targeting
102
TILs and CAR T cell therapies
Next-Generation CAR-T Cells
Q: How are newer CAR-T cells being improved?
Enhanced specificity
Reduced toxicity
Improved persistence and function
103
TILs and CAR T cell therapies
Genetic Enhancements in CAR-T
Q: What genetic modifications improve CAR-T cells?
Increased cytotoxicity
Better survival in TME
Resistance to immunosuppression
104
TILs and CAR T cell therapies
Combination Therapies
Q: Why combine CAR-T with other therapies?
Overcome TME suppression
Improve efficacy
Examples: checkpoint inhibitors
105
TILs and CAR T cell therapies
Key Comparison
Q: What is the key difference between TIL and CAR-T therapy?
TILs: naturally tumour-reactive cells
CAR-T: engineered specificity to defined antigen
106
TILs and CAR T cell therapies
Q: What is the goal of adoptive T cell therapies?
Increase number and effectiveness of tumour-targeting T cells
Achieve tumour clearance
107
Goal of Modulating the TME
Q: What is the aim of modulating the tumour microenvironment (TME)?
Make the TME more permissive for T cell infiltration and function
Achieved by:
Blocking immunosuppressive factors
Enhancing T cell trafficking
108
Key Strategy – TME Modulation
Q: How can the TME be modified to improve therapy?
Reduce immunosuppression (e.g. cytokines, checkpoints)
Increase immune cell recruitment
Improve T cell survival and activity
109
CCR5 Function
Q: What is CCR5 and what does it do?
A chemokine receptor on T cells
Binds chemokines (e.g. CCL5)
Guides T cells to tumour sites → improves infiltration
110
CCR5 in CAR-T Therapy
Q: How does CCR5 improve CAR-T cell therapy?
Enhances migration and tumour infiltration
Increases CAR-T cell presence within tumours
111
IL-12 Function
Q: What is the role of IL-12 in tumour immunotherapy?
Pro-inflammatory cytokine
Boosts T cell activation and cytotoxicity
Counteracts immunosuppressive TME
112
CCR5 + IL-12 Co-Expression
Q: Why combine CCR5 and IL-12 in CAR-T cells?
CCR5: improves trafficking to tumour
IL-12: enhances function within tumour
→ Together: stronger anti-tumour response
113
Clinical Evidence
Q: What is CARTmeso-5-12?
CAR-T cells co-expressing CCR5 and IL-12
Show improved efficacy in oesophageal carcinoma models
114
Effects of CCR5 + IL-12 Therapy
Q: What are the outcomes of CCR5 + IL-12 modification?
Increased tumour infiltration
Enhanced CAR-T functionality
Reduced impact of TME suppression
115
Combination Therapies
Q: Why combine CAR-T with other therapies?
Overcome immunosuppressive TME
Enhance T cell activity
Improve treatment outcomes
116
Examples of Combination Approaches
Q: What therapies can be combined with CAR-T?
Immune checkpoint inhibitors (ICIs)
Cytokine therapies
Antibody-based therapies
Chemotherapeutics
117
Effects of Combination Therapy
Q: What are the benefits of combination therapy?
Inhibits tumour growth
Stimulates immune response
Improves therapeutic outcomes
118
Big Picture – Modulating T Cells in Cancer
Q: What are the key approaches to improving T cell-based cancer therapy?
1. Enhance T cell trafficking (e.g. CCR5)
2. Boost T cell function (e.g. IL-12)
3. Modify TME
4. Use combination therapies
119
Final Summary
Q: Summarise how tumour immunology informs therapy design.
Tumours suppress immune responses via the TME
Therapies aim to:
Restore T cell function
Improve infiltration
Overcome immune evasion
→ Leads to improved cancer treatment outcomes
Y3 Immunology
flashcards
Decks in class (25)
# Cards
-
week 1 - Evolution of innate immunity41
-
week 2 - non cellular immunity37
-
week 2 - phagocytes69
-
week 3 - Phagocytosis and phagosome maturation70
-
week 3 - phagosome maturation notes from Freeman and Grinstein 201415
-
week 3 - adaptive immunity94
-
week 4 - adaptive immunity II108
-
week 4 - adaptive immunity III138
-
week 5 - Pattern recognition receptors166
-
week 5 - pattern recognition receptors - NAIP2-NRCL4 inflammasome47
-
week 5 - PRR - RIG-I PAPER NOTES (Nature 2011)26
-
week 6 - b cell receptors128
-
week 6 - t cell receptors - part 1113
-
week 6 - t cell receptors - part 273
-
week 6 - t cell receptors - part 350
-
week 8 - allergy and autoimmunity155
-
week 8 – Immune receptor signalling128
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week 8 - therapeutic antibodies - Why antibodies as therapeutic agents?36
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week 8 - therapeutic antibodies - How are (therapeutic) antibodies made?21
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week 8 - examples of therapeutic antibodies33
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week 8 - therapeutic antibodies - effector mechanisms113
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week 8 - therapeutic antibodies - new possibilities through genetic engineering30
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week 9 - cancer immunotherapy180
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week 10 - T cell function in solid cancers120
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week 10 - Imaging T cell function86
