L17 - Immunotherapy: T-cell therapy in Cancer (Prof Linda Wooldridge) Flashcards
How common is cancer in the UK?
π Around 375,000 new cancer cases occur annually in the UK (2016-2018 average), equating to 1,000 cases per day.
How often is someone diagnosed with cancer in the UK?
β³ Every 2 minutes, someone in the UK is diagnosed with cancer.
What are the future projections for cancer incidence in the UK?
π By 2038-2040, annual cancer cases in the UK are expected to rise to ~506,000 per year.
What are the three leading causes of death worldwide?
β οΈ Cancer, infectious diseases and cardiovascular disease
How many people die from cancer in the UK each year?
β°οΈ Approximately 167,000 cancer deaths occur annually in the UK (2017-2019 average).
Why is cancer research a priority?
π§ͺ Due to the rising incidence and high mortality rates, developing new and more effective cancer treatments is crucial.
What is cancer immunotherapy?
π‘οΈ Cancer immunotherapy is a treatment approach that uses the immune system to fight and eliminate cancer cells.
Why has cancer immunotherapy gained attention?
π It was named Breakthrough of the Year by Science in 2013, marking its growing impact on cancer treatment.
What is the goal of cancer treatment?
π― The complete removal or destruction of all malignant cells without harming the patient.
Why are T cells important in immunotherapy?
π₯ T cells are crucial as they can recognise and kill cancer cells, making them key players in many immunotherapy strategies.
Can immunotherapy be combined with other treatments?
π Yes! It can be used alongside surgery or chemotherapy to reduce tumour load :before (neoadjuvant) or after (adjuvant) (research suggesting that neoadjuvant immunotherapy, given before surgery, can improve outcomes in certain cancers, particularly melanoma and potentially lung cancer, while adjuvant immunotherapy, given after surgery, can help reduce the risk of recurrence)
What are some existing immunotherapy treatments?
β Licensed therapies include:
IL-2 Therapy π§ͺ
Checkpoint Blockade π§
CAR-T Cell Therapy π¦
π Many new therapies are in clinical trials and under development.
Why is immunotherapy considered a major hope for cancer treatment?
π Funders and researchers see it as a promising approach to improving survival rates and cancer outcomes.
How do research funders influence cancer treatment progress?
π° Major funders release strategic plans every five years to prioritize research areas with the highest potential impact.
Which UK organisation is a major funder of cancer research?
ποΈ Cancer Research UK (CRUK) β a well-known charity funding cancer research through grants, fundraising events, and charity shops.
Why does CRUK prioritize cancer immunology projects?
π They recognize immunotherapyβs potential to reduce cancer cases and improve survival rates, aligning with their long-term strategy.
Why are T cells important in tumour rejection?
π¦ They recognise tumour rejection antigens and mediate tumour destruction proving their role in anti-tumour immunity
What experiment demostrated T cellsβ role in tumour immunity?
π Inbred mouse models were used, where:
πΉ Transplantable tumours grew and killed normal mice.
πΉ Mice immunised with irradiated tumour cells rejected a later tumour challenge.
πΉ T-cell deficient mice failed to reject tumours, proving T cells are essential.
What did the experiment reveal about tumour antigens?
π― Tumours express tumour rejection antigens, which serve as targets for T cell-mediated immune responses.
What are tumour rejection antigens?
π― Tumour rejection antigens are proteins expressed on tumour cells that the immune system can recognise, triggering a T cell response to eliminate the tumour.
What are the two main types of tumour antigens?
πΉ Tumour-Specific Antigens (TSA) π β Found only on tumour cells, e.g., mutated proteins from oncogenes.
πΉ Tumour-Associated Antigens (TAA) β οΈ β Found on both normal and tumour cells, but overexpressed in tumours, e.g., HER2 in breast cancer.
How do T cells recognise tumour rejection antigens?
π¬ Antigen-presenting cells (APCs) process and present tumour antigens via MHC molecules, activating CD8+ cytotoxic T cells, which then target and destroy tumour cells.
What is cancer immunoediting
π Cancer immunoediting describes how the immune system shapes tumour evolution through:
1οΈβ£ Elimination β Immune system destroys tumour cells.
2οΈβ£ Equilibrium β Some tumour cells survive and mutate.
3οΈβ£ Escape β Mutated cells evade immunity and grow uncontrollably.
What are the three phases of tumour growth
π‘οΈ Elimination phase β The immune system recognises and destroys tumour cells (immune surveillance).
βοΈ Equilibrium phase β Tumour cells mutate to enhance survival (cancer immunoediting).
π¨ Escape phase β Tumour evades immune response and grows uncontrollably.
How do tumours evade immune detection
π¦ Low immunogenicity β Downregulation of MHC I and II, loss of adhesion and costimulatory molecules.
π Immune suppression β Tumours express PD-L1, which binds PD-1 on T cells, inactivating them.
π Antigenic modulation β Antibodies trigger endocytosis and degradation of tumour antigens, allowing antigen-loss variants to grow.
π‘οΈ Physical barriers β Tumour microenvironment releases factors that block immune cell infiltration.
How do tumours create an immunosuppressive microenvironment
π Checkpoint inhibition β Tumours express PD-L1, which binds PD-1 on T cells, inactivating them.
π¦ Regulatory T cells (Tregs) β Suppress anti-tumour immune responses.
π§ͺ Immunosuppressive cytokines β Tumours release TGF-Ξ² and IL-10, which inhibit T cells and promote tumour growth.
π‘οΈ Physical barriers β Tumour stroma and extracellular matrix prevent immune infiltration.
How do tumours resist immune recognition?
π¦ Downregulation of MHC I & II β Reduces antigen presentation to T cells.
π« Loss of costimulatory molecules β Prevents activation of tumour-specific T cells.
π Antigenic loss variants β Tumour cells lose highly immunogenic antigens over time.
How does tumour antigenic modulation contribute to immune evasion?
How does tumour antigenic modulation contribute to immune evasion?
What are the major challenges in tumour immunotherapy?
π¦ Low immunogenicity β Tumours lack strong antigens to trigger a response.
π Checkpoint blockade β Tumours suppress T cells using PD-L1/PD-1 interaction.
π Tumour heterogeneity β Different tumour cells express different antigens, making therapy less effective.
βοΈ Balancing autoimmunity & tumour rejection β Overactivation of the immune system can lead to autoimmune side effects.
How do CD8 T cells recognise cancer cells
π― CD8 cytotoxic T cells (CTLs) recognise tumour cells via MHC class I presentation of tumour antigens.
How do CD8 T cells kill cancer cells once activated?
π‘οΈ Once activated, they kill tumour cells through:
Perforin & granzymes β Induce apoptosis.
Fas-FasL interaction β Triggers cell death.
Cytokine release (IFN-Ξ³, TNF-Ξ±) β Enhances immune response & tumour clearance.
How do CD4+ T helper cells support tumour rejection ( what is their role in tumour immunity)?
1οΈβ£ Activating CD8 T cells β Essential for robust cytotoxic responses.
2οΈβ£ Establishing memory T cells β Ensuring long-term immune surveillance.
3οΈβ£ Direct tumour killing β Some CD4 cells release TNF-Ξ± and IFN-Ξ³, inducing tumour apoptosis.
Why is tumour rejection mainly mediated by CD8+ t cel;s
π¬Because they directly recognise and kill tumour cells presenting MHC-I antigens.
CD4 T cells mostly act as helpers, supporting CD8 responses.
Tumour rejection relies on strong cytotoxic activity, which CD8 T cells provide.
Which cells does immunotherapy mostly focus on
π‘οΈ CD8 T cells β Core of tumour-killing strategies.
π‘οΈ CD4 T cells β Assist in activation & memory formation
What are emerging approaches to tumour immunotherapy?
Ξ³Ξ΄ T cells β Recognise stressed tumour cells independently of MHC.
MAIT cells β Recognise bacterial metabolites in tumour microenvironments.
Natural Killer (NK) cells β Kill tumour cells without antigen priming.
what do most T cell-based therapy aim to enhance
nhance CD8 function, including:
Checkpoint inhibitors (e.g., anti-PD-1, anti-CTLA-4).
CAR-T cell therapy β Genetically engineered CD8 T cells.
Adoptive T cell transfer β Expansion of tumour-specific CD8 T cells.
How are CD4+ T cells used in T cell immunotherapy?
π οΈ CD4 T cells enhance CD8 therapy by:
Boosting activation & persistence of CD8 responses.
Promoting cytokine secretion (IL-2, IFN-Ξ³) to strengthen immunity.
π¬ Some therapies engineer tumour-reactive CD4 T cells to directly attack cancer.
Why do tumour cells present a challenge to the immune system?
π§Tumour cells contain abnormal proteins that are buried inside the cell. this means that the immune system cannot directly detect them. To overcome this, tumour proteins are processed, and presented on the surface of MHC class I
How are tumour antigens processed and presented to CD8+ T cells
π¬ Proteasome degradation: Tumour proteins are broken into small peptide fragments (8-13 amino acids).
π¦ MHC-I loading: Peptides are transported to the ER and loaded onto MHC class I molecules.
π Cell surface transport: The peptide-MHC complex is presented for CD8 T cell recognition.
What do CD8+ T cells recognise on tumour cells
βοΈCD8+T cells recognise the peptide-MHC I complex through its TCR. It then binds to both the tumour antigen peptide and the MHC-I molecule and the CD8 co-receptor binds to the MHC I separately improving T cell stability / sensitivity
What is the role of the TCR in antigen recognition?
π The TCR (T Cell Receptor) provides specificity by recognising both:
1οΈβ£ The peptide antigen derived from the tumour.
2οΈβ£ The MHC-I molecule presenting the antigen.
π οΈ This ensures that only tumour cells displaying the correct antigen are targeted.
How does the TCR-CD8 interaction contribute to immunotherapy?
π οΈ TCR Engineering: Scientists modify TCRs to improve tumour recognition.
π‘ CAR-T Therapy: Uses genetically engineered receptors for stronger tumour targeting.
βοΈ CD8 Co-receptor Manipulation: Fine-tuning CD8 binding can adjust T cell responses for better cancer treatment.
Why is identifying candidate tumour antigens challenging?
π Many tumour antigens are self-antigens, meaning they are also found on normal tissues.
β οΈ Risk of autoimmunity β Targeting self-antigens can lead to damage in healthy tissues.
𧩠Tumour-specific antigens are rare, making it hard to find an ideal target.
What is an example of tissue damage caused by T cell therapy?
β« Vitiligo has been observed in melanoma patients treated with T-cell therapy. This happens because melanoma cells and normal skin cells share some antigens, leading to T cell attack on both.
Why do tumour specific TCRs often have low affinity?
π High-affinity TCRs for self-antigens are eliminated during thymic selection (to prevent autoimmunity).
π As a result, tumour-reactive TCRs tend to have low affinity, making it harder to activate T cells.
How does low TCR affinity affect T cell acivation
βοΈ T cell activation requires crossing a threshold of TCR engagement.
π‘ Low-affinity TCRs struggle to reach this threshold, making immune responses weaker.
π¬ Stronger TCR-antigen binding = better immune response.
How do engineered TCRs improve tumour recognition
π§ Scientists can modify TCRs to increase affinity for tumour antigens.
π― This enhances T cell activation and tumour targeting.
π‘ TCR engineering is an active area of cancer immunotherapy research.
What are the main strategies to enhance immune response against cancer?
𧬠Cancer vaccination β Uses neoantigens in RNA vaccines to stimulate an immune response.
π Adoptive transfer therapy β Expands and reactivates patient T cells outside the body before reinfusion.
π οΈ Genetic engineering of T cells β Enhances tumour recognition
how are T cells genetically engineered to enhance immune responses against cancer?
using:
π§ͺ TCR engineering (higher affinity receptors)
π₯ High-affinity CD8 (stronger T cell activation)
βοΈ CAR-T cells (chimeric antigen receptors for targeted killing)
π Soluble TCRs β Engineered receptors that can bind tumour antigens and act as treatments.
What is adaptive T cell therapy?
π©Έ T cells are extracted from a patient and grown in the lab.
π They are expanded in number and stimulated with cytokines to boost function.
π The activated T cells are then reinfused into the patient to fight cancer.
Why is adaptive T cell therapy beneficial
π± Overcomes tumour immunosuppression β T cells are reactivated outside the tumour environment.
πͺ Increases the number of cancer-fighting T cells in the body.
π― Can be personalised for better tumour targeting.
adaptive T cell therapy full:
A treatment used to help the immune system fight diseases, such as cancer and infections with certain viruses. T cells are collected from a patient and grown in the laboratory. This increases the number of T cells that are able to kill cancer cells or fight infections. These T cells are given back to the patient to help the immune system fight disease
What is Tumour-Infiltrating Lymphocyte (TIL) Therapy?
π©Έ TIL therapy is a form of adoptive T cell therapy that uses T cells extracted from the tumour itself.
How does Tumour-infiltrating lymphocyte (TIL) therapy work?
1οΈβ£ π₯ Tumour resection β A sample of the tumour is surgically removed.
2οΈβ£ π¬ Isolation of TILs β Tumour-infiltrating lymphocytes (TILs) are extracted.
3οΈβ£ π Expansion β TILs are grown in the lab using cytokines (e.g., IL-2).
π οΈ A Rapid Expansion Protocol (REP) can be used to increase cell numbers.
4οΈβ£ π Infusion into patient β The expanded TILs are returned to the patient to fight the tumour.
What does the figure from Rosenberg & Dudley (2009) demonstrate about T-cell transfer therapy in metastatic melanoma?
ππ¬ The figure shows clinical regression in patients with metastatic melanoma treated with T-cell transfer therapy. Tumors dramatically shrink or even disappear after treatment. This highlights the potential effectiveness of this approach. ππ¬
What strategies have been explored to improve response rates in TIL therapy?w
π§ΉLymphodepletion before therapy to enhance effectiveness
πHigh-dose IL-2 administration to support T-cell survival
π―Enrichment for neoantigen-specific TILs, focusing on cancer-specific T cells
πThese strategies aim to increase the success rate of TIL therapy.
What are the objective response rates for TIL therapy in metastatic melanoma?
Up to 40%
What are the complete response rates for TIL therapy in metastatic melanoma?
around 15% (while promising these numbers suggest there is room for improvement in therapy effectiveness)
Why doesnβt TIL therapy work for all patients?
β
Like checkpoint blockade therapy, TIL therapy shows remarkable responses in some patients but little to no response in others. π€·ββοΈ
π¬ Research is ongoing to understand why some patients respond while others donβt, which could lead to better treatment strategies.
In which cancers, besides melanoma, has TIL therapy shown promise?
TIL therapy has potential in:
β
Cervical cancer
β
Lung cancer
β
Breast cancer
β
Colorectal cancer
π§¬π While still experimental, these findings suggest broader applications beyond melanoma.
Is TIL therapy currently licensed for clinical use?
No, however multiple clinical trials are ongoing to evaluate its safety and effectiveness
What major mulestone did TIL therapy achieve in February 2024?
πThe first-ever FDA approval of a TIL therapy for treating unresectable or metastatic melanoma! This marks a breakthrough in cell-based cancer immunotherapy π₯π¬
How are T-cells isolated and prepared for genetic engineering?
1οΈβ£ Isolating T-cells from blood π©Έ
2οΈβ£ Culturing them in vitro with cytokines (e.g., IL-2, IL-7, IL-15, IL-21) π§ͺ
This primes them for genetic modifications to enhance their anti-cancer activity.
How are T-cells genetically modifed
vectors are used to introduce desired genes :
π― TCRs (T-cell receptors) to enhance antigen recognition
π‘οΈCARs (Chimeric Antigen Receptors) for targeted cancer cell killing
π§¬CD8 molecules engineered for higher affinity to MHC
These modifications improve T-cell activation and tumor recognition.
Which are the two most common viral vectors used for genetic modification of T-cells?
π¦ Ξ³-Retroviruses
π§¬Lentiviruses
πΉ These viruses are engineered to be replication-incompetent by removing genes that encode vital proteins, reducing safety risks.
What happens to the introduced genes in genetically engineered T-cells?
π§¬The genes of interest (TCR, CAR, etc.) become incorporated into the T-cell genome so the T-cell can express the newly introduced receptor, enhancing its ability to detect and attack cancer cells. π¦ π«
What are the main safety concerns of using viral vectors in T cell engineering?
ββ οΈ The primary concern is the generation of replication-competent viruses although advances in vector design (third-generation vectors) have improved safety by splitting essential genes across different plasmids, reducing risk.
What are the advantages of TCR-T therapy
β TCR-T therapy offers several benefits:
Can rapidly generate large number of cancer-specific T-cells in large numbers π₯π¦
Can target tumor antigens like MAGE-A3 & NY-ESO-1 π―
Affinity enhancement through amino acid substitutions in the TCR CDR regions π οΈ
What is a major limitation when choosing targets for TCR-T therapy
πΉtrying to identify a suitable MHC class I-restricted tumour antigen (this is tricky as not all tumours express clear, specific antigens that can be safely targeted and finding a tumour-specific TCR is also difficult and time-consuming)
What risks are associated with increasing TCR affinity?
Higher affinity can lead to loss of specificity or unwanted recognition π¨
Example: A MAGE-A3-specific TCR was modified to enhance affinity but started recognizing the muscle protein Titin, leading to cardiac toxicity and patient deaths πβ οΈ
Careful screening is needed to avoid these off-target effects.
How can CART-T therapy overcome the limitations of TCR-T therapy?
β𧬠CAR-T therapy does NOT rely on MHC restriction, unlike TCR-T and can target cell surface antigens, making them applicable to more patients.
Engineered CD8 molecules in CAR-T cells can improve activation
π This makes CAR-T therapy a viable alternative to TCR-T therapy.
What does CAR stand for
CAR = Chimeric Antigen Receptor π¬
how does CAR-T therapy differ from TCR-T
Unlike TCR-T, CAR-T cells do not rely on MHC-I restriction π«π§¬
CARs recognize specific antigens on tumor cells using an extracellular single-chain antibody πΉπ―
This allows them to work across different patient HLA types
What is the structure of a CAR receptor?
1οΈβ£ Extracellular domain: Single-chain antibody fragment (scFv) π€
2οΈβ£ Transmembrane domain: Anchors receptor in the cell membrane π
3οΈβ£ Intracellular signaling domain: Activates the T cell β‘
This design allows T-cells to target and kill cancer cells without MHC restriction.
How have CAR-T cells evolved over different generations?
1οΈβ£ 1st Gen: CD3ΞΆ only (basic activation) ποΈ
2οΈβ£ 2nd Gen: CD3ΞΆ + one co-stimulatory domain (e.g., CD28 or 4-1BB) β‘π
3οΈβ£ 3rd Gen: CD3ΞΆ + two co-stimulatory domains (stronger activation) πͺπ‘
4οΈβ£ 4th Gen: βArmoredβ CAR-T cells, including cytokine-secreting CAR-Ts π‘οΈπΏ
Why is CAR-T therapy considered a breakthrough in cancer treatment?
π―It provides highly specific tumor targeting
π₯π¨ββοΈIt works in all patients, regardless of HLA type `
π¬ It can be engineered to enhance activation and persistence
(this has led to successful treatments for blood cancers like leukemia and lymphoma)
What are βarmoredβ CAR-T cells, and why are they important?
β 4th Generation CAR-T cells are βarmoredβ CARs π¦Ύπ‘οΈ
πΏπ₯They can express cytokines to boost their activity
π°Some are designed to overcome the immunosuppressive tumor environment
These refinements improve effectiveness and durability of CAR-T therapy.
How is a CAR-T therapy product generated
1οΈβ£ Isolate T cells from the patient π₯π©Έin the clnic, the patientβs T cells are separated from the rest of their blood and sent to the lab
2οΈβ£ Use a viral vector (e.g., lentivirus) to introduce CAR genes into the T cells π¦ 𧬠The T cells now express CAR on their surfaces and are known as CAR T cells
3οΈβ£ Expand the modified T cells in the lab π¬π
4οΈβ£ Infuse the engineered CAR-T cells back into the patient π
5οΈβ£ CAR-T cells identify and destroy cancer cells π―π₯
What was the first FDA-approved CAR-T therapy?
Kymriah (Tisagenlecleucel) π- marked a milestone in personalised cancer therapy
When was Kymriah (Tisagenlecleucel) approved and what is it used to treat
π₯it was first approved in 2017 to treat pediatric and young adult B cell ALL (acute Lymphoblastic Leukemia)`
how many CAR-T therapies are currently FDA-approved?
6
What are CAR-T cells typically used for
Used mainly for B-cell malignancies (like leukemia & lymphoma) and multiple myeloma
Each therapy targets a specific antigen (e.g., CD19, BCMA)
Revolutionized blood cancer treatments
What are some challenges of CAR-T therapy
1οΈβ£ Cytokine Release Syndrome (CRS) β excessive immune activation ππ₯
2οΈβ£ Neurotoxicity β confusion, seizures, brain swelling π§ β‘
3οΈβ£ Limited success in solid tumors β tumor microenvironment blocks CAR-T infiltration π§
4οΈβ£ High cost & complexity β patient-specific manufacturing $$$ π°
cytokine release syndrome (CRS) in CAR-T therapy:
Caused by excessive cytokine release (IL-1, IL-6)
Symptoms: Fever, hypertension, systemic inflammation π€β οΈ
Treated with Tocilizumab (anti-IL-6 receptor antibody) π
on target, off tumour toxicity in CAR-T therapy
CAR-T cells attack normal tissues expressing the same antigen
Example: CD19-targeted CAR-T therapy depletes normal B cells, leading to B-cell aplasia π©Έ
Can cause severe immune system depletion and long-term complications π¨
Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)?
Inflammation-related neurotoxicity caused by CAR-T cells
Symptoms: Confusion, seizures, brain swelling, coma π₯
Can be life-threatening if severe
Why are post CAR-T therapy infections a concern?
π¦ βCAR-T therapy can cause long-term immune suppression which leaves patients vulnerable to bacterial, viral and fungal infections. Infections can be a major cause of mortality, not just cancer relapse π·
What are some key challenges in CAR-T therapy?
1οΈβ£ π° High cost β Personalized manufacturing is expensive
2οΈβ£ π Limited success in solid tumors β Poor tumor infiltration, immunosuppressive environment
3οΈβ£ β³ Need for an βOff-Switchβ β How to deactivate CAR-T cells safely
4οΈβ£ β οΈ Long-term effects β Persistent immune suppression, toxicity risks
What is the function of soluble TCR receptor therapies like ImmTacs
Thiey redirect endogenous T cells to cancer cells by binding to tumor antigens and activating local T cells via an anti-CD3 fragment.
What is ImmTacs and what cancer does it treat?
a soluble therapy which combines a high affinity TCR fused with a stimulatory anti-CD8 antibody fragment
When was ImmTacs FDA approved
in 2022 for metastatic uveal melanoma
What are immune checkpoint inhibitors, and how do they work?
What are immune checkpoint inhibitors, and how do they work?
What are two FDA-approved checkpoint inhibitors?
- Pembrolizumab (Keytruda) β anti-PD-1
- Ipilimumab (Yervoy) β anti-CTLA-4
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