BN - Precision medicine and personalised cancer immunotherapies

Question 1

Q1: What is precision medicine and how does it differ from personalised medicine? (4)

Answer 1

• Precision medicine: Tailors treatment based on genetic, environmental, and lifestyle differences across patient subgroups.
• Focuses on population-level characteristics and molecular phenotypes (e.g. genome, proteome, metabolome).
• Personalised medicine: Tailored to an individual patient’s unique profile.
• While often used interchangeably, personalised is more individualised than precision medicine.

Question 2

Q2: What technological advancements are enabling precision medicine? (3)

Answer 2

• Omics technologies: Genomics, transcriptomics, proteomics, metabolomics, lipidomics.
• Especially pharmacogenomics: Studies how genetic makeup influences drug response.
• Use of next-generation sequencing enables rapid identification of disease-causing mutations.

Question 3

Q3: What are some clinical applications of precision medicine? (5)

Answer 3

• Gene therapy for spinal muscular atrophy, cystic fibrosis, and sickle cell disease.
• Targeted drugs for HER2+ breast cancer (e.g., trastuzumab).
• BCR-ABL inhibitors (e.g., imatinib) for CML.
• Anti-CD20/CD19/CD79b mAbs in lymphomas.
• Over 200 FDA-approved drugs now include pharmacogenomic label info.

Question 4

Q4: How does precision medicine improve cancer care? (3)

Answer 4

• Helps stratify patients based on molecular phenotype to optimise therapy.
• Targets known molecular pathways or tumour locations.
• Improves treatment precision via proteogenomic stratification (integrates genomic + proteomic data).

Question 5

Q5: How does the immune system naturally respond to tumours? (6)

Answer 5

• Innate immunity: Rapid, non-specific response; presents antigens to adaptive system.
• Adaptive immunity: Slow, specific, memory-forming response.
• Immune system normally recognises and removes abnormal cells (immune surveillance).
• Tumours evade detection via weak immune responses, loss of MHC, or being immunocompromised.
• Tumour-associated antigens (TAAs) are often weak and hard to target.
• T cell responses are often weak or exhausted, allowing tumour survival.

Question 6

Q6: What makes tumour cells recognizable or invisible to the immune system? (5)

Answer 6

• Some tumours contain microbes or arise from viruses (foreign signal).
• Many lose MHC (HLA) display, making them “invisible” to T cells.
• Tumours express TAAs (e.g., NY-ESO-1, MAGE) – abnormal in time, location, or amount.
• Tumour-specific antigens (TSAs) arise from mutations and are truly foreign.
• These differences determine how “self” or “non-self” a tumour appears immunologically.

Question 7

Q7: How do lymph nodes contribute to anti-tumour immunity? (5)

Answer 7

• Serve as immune hubs that filter lymph fluid for antigens.
• B cells in the cortex respond to matching antigens via BCRs.
• B cells interact with helper T cells → undergo class switching and differentiation.
• T cells and dendritic cells are drawn to nodes via CCR7 signaling.
• Lymph nodes facilitate T and B cell activation and coordinate immune attack.

Question 8

Q8: How are tumour antigens presented to T cells via MHC pathways? (3)

Answer 8

1. Endogenous (MHC I):
   • Intracellular proteins degraded by proteasome, peptides loaded onto MHC I via TAP, presented to CD8+ T cells.
2. Exogenous (MHC II):
   • Engulfed proteins are processed in lysosomes, loaded onto MHC II via HLA-DM, presented to CD4+ helper T cells.
3. Cross-Presentation:
   • APCs can present exogenous proteins on MHC I, crucial for initiating cytotoxic T cell responses to tumours.

Question 9

Q9: What are the major immunotherapy strategies for cancer? (5)

Answer 9

• Immune checkpoint inhibitors – e.g., anti-PD-1/PD-L1 to boost T cell activity.
• Adoptive T cell therapy – e.g., CAR-T cell therapy.
• Monoclonal antibodies – e.g., anti-TAA antibodies.
• Therapeutic vaccines – deliver TAAs to stimulate immunity.
• Immunomodulators – e.g., cytokines, BCG, angiogenesis inhibitors.

Question 10

Q10: What is T cell exhaustion and how is it reversed by checkpoint inhibitors? (4)

Answer 10

• Acute stimulation triggers response, followed by downregulation via PD-1/PD-L1 to avoid autoimmunity.
• Chronic stimulation in tumours leads to T cell exhaustion (upregulation of PD-1, Tim-3, LAG-3).
• Exhausted T cells are ineffective against tumours.
• Checkpoint inhibitors block PD-1/PD-L1, reinvigorating T cells to attack cancer.

Question 11

Q11: What is the relationship between mutational burden and checkpoint inhibitor efficacy? (4)

Answer 11

• High TMB increases the likelihood of neoantigen formation.
• More mutations = more T cell-recognisable targets.
• Cancer types with high TMB (e.g., melanoma, lung cancer) respond better to PD-1 blockade.
• TMB is now used as a biomarker for immunotherapy suitability.

Question 12

Q12: What types of gene mutations contribute to tumour formation? (4)

Answer 12

• Driver mutations: Promote tumour growth.
• Passenger mutations: Accidental, neutral.
• Proto-oncogenes: Normal growth genes; when mutated → oncogenes (overactive).
• Tumour suppressor genes & DNA repair genes: When inactivated → loss of growth control and mutation accumulation.

Question 13

Q13: What causes mutations leading to cancer and how do they affect proteins? (5)

Answer 13

• Causes: UV, smoke, viruses, alcohol, cell division errors, inheritance.
• Missense mutations → amino acid changes = neoantigens.
• Mutated p53 = common loss-of-function mutation, promotes tumour formation.
• Mutant proteins can disrupt cell growth regulation.
• If recognised as “non-self”, these proteins can be T cell targets.

Question 14

Q14: How do tumour-associated antigens (TAAs) differ from tumour-specific antigens (TSAs)? (4)

Answer 14

TAAs:

• Overexpressed in tumours but also found in healthy tissues.
• Risk of off-target effects in therapy.

TSAs (Neoantigens):

• Result from unique mutations in tumours.
• Not found elsewhere in the body → high specificity, low side effects.

P53 can act as either, depending on context.

Question 15

Q15: How do T cells recognise and respond to tumour mutations? (4)

Answer 15

• T cells detect peptides presented by MHC molecules.
• Tumours can produce abnormal or developmental proteins (CTAs, splice variants).
• Challenge: TCRs do not reveal the identity of target peptides.
• Identifying true neoantigens remains difficult; only 5–20 clonotypes usually active per tumour.

Question 16

Q16: What are the main takeaways from precision cancer immunotherapy? (6)

Answer 16

• Omics enables stratification and targeted treatment.
• Mutations drive tumour formation and define therapy responses.
• Checkpoint blockade works best in high-TMB tumours.
• Neoantigens from non-synonymous mutations are ideal immune targets.
• Effective therapy requires recognition of MHC-bound peptides.
• Precision targeting of mutated proteins is key to advancing safe, potent immunotherapies.