AR - Pre-clinical models II

Question 1

Q1: Why are humanised mice valuable in modelling human disease? (4)

Answer 1

• Enable development of a functional human immune system in vivo.
• Support long-term experiments due to being lymphoma-resistant and long-lived.
• Allow study of human hematopoietic and immune responses.
• Critical for HIV, cancer immunotherapy, and infectious disease research.

Question 2

Q2: What are essential characteristics of immunodeficient mice used for humanisation? (6)

Answer 2

• Lack functional B and T cells.
• No NK cell activity.
• No immune leakiness with age.
• Lymphoma-resistant, allowing long-term studies.
• Superior engraftment of human hematopoietic stem cells (HSCs).
• Enable robust development of human lymphoid and myeloid cells.

Question 3

Q3: How are robust humanised mouse models engineered? (3)

Answer 3

• Use of immunodeficient strains (e.g., NSG, NOG mice).
• Transplantation of human HSCs into irradiated recipients.
• Leads to differentiation into functional human leukocytes (T cells, B cells, myeloid cells).

Question 4

Q4: How can humanised mice be used to predict CRS in immunotherapy? (3)

Answer 4

• CRS modeling using humanised mice replicates human immune responses.
• Example: Predicted TGN1412 toxicity that was missed in monkey models.
• CRS involves massive cytokine release from activated human T cells in vivo.

Question 5

Q5: What evidence shows tumour–immune interactions in humanised mice? (4)

Answer 5

• Human CD45+ leukocytes infiltrate tumour tissues.
• Detected populations: CD3+ T cells, CD14+ myeloid cells, CD19+ B cells.
• Human immune cells actively engraft into tumour microenvironment.
• Allows study of immune-tumour dynamics under humanised conditions.

Question 6

Q6: How are breast cancer models established in humanised mice? (2)

Answer 6

• Subcutaneous inoculation of human tumour cells into humanised mice.
• Disseminated models via ultrasound-guided intra-cardiac injection mimic metastasis and tumour spread.

Question 7

Q7: What therapeutic strategies can be tested using humanised mice? (3)

Answer 7

• Chemotherapy and immunotherapy combinations in solid cancers.
• Example: Enhanced tumour control with dual-agent regimens.
• Reflects real-world clinical approaches to treatment-resistant cancers.

Question 8

Q8: What types of haematological cancer models are supported in humanised mice? (4)

Answer 8

• Human B cell lymphoma models – reflect clinical immunotherapy responses.
• Acute Myeloid Leukaemia (AML) models via CD34+ HSC engraftment + NPM1c mutation.
• NPM1c mutation mimics M4/M5 subtype AML, found in \~30% of adult AML patients.
• AML-bearing mice show normal leukocyte development and are used for T cell–based therapies.

Question 9

Q9: How are bispecific antibodies used to target AML in humanised models? (3)

Answer 9

• Use CD3 × CD123 bispecific antibodies to direct T cell killing of AML cells.
• Requires human T cells and functional immune engagement.
• Allows precise evaluation of T cell-mediated cytotoxicity in vivo.

Question 10

Q10: What are “mouse avatars” and how do they support personalised medicine? (3)

Answer 10

• Mice implanted with tumours or cells from individual patients.
• Allow direct testing of customised therapies for that patient.
• Enable real-time preclinical modelling of personalised treatment responses.

Question 11

Q11: How are humanised mice used to evaluate CAR T cell therapy? (3)

Answer 11

• Enable functional testing of engineered CAR T cells against human leukaemia.
• Allow study of toxicity, persistence, and tumour clearance.
• Offer a bridge between in vitro data and clinical trial readiness.

Question 12

Q12: What infectious diseases are studied using humanised mice? (3)

Answer 12

• HIV – modelled with humanised mice to test broadly neutralising mAbs (e.g., Klein et al.).
• COVID-19 – via mice expressing human ACE2 receptors (e.g., Sefi et al., 2021).
• Support real-world development of vaccines, antivirals, and immunotherapies.

Question 13

Q13: What are the key takeaways about humanised mouse models from this lecture? (4)

Answer 13

• Overcome limitations of traditional mouse models for human disease.
• Allow development of human immune responses for testing cancer and infectious therapies.
• Support preclinical translational research, bridging the gap to clinical trials.
• Enable testing of immunotherapies, bispecifics, CAR-T, and personalised regimens.