"Essential modelling & bioinformatics to advance preclinical decision making"

Workshop

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18. Essential modelling & bioinformatics to advance preclinical decision making. Tumour models (Hanson Wade), DoubleTree by Hilton - Tower of London, London (12/2019) PDF (Parts 1 & 3), PDF (Part 2)

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Objectives

• Recognise the importance of translation

• Xenograft model: Characterisation, translation, evaluation

• Syngeneic model: Characterisation, translation

• Patient population: Characterisation, translation

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Lecture 1. Clinical translation of xenograft models (Tao)

The importance of translation

• Regulatory approval requirements

• Success rate in oncology drug discovery & development projects

• 3 pillars & 5Rs

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Clinical translation of xenograft models

• NCI: Mouse MTD efficacy does not predict clinical efficacy

• Chemo: Mouse MTD AUC and clinical AUC => clinical fate

• Chemo: Qualify A2780 (ovarian) xenograft model with PK/PD modelling

• Chemo & Targeted therapy: Preclinical efficacy => Clinical efficacy (ORR)

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Lecture 2. Using bioinformatics to aid clinical translation to models (John Prime)

Range of omics data types

• Data complexity in clinical/patient samples 

• Value of integrating the right models to the right granularity of patient data

 

Example I:

• Small molecules/targeted therapy – Selecting the right PDX models to match a patient subset

• Challenges, caveats and pitfall

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Tools and omics data sources (i) 

 

Biologics – Cancer Immunotherapy

• The challenges of modelling the immune system in cancer

• Response: Tissue of origin not accurate predictor 

• Cancer immunotherapy – Requires a holistic data paradigm

 

Example II:

• Biologics - Immunotherapy

• Further challenges, caveats and pitfalls

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Tools and omics data sources (ii) – Cancer Immunotherapy

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Group exercise 1 (John Prime)

Characterise a patient population for a new CI target and match it to in vitro/in vivo models

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Lecture 3. Clinical translation of syngeneic models (Tao)

Clinical translation of syngeneic models

• Adaptive immunity to tumours

• Resistance mechanisms to immunotherapy

Case study: Modelling efficacy of RT/αPD-L1 combination treatment in CT26 syngeneic tumour model

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Group exercise 2 (Tao)

What are the questions to consider when prospectively translating syngeneic model results into the clinics? 

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Licence

The slides (containing the aPD-L1 - RT PK/PD model in P59~64) are made available as part of The Open Project (https://github.com/theopenproject):

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GNU General Public Licence v3.0

• https://github.com/TheOpenProject/TOM/blob/master/LICENSE

• Permissions of this strong copyleft licence are conditioned on making available complete source code of licensed works

and modifications, which include larger works using a licensed work, under the same licence. Copyright and licence

notices must be preserved. Contributors provide an express grant of patent rights.