Andrew M. Stein

ACoP - November 10, 2021

Executive Summary

• Situation
• How do we apply model informed drug development for CART therapy
• Unlike traditional PopPK, there is no consensus on model structures for CART.
• Question
• Is there a concise set of models we should explore for CART, as for PopPK?
• Answer
• Thorough investigation of Cellular-Kinetic – Pharmacodynamic structural models
• Survey of key scientific findings from literature that show cases where a more complex model can be utilized to answer the questions of interest.

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CAR-T therapy overview

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In vivo

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Ex vivo

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Anti-target

CAR construct

Cytokine release

CAR-T cell expansion

• Structure of Chimeric Antigen Receptor (CAR)

• A living drug designed to target tumor cells (Kymriah^® as an example)

CART Cellular kinetic model

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Expand until tmax

Application: Describes CART kinetics

• Demonstrated lack of impact of co-medications (tocilizumab and corticosteroids) on growth rate

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~α

β

Stein AM, Grupp SA, Levine JE, et al. Tisagenlecleucel model based cellular kinetic analysis of chimeric antigen receptor–T Cells. CPT Pharmacometrics Syst Pharmacol. 2019;8(5):285-295.

Comed

CART Cellular Kinetic – Pharmacodynamic model

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Application

• Assess impact of tumor burden on CART kinetics.
• Characterize relationship between dose, cellular kinetics and tumor killing.

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Question/Challenge

• Choosing correct functional forms for growth and killing

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Example: Lotka-Volterra Predator-Prey Model^1-2 is frequently used, but has cycles

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1. https://en.wikipedia.org/wiki/Lotka%E2%80%93Volterra_equations
2. Wodarz, Dominik. J PKPD 41.5 (2014): 415-429.

Cyclic behavior is not observed

in the clinic.

List of criteria a CellK-PD model should have

1. Exponential expansion
2. Fast initial decline
3. Slow long term slow decline
4. No cyclic behavior
5. Antigen drives expansion
6. CART expansion is not infinite, despite large antigen burden

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EC50 expansion + EC50 killing model had all desired properties

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Newly proposed CART CellK-PD model structure that meets all criteria

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k_EP

k_PE

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EC50 formula is derived from a traditional binding model.

Mayer, Andreas, et al. "Regulation of T cell expansion by antigen presentation dynamics." Proceedings of the National Academy of Sciences 116.13 (2019): 5914-5919.

Confounding factors that make E-R analyses challenging^1-3

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• Antigen Expression
• Immune cell phenotypes
• T cell exhaustion
• Genotype

Challenge

• Factors that can affect both exposure and response mean that E-R relationship may not be causal

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Path Forward

• Measure as many confounders as possible
• Build more mechanistic models

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1. https://en.wikipedia.org/wiki/Simpson%27s_paradox
2. https://sites.google.com/site/andrewsteinphd/causality
3. Yang, Jun, et al. "The combination of exposure‐response and case‐control analyses in regulatory decision making." �The Journal of Clinical Pharmacology 53.2 (2013): 160-166.

Introduction of binding kinetics to account for antigen burden

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Application

• Assess optimal binding affinity
• Assess impact on cellular antigen density on CART kinetics

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Challenge: potential umbrella shaped affinity-response curve [1]

1. Exhaustion (excessive signaling),
2. Restrict T cell killing to only one tumor cell due to lasting synapse
3. Restrict the T cell’s ability to generate persistent memory cells.
4. T cell loss via activation-induced cell death

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1. Watanabe K, Kuramitsu S, Posey AD, June CH. Expanding the therapeutic window for CAR-T cell therapy in solid tumors: The knowns and unknowns of CAR-T cell biology. Front Immunol. 2018;9(OCT):1-12.

Immunophenotype modeling framework

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Application

• Understanding how immunophenotype properties of the product impact tumor kinetics

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Challenge

• Choosing which cell surface markers to use.
• Identifying the right structural model to characterize both expanding cells and persistent cells. Published preclinical models currently focus on the expansion phase [1]
• Collecting sufficient clinical data to inform model (more subsets mean more BLOQ data)

1. Buchholz VR, Flossdorf M, Hensel I, et al. Disparate individual fates compose robust CD8+ T cell immunity. Science. 2013;340(6132):630-635.

Importance of genotype heterogeneity

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1. Fraietta JA, Nobles CL, Sammons MA, et al. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature. 2018;558(7709):307-312.
2. Shah NN, Qin H, Yates B, et al. Clonal expansion of CAR-T cells harboring lentivector integration in the CBL gene following anti-CD22 CAR-T cells therapy. Blood Adv. 2019;3(15):2317-2322.

Challenge

• Insertion of CAR gene can disrupt another gene �(e.g. TET2 or CBL-B) [1, 2], which can lead to a single clone that contributes to response.

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Path Forward

• Collection of clonal heterogeneity data is crucial to understanding response.

Summary

• We propose a framework for cellular kinetic pharmacodynamic (CellK-PD) model structure to try out for future preclinical and clinical studies.
• Many model extensions were proposed, but each have challenges associated with them.

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Acknowledgements

• Coauthors:
• Anwesha Chaudhury
• Sue Zhu
• Lulu Chu
• Ardeshir Goliaei
• Carl June
• Jeff Kearns
• Kymriah, YTB323, and PHE885 clinical teams
• Boris Engels
• Attilio Bondanza
• Karen Thudium Mueller

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