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Improving the therapeutic index in adoptive cell therapy: key factors that impact efficacy

The therapeutic index (TI) is a quantitative assessment of a drug safety proportional to its effectiveness. The estimation is intuitive when the engagement of the product with its target is dependent on stable chemistry and predictable pharmacokinetics as is the case for small molecules or antibodie...

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Autores principales: Wang, Ena, Cesano, Alessandra, Butterfield, Lisa H, Marincola, Francesco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539608/
https://www.ncbi.nlm.nih.gov/pubmed/33023983
http://dx.doi.org/10.1136/jitc-2020-001619
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author Wang, Ena
Cesano, Alessandra
Butterfield, Lisa H
Marincola, Francesco
author_facet Wang, Ena
Cesano, Alessandra
Butterfield, Lisa H
Marincola, Francesco
author_sort Wang, Ena
collection PubMed
description The therapeutic index (TI) is a quantitative assessment of a drug safety proportional to its effectiveness. The estimation is intuitive when the engagement of the product with its target is dependent on stable chemistry and predictable pharmacokinetics as is the case for small molecules or antibodies. But for therapeutics with complex biodistribution and context-dependent potency such as adoptive cell therapy (ACT) products, TI estimations need to consider a broader array of factors. These include product-dependent variability such as functional fitness, unpredictable pharmacokinetics due to non-specific trapping, sequestration and extravasation into normal tissues and variable rates of in vivo expansion. In the case of solid malignancies, additional modifiers dependent on individual tumor immune biology may affect pharmacodynamics, including differential trafficking to benign compared with cancer tissue, hampered engagement with target cells, immune suppression and cellular dysfunction due to unfavorable metabolic conditions. Here, we propose a patient-specific assessment of factors affecting on-tumor from off-tumor activity in disparate immunologic environments that impact ACT’s clinical efficacy and may favorably balance the TI. for ACT products.
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spelling pubmed-75396082020-10-19 Improving the therapeutic index in adoptive cell therapy: key factors that impact efficacy Wang, Ena Cesano, Alessandra Butterfield, Lisa H Marincola, Francesco J Immunother Cancer Commentary The therapeutic index (TI) is a quantitative assessment of a drug safety proportional to its effectiveness. The estimation is intuitive when the engagement of the product with its target is dependent on stable chemistry and predictable pharmacokinetics as is the case for small molecules or antibodies. But for therapeutics with complex biodistribution and context-dependent potency such as adoptive cell therapy (ACT) products, TI estimations need to consider a broader array of factors. These include product-dependent variability such as functional fitness, unpredictable pharmacokinetics due to non-specific trapping, sequestration and extravasation into normal tissues and variable rates of in vivo expansion. In the case of solid malignancies, additional modifiers dependent on individual tumor immune biology may affect pharmacodynamics, including differential trafficking to benign compared with cancer tissue, hampered engagement with target cells, immune suppression and cellular dysfunction due to unfavorable metabolic conditions. Here, we propose a patient-specific assessment of factors affecting on-tumor from off-tumor activity in disparate immunologic environments that impact ACT’s clinical efficacy and may favorably balance the TI. for ACT products. BMJ Publishing Group 2020-10-06 /pmc/articles/PMC7539608/ /pubmed/33023983 http://dx.doi.org/10.1136/jitc-2020-001619 Text en © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/ http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Commentary
Wang, Ena
Cesano, Alessandra
Butterfield, Lisa H
Marincola, Francesco
Improving the therapeutic index in adoptive cell therapy: key factors that impact efficacy
title Improving the therapeutic index in adoptive cell therapy: key factors that impact efficacy
title_full Improving the therapeutic index in adoptive cell therapy: key factors that impact efficacy
title_fullStr Improving the therapeutic index in adoptive cell therapy: key factors that impact efficacy
title_full_unstemmed Improving the therapeutic index in adoptive cell therapy: key factors that impact efficacy
title_short Improving the therapeutic index in adoptive cell therapy: key factors that impact efficacy
title_sort improving the therapeutic index in adoptive cell therapy: key factors that impact efficacy
topic Commentary
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539608/
https://www.ncbi.nlm.nih.gov/pubmed/33023983
http://dx.doi.org/10.1136/jitc-2020-001619
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