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Rationalizing the pathway to personalized neoadjuvant immunotherapy: the Lombard Street Approach

Neoadjuvant chemo(radio)therapy is part of the established standard of care in cancer treatment; neoadjuvant application of immunotherapy, however, is only performed within recent trials. Combination of programmed cell death protein 1 and cytotoxic T lymphocyte antigen 4 blockade shows promising res...

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Autores principales: Versluis, Judith M, Thommen, Daniela S, Blank, Christian U
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449311/
https://www.ncbi.nlm.nih.gov/pubmed/32843494
http://dx.doi.org/10.1136/jitc-2020-001352
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author Versluis, Judith M
Thommen, Daniela S
Blank, Christian U
author_facet Versluis, Judith M
Thommen, Daniela S
Blank, Christian U
author_sort Versluis, Judith M
collection PubMed
description Neoadjuvant chemo(radio)therapy is part of the established standard of care in cancer treatment; neoadjuvant application of immunotherapy, however, is only performed within recent trials. Combination of programmed cell death protein 1 and cytotoxic T lymphocyte antigen 4 blockade shows promising results with high pathologic response rates in the neoadjuvant setting and a very low relapse rate in the responding patients. In addition, neoadjuvant administration allows direct determination of treatment efficacy within the individual patient, and offers easy access to paired tumor material, both pretherapy and post-therapy, thus facilitates the rational development of new combinations driven by preclinical analyses. Patient-derived human tumor explant systems such as a recently developed human patient-derived tumor fragment platform can provide an additional tool to further rationalize the development of new treatment combinations. We will discuss neoadjuvant immunotherapy as a unique opportunity for rational trial design, the development of immune signatures for non-responding patients to steer clinical trial development, and the use of patient-derived ex vivo models to identify new personalized immunotherapy combinations. In this context, we propose the ‘Lombard Street Approach’, a back and forth approach of characterizing non-responders on neoadjuvant immunotherapy combinations, identifying promising new combinations for this group in the tumor fragment platform, and performing subsequently signature-driven small proof-of-concept combination trials. Repeating this approach with smaller and smaller groups of non-responders will step by step increase the percentage of patients benefiting from neoadjuvant immunotherapy in a rational and fast manner.
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spelling pubmed-74493112020-09-02 Rationalizing the pathway to personalized neoadjuvant immunotherapy: the Lombard Street Approach Versluis, Judith M Thommen, Daniela S Blank, Christian U J Immunother Cancer Review Neoadjuvant chemo(radio)therapy is part of the established standard of care in cancer treatment; neoadjuvant application of immunotherapy, however, is only performed within recent trials. Combination of programmed cell death protein 1 and cytotoxic T lymphocyte antigen 4 blockade shows promising results with high pathologic response rates in the neoadjuvant setting and a very low relapse rate in the responding patients. In addition, neoadjuvant administration allows direct determination of treatment efficacy within the individual patient, and offers easy access to paired tumor material, both pretherapy and post-therapy, thus facilitates the rational development of new combinations driven by preclinical analyses. Patient-derived human tumor explant systems such as a recently developed human patient-derived tumor fragment platform can provide an additional tool to further rationalize the development of new treatment combinations. We will discuss neoadjuvant immunotherapy as a unique opportunity for rational trial design, the development of immune signatures for non-responding patients to steer clinical trial development, and the use of patient-derived ex vivo models to identify new personalized immunotherapy combinations. In this context, we propose the ‘Lombard Street Approach’, a back and forth approach of characterizing non-responders on neoadjuvant immunotherapy combinations, identifying promising new combinations for this group in the tumor fragment platform, and performing subsequently signature-driven small proof-of-concept combination trials. Repeating this approach with smaller and smaller groups of non-responders will step by step increase the percentage of patients benefiting from neoadjuvant immunotherapy in a rational and fast manner. BMJ Publishing Group 2020-08-24 /pmc/articles/PMC7449311/ /pubmed/32843494 http://dx.doi.org/10.1136/jitc-2020-001352 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 Review
Versluis, Judith M
Thommen, Daniela S
Blank, Christian U
Rationalizing the pathway to personalized neoadjuvant immunotherapy: the Lombard Street Approach
title Rationalizing the pathway to personalized neoadjuvant immunotherapy: the Lombard Street Approach
title_full Rationalizing the pathway to personalized neoadjuvant immunotherapy: the Lombard Street Approach
title_fullStr Rationalizing the pathway to personalized neoadjuvant immunotherapy: the Lombard Street Approach
title_full_unstemmed Rationalizing the pathway to personalized neoadjuvant immunotherapy: the Lombard Street Approach
title_short Rationalizing the pathway to personalized neoadjuvant immunotherapy: the Lombard Street Approach
title_sort rationalizing the pathway to personalized neoadjuvant immunotherapy: the lombard street approach
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449311/
https://www.ncbi.nlm.nih.gov/pubmed/32843494
http://dx.doi.org/10.1136/jitc-2020-001352
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