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The Goldilocks Window of Personalized Chemotherapy: Getting the Immune Response Just Right.

ABSTRACT: The immune system is a robust and often untapped accomplice of many standard cancer therapies. A majority of tumors exist in a state of immune tolerance where the patient's immune system has become insensitive to the cancer cells. Because of its lymphodepleting effects, chemotherapy has the potential to break this tolerance. To investigate this, we created a mathematical modeling framework of tumor-immune dynamics. Our results suggest that optimal chemotherapy scheduling must balance two opposing objectives: maximizing tumor reduction while preserving patient immune function. Successful treatment requires therapy to operate in a "Goldilocks Window" where patient immune health is not overly compromised. By keeping therapy "just right," we show that the synergistic effects of immune activation and chemotherapy can maximize tumor reduction and control. SIGNIFICANCE: To maximize the synergy between chemotherapy and antitumor immune response, lymphodepleting therapy must be balanced in a "Goldilocks Window" of optimal dosing.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/20/5302/F1.large.jpg.

SUBMITTER: Park DS

PROVIDER: S-EPMC6801094 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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The Goldilocks Window of Personalized Chemotherapy: Getting the Immune Response Just Right.

Park Derek S DS Robertson-Tessi Mark M Luddy Kimberly A KA Maini Philip K PK Bonsall Michael B MB Gatenby Robert A RA Anderson Alexander R A ARA

Cancer research 20190806 20

The immune system is a robust and often untapped accomplice of many standard cancer therapies. A majority of tumors exist in a state of immune tolerance where the patient's immune system has become insensitive to the cancer cells. Because of its lymphodepleting effects, chemotherapy has the potential to break this tolerance. To investigate this, we created a mathematical modeling framework of tumor-immune dynamics. Our results suggest that optimal chemotherapy scheduling must balance two opposin ...[more]

PMID: 31387920

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Project description:BackgroundAt the start of the COVID-19 pandemic, guidance was needed more than ever to direct frontline healthcare and national containment strategies. Rigorous guidance based on robust research was compromised by the emergence of the pandemic and the urgency of need for guidance. Rather than aiming to "get guidance right", guidance developers needed to "get guidance right now".AimTo examine how guidance developers have responded to the need for credible guidance at the start of the COVID-19 pandemic.MethodsAn exploratory mixed-methods study was conducted among guidance developers. A web-based survey and follow-up interviews were used to examine the most pertinent challenges in developing COVID-19 guidance, strategies used to address these, and perspectives on the implications of the COVID-19 pandemic on future guidance development.ResultsThe survey was completed by 46 guidance developers. Survey findings showed that conventional methods of guidance development were largely unsuited for COVID-19 guidance, with 80% (n = 37) of respondents resorting to other methods. From the survey and five follow-up interviews, two themes were identified to bolster the credibility of guidance in a setting of extreme uncertainty: (1) strengthening end-user involvement and (2) conjoining evidence review and recommendation formulation. 70% (n = 32) of survey respondents foresaw possible changes in future guidance production, most notably shortening development time, by reconsidering how to balance between rigour and speed for different types of questions.Conclusion"Getting guidance right" and "getting guidance right now" are not opposites, rather uncertainties are always part of guidance development and require guidance developers to balance scientific robustness with usability, acceptability, adequacy and contingency. This crisis points to the need to acknowledge uncertainties of scientific evidence more explicitly and points to mechanisms to live with such uncertainty, thus extending guidance development methods and processes more widely.

Dataset Information

The Goldilocks Window of Personalized Chemotherapy: Getting the Immune Response Just Right.

Publications

The Goldilocks Window of Personalized Chemotherapy: Getting the Immune Response Just Right.

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