Delicate Balances in Cancer Chemotherapy: Modeling Immune Recruitment and Emergence of Systemic Drug Resistance

Tran, Anh Phong; Al-Radhawi, M. Ali; Kareva, Irina; Wu, Junjie; Waxman, David J.; Sontag, Eduardo D.

doi:10.3389/fimmu.2020.01376

Cited by 27 publications

(22 citation statements)

References 84 publications

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“…Thus far, however, clinical data reporting the combination of conventional chemotherapy and CAR-T therapy for solid tumours are lacking. Indeed, recent publications have attempted to use mathematical modelling to determine how to maximise the positive immunomodulatory effects of chemotherapy [ 127 , 128 ]. Further clinical studies testing combinations of chemotherapy with the newest and most successful form of T-cell therapy, CAR-T cells, are clearly warranted.…”

Section: Potential Supra-additive Anti-tumour Effects Of Chemotherapymentioning

confidence: 99%

Effects of Chemotherapy Agents on Circulating Leukocyte Populations: Potential Implications for the Success of CAR-T Cell Therapies

Truong

Gargett

Brown

et al. 2021

Cancers

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Adoptive T-cell therapy using autologous T cells genetically modified to express cancer-specific chimeric antigen receptors (CAR) has emerged as a novel approach for cancer treatment. CAR-T cell therapy has been approved in several major jurisdictions for treating refractory or relapsed cases of B-cell precursor acute lymphoblastic leukaemia and diffuse large B-cell lymphoma. However, in solid cancer patients, several clinical studies of CAR-T cell therapy have demonstrated minimal therapeutic effects, thus encouraging interest in better integrating CAR-T cells with other treatments such as conventional cytotoxic chemotherapy. Increasing evidence shows that not only do chemotherapy drugs have tumoricidal effects, but also significantly modulate the immune system. Here, we discuss immunomodulatory effects of chemotherapy drugs on circulating leukocyte populations, including their ability to enhance cytotoxic effects and preserve the frequency of CD8+ T cells and to deplete immunosuppressive populations including regulatory T cells and myeloid-derived suppressor cells. By modulating the abundance and phenotype of leukocytes in the blood (the ‘raw material’ for CAR-T cell manufacturing), we propose that prior chemotherapy could facilitate production of the most effective CAR-T cell products. Further research is required to directly test this concept and identify strategies for the optimal integration of CAR-T cell therapies with cytotoxic chemotherapy for solid cancers.

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Section: Potential Supra-additive Anti-tumour Effects Of Chemotherapymentioning

confidence: 99%

Effects of Chemotherapy Agents on Circulating Leukocyte Populations: Potential Implications for the Success of CAR-T Cell Therapies

Truong

Gargett

Brown

et al. 2021

Cancers

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“…Conventional chemotherapy regiments prescribe long intervals to allow normal cells to recover and limit side effects, however, this may allow cancer cells to regenerate and acquire resistance. [ 28 , 29 ] MC does not rely on powerful killing effect but inhibits tumor by influencing multiple mechanisms such as apoptosis, senescence, non-apoptotic cell death and immunogenic cell death, anti-angiogenesis and immune regulation, and is less likely to develop drug resistance. [ 30 , 31 ] This may be why MC works better than conventional chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Comparative efficacy and safety of metronomic chemotherapy in breast cancer

Xie

Chen

et al. 2021

Medicine

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Background: Metronomic chemotherapy (MC) strategy has been used in breast cancer for more than a decade since it was first proposed. The purpose of this study is to systematically evaluate its efficacy and safety for breast cancer patients at various stages, as well as to clarify the most effective medication strategy when applying MC and discover its most sensitive subpopulation in breast cancer patients. Method: We will systematically retrieve random controlled trials evaluating the efficacy and safety of MC in breast cancer on PubMed, Cochrane Library, Embase, and web of science to perform this network meta-analysis. Markov chain Monte Carlo method based on Bayesian Theory will be used to conduct network meta-analysis and the efficacy and safety will be ranked by combining direct and indirect evidence in mixed treatment comparisons. We will assess the quality of literatures with the Cochrane Risk Bias Assessment Tool and assess the strength of the evidence using the GRADE methodology. Data analysis will be completed with the WinBUGS, R, Stata and RevMan softwares. Results and conclusion: Through the analysis, we can obtain the ranking of efficacy and safety in different MC strategy, and reveal the specific breast cancer groups that are more sensitive to MC. We access the effectiveness by disease free survival, progress free survival, time to progress, objective response rate, and overall survival, and measure the toxicity by dose-limiting toxicity. The result of our study could provide evidence for clinicians to make a better choice when they consider MC. Inplasy registration number: INPLASY202140142.

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“… 53 Large descriptive models are being developed to capture the increasing knowledge about specifics of cancer-immune interactions, 54 but there arguably also exists a need for smaller conceptual models that may lend themselves to analysis and hypothesis testing. Such models may help answer questions that pertain to timing and scheduling of immunotherapy 55 , 56 as well as try to generate testable hypotheses underlying difference in response subject to changing order of therapy administration. 57 - 59 A descriptive multi-scale model may provide too many degrees of freedom to generate testable hypotheses, which may be less of an issue with a smaller conceptual model that can act as an experimental system that requires many fewer resources and less time to investigate compared to an experimental setup.…”

Section: Examples Of What Models Can Addressmentioning

confidence: 99%

“…This requirement can occasionally be partially circumvented by a well-constructed empirical model, such as the one developed by Tran et al, 56 where the authors develop a PKPD model aimed at finding the optimal dose-schedule relationship to maximize cancer cell kill while preserving anti-cancer immunity. In this model, only 2 of 5 variables can be measured experimentally; the relationship between other variables is essentially an educated guess.…”

Section: Coping With Uncertaintymentioning

confidence: 99%

How Should Cancer Models Be Constructed?

2020

Self Cite

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Choosing and optimizing treatment strategies for cancer requires capturing its complex dynamics sufficiently well for understanding but without being overwhelmed. Mathematical models are essential to achieve this understanding, and we discuss the challenge of choosing the right level of complexity to address the full range of tumor complexity from growth, the generation of tumor heterogeneity, and interactions within tumors and with treatments and the tumor microenvironment. We discuss the differences between conceptual and descriptive models, and compare the use of predator-prey models, evolutionary game theory, and dynamic precision medicine approaches in the face of uncertainty about mechanisms and parameter values. Although there is of course no one-size-fits-all approach, we conclude that broad and flexible thinking about cancer, based on combined modeling approaches, will play a key role in finding creative and improved treatments.

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Delicate Balances in Cancer Chemotherapy: Modeling Immune Recruitment and Emergence of Systemic Drug Resistance

Cited by 27 publications

References 84 publications

Effects of Chemotherapy Agents on Circulating Leukocyte Populations: Potential Implications for the Success of CAR-T Cell Therapies

Effects of Chemotherapy Agents on Circulating Leukocyte Populations: Potential Implications for the Success of CAR-T Cell Therapies

Comparative efficacy and safety of metronomic chemotherapy in breast cancer

How Should Cancer Models Be Constructed?

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