Chemoimmunotherapy Administration Protocol Design for the Treatment of Leukemia through Mathematical Modeling and In Silico Experimentation
Cancer with all its more than 200 variants continues to be a major health problem around the world with nearly 10 million deaths recorded in 2020, and leukemia accounted for more than 300,000 cases according to the Global Cancer Observatory. Although new treatment strategies are currently being deve...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-07-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/7/1396 |
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| author | Paul A. Valle Raul Garrido Yolocuauhtli Salazar Luis N. Coria Corina Plata |
| author_facet | Paul A. Valle Raul Garrido Yolocuauhtli Salazar Luis N. Coria Corina Plata |
| author_sort | Paul A. Valle |
| collection | DOAJ |
| description | Cancer with all its more than 200 variants continues to be a major health problem around the world with nearly 10 million deaths recorded in 2020, and leukemia accounted for more than 300,000 cases according to the Global Cancer Observatory. Although new treatment strategies are currently being developed in several ongoing clinical trials, the high complexity of cancer evolution and its survival mechanisms remain as an open problem that needs to be addressed to further enhanced the application of therapies. In this work, we aim to explore cancer growth, particularly chronic lymphocytic leukemia, under the combined application of CAR-T cells and chlorambucil as a nonlinear dynamical system in the form of first-order Ordinary Differential Equations. Therefore, by means of nonlinear theories, sufficient conditions are established for the eradication of leukemia cells, as well as necessary conditions for the long-term persistence of both CAR-T and cancer cells. Persistence conditions are important in treatment protocol design as these provide a threshold below which the dose will not be enough to produce a cytotoxic effect in the tumour population. In silico experimentations allowed us to design therapy administration protocols to ensure the complete eradication of leukemia cells in the system under study when considering only the infusion of CAR-T cells and for the combined application of chemoimmunotherapy. All results are illustrated through numerical simulations. Further, equations to estimate cytotoxicity of chlorambucil and CAR-T cells to leukemia cancer cells were formulated and thoroughly discussed with a <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mn>95</mn><mo>%</mo></mrow></semantics></math></inline-formula> confidence interval for the parameters involved in each formula. |
| first_indexed | 2024-03-09T13:11:19Z |
| format | Article |
| id | doaj.art-2047f2be5b7e47f08f5e3621567e04c1 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T13:11:19Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-2047f2be5b7e47f08f5e3621567e04c12023-11-30T21:41:39ZengMDPI AGPharmaceutics1999-49232022-07-01147139610.3390/pharmaceutics14071396Chemoimmunotherapy Administration Protocol Design for the Treatment of Leukemia through Mathematical Modeling and In Silico ExperimentationPaul A. Valle0Raul Garrido1Yolocuauhtli Salazar2Luis N. Coria3Corina Plata4Postgraduate Program in Engineering Sciences, BioMath Research Group, Tecnológico Nacional de México/IT Tijuana, Blvd. Alberto Limón Padilla s/n, Tijuana 22454, MexicoPostgraduate Program in Engineering Sciences, BioMath Research Group, Tecnológico Nacional de México/IT Tijuana, Blvd. Alberto Limón Padilla s/n, Tijuana 22454, MexicoPostgraduate Program in Engineering, Tecnológico Nacional de México/IT Durango, Blvd. Felipe Pescador 1830 ote., Durango 34080, MexicoPostgraduate Program in Engineering Sciences, BioMath Research Group, Tecnológico Nacional de México/IT Tijuana, Blvd. Alberto Limón Padilla s/n, Tijuana 22454, MexicoPostgraduate Program in Engineering Sciences, BioMath Research Group, Tecnológico Nacional de México/IT Tijuana, Blvd. Alberto Limón Padilla s/n, Tijuana 22454, MexicoCancer with all its more than 200 variants continues to be a major health problem around the world with nearly 10 million deaths recorded in 2020, and leukemia accounted for more than 300,000 cases according to the Global Cancer Observatory. Although new treatment strategies are currently being developed in several ongoing clinical trials, the high complexity of cancer evolution and its survival mechanisms remain as an open problem that needs to be addressed to further enhanced the application of therapies. In this work, we aim to explore cancer growth, particularly chronic lymphocytic leukemia, under the combined application of CAR-T cells and chlorambucil as a nonlinear dynamical system in the form of first-order Ordinary Differential Equations. Therefore, by means of nonlinear theories, sufficient conditions are established for the eradication of leukemia cells, as well as necessary conditions for the long-term persistence of both CAR-T and cancer cells. Persistence conditions are important in treatment protocol design as these provide a threshold below which the dose will not be enough to produce a cytotoxic effect in the tumour population. In silico experimentations allowed us to design therapy administration protocols to ensure the complete eradication of leukemia cells in the system under study when considering only the infusion of CAR-T cells and for the combined application of chemoimmunotherapy. All results are illustrated through numerical simulations. Further, equations to estimate cytotoxicity of chlorambucil and CAR-T cells to leukemia cancer cells were formulated and thoroughly discussed with a <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mn>95</mn><mo>%</mo></mrow></semantics></math></inline-formula> confidence interval for the parameters involved in each formula.https://www.mdpi.com/1999-4923/14/7/1396cancerCAR-T cellschlorambucilcytotoxicityin silicoleukemia |
| spellingShingle | Paul A. Valle Raul Garrido Yolocuauhtli Salazar Luis N. Coria Corina Plata Chemoimmunotherapy Administration Protocol Design for the Treatment of Leukemia through Mathematical Modeling and In Silico Experimentation Pharmaceutics cancer CAR-T cells chlorambucil cytotoxicity in silico leukemia |
| title | Chemoimmunotherapy Administration Protocol Design for the Treatment of Leukemia through Mathematical Modeling and In Silico Experimentation |
| title_full | Chemoimmunotherapy Administration Protocol Design for the Treatment of Leukemia through Mathematical Modeling and In Silico Experimentation |
| title_fullStr | Chemoimmunotherapy Administration Protocol Design for the Treatment of Leukemia through Mathematical Modeling and In Silico Experimentation |
| title_full_unstemmed | Chemoimmunotherapy Administration Protocol Design for the Treatment of Leukemia through Mathematical Modeling and In Silico Experimentation |
| title_short | Chemoimmunotherapy Administration Protocol Design for the Treatment of Leukemia through Mathematical Modeling and In Silico Experimentation |
| title_sort | chemoimmunotherapy administration protocol design for the treatment of leukemia through mathematical modeling and in silico experimentation |
| topic | cancer CAR-T cells chlorambucil cytotoxicity in silico leukemia |
| url | https://www.mdpi.com/1999-4923/14/7/1396 |
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