Enhancement of chemotherapy using oncolytic virotherapy: Mathematical and optimal control analysis

Oncolytic virotherapy (OV) has been emerging as a promising novel cancer treatment that may be further combined with the existing therapeutic modalities to enhance their effects. To investigate how OV could enhance chemotherapy, we propose an ODE based model describing the interactions between tumour cells, the immune response, and a treatment combination with chemotherapy and oncolytic viruses. Stability analysis of the model with constant chemotherapy treatment rates shows that without any form of treatment, a tumour would grow to its maximum size. It also demonstrates that chemotherapy alone is capable of clearing tumour cells provided that the drug efficacy is greater than the intrinsic tumour growth rate. Furthermore, OV alone may not be able to clear tumour cells from body tissue but would rather enhance chemotherapy if viruses with high viral potency are used. To assess the combined effect of OV and chemotherapy we use the forward sensitivity index to perform a sensitivity analysis, with respect to chemotherapy key parameters, of the virus basic reproductive number and the tumour endemic equilibrium. The results from this sensitivity analysis indicate the existence of a critical dose of chemotherapy above which no further significant reduction in the tumour population can be observed. Numerical simulations show that a successful combinational therapy of the chemotherapeutic drugs and viruses depends mostly on the virus burst size, infection rate, and the amount of drugs supplied. Optimal control analysis was performed, by means of Pontryagin's principle, to further refine predictions of the model with constant treatment rates by accounting for the treatment costs and sides effects.Comment: This is a preprint of a paper whose final and definite form is with 'Mathematical Biosciences and Engineering', ISSN 1551-0018 (print), ISSN 1547-1063 (online), available at [http://www.aimsciences.org/journal/1551-0018]. Submitted 27-March-2018; revised 04-July-2018; accepted for publication 10-July-201

Discrete Evolutionary Population Models: A New Approach

In this paper, we apply a new approach to a special class of discrete time evolution models and establish a solid mathematical foundation to analyse them. We propose new single and multi-species evolutionary competition models using the evolutionary game theory that require a more advanced mathematical theory to handle effectively. A key feature of this new approach is to consider the discrete models as non-autonomous difference equations. Using the powerful tools and results developed in our recent work [E. D\u27Aniello and S. Elaydi, The structure of ω-limit sets of asymptotically non-autonomous discrete dynamical systems, Discr. Contin. Dyn. Series B. 2019 (to appear).], we embed the non-autonomous difference equations in an autonomous discrete dynamical systems in a higher dimension space, which is the product space of the phase space and the space of the functions defining the non-autonomous system. Our current approach applies to two scenarios. In the first scenario, we assume that the trait equations are decoupled from the equations of the populations. This requires specialized biological and ecological assumptions which we clearly state. In the second scenario, we do not assume decoupling, but rather we assume that the dynamics of the trait is known, such as approaching a positive stable equilibrium point which may apply to a much broader evolutionary dynamics

Intracellular and immune-response delays effects on the interaction between tumor cells, oncolytic viruses and the immune system

Paper presented at the 4th Strathmore International Mathematics Conference (SIMC 2017), 19 - 23 June 2017, Strathmore University, Nairobi, Kenya.Background: Oncolytic viruses are used as a form of cancer treatment since they lyse the tumor cells whilst leaving normal cells largely unharmed. The oncolytic effect depends on both the viral replication ability as well as the type of immune response induced by the said replication. One major challenge to this therapy is the delays that can occur during viral replication combined with a fast immune response. Aim: We therefore aim at investigating the possible trade-offs between the tumor cells, oncolytic viruses and the immune systems with particular focus will be on the simultaneous effects of these two delays. Methods: We extend recently published mathematical models on viro therapy by taking into account the simultaneous effects of the two delays and considering various forms of virus cell infections; namely mass-action, frequency- dependent and Holing-type. We investigate the models’ stability and bifurcation behaviour and then fit them to data. Consequently, carry out numerical simulations to explore various scenarios of model treatment Results: We derived an explicit formula for the trade off between the two delays that leads to tumor eradication. One of the main findings is the occurrence of delay-induced Hopf bifurcation, indicative of tumor relapse.University of Pretoria,University of Stellenbosch, Stellenbosch, South Afric

Dynamic interplay between tumour, stroma and immune system can drive or prevent tumour progression

In the tumour microenvironment, cancer cells directly interact with both the immune system and the stroma. It is firmly established that the immune system, historically believed to be a major part of the body's defence against tumour progression, can be reprogrammed by tumour cells to be ineffective, inactivated, or even acquire tumour promoting phenotypes. Likewise, stromal cells and extracellular matrix can also have pro-and anti-tumour properties. However, there is strong evidence that the stroma and immune system also directly interact, therefore creating a tripartite interaction that exists between cancer cells, immune cells and tumour stroma. This interaction contributes to the maintenance of a chronically inflamed tumour microenvironment with pro-tumorigenic immune phenotypes and facilitated metastatic dissemination. A comprehensive understanding of cancer in the context of dynamical interactions of the immune system and the tumour stroma is therefore required to truly understand the progression toward and past malignancy.Comment: 36 pages, 4 figures, 1 tabl

Mesenchymal stem cells used as carrier cells of oncolytic adenovirus results in enhanced oncolytic virotherapy

Mesenchymal stem cells (MSCs) loaded with oncolytic viruses are presently being investigated as a new modality of advanced/metastatic tumors treatment and enhancement of virotherapy. MSCs can, however, either promote or suppress tumor growth. To address the critical question of how MSCs loaded with oncolytic viruses affect virotherapy outcomes and tumor growth patterns in a tumor microenvironment, we developed and analyzed an integrated mathematical-experimental model. We used the model to describe both the growth dynamics in our experiments of firefly luciferase-expressing Hep3B tumor xenografts and the effects of the immune response during the MSCs-based virotherapy. We further employed it to explore the conceptual clinical feasibility, particularly, in evaluating the relative significance of potential immune promotive/suppressive mechanisms induced by MSCs loaded with oncolytic viruses. We were able to delineate conditions which may significantly contribute to the success or failure of MSC-based virotherapy as well as generate new hypotheses. In fact, one of the most impactful outcomes shown by this investigation, not inferred from the experiments alone, was the initially counter-intuitive fact that using tumor-promoting MSCs as carriers is not only helpful but necessary in achieving tumor control. Considering the fact that it is still currently a controversial debate whether MSCs exert a pro- or anti-tumor action, mathematical models such as this one help to quantitatively predict the consequences of using MSCs for delivering virotherapeutic agents in vivo. Taken together, our results show that MSC-mediated systemic delivery of oncolytic viruses is a promising strategy for achieving synergistic anti-tumor efficacy with improved safety profiles

Mesenchymal stem cells used as carrier cells of oncolytic adenovirus results in enhanced oncolytic virotherapy

Mesenchymal stem cells (MSCs) loaded with oncolytic viruses are presently being investigated as a new modality of advanced/metastatic tumors treatment and enhancement of virotherapy. MSCs can, however, either promote or suppress tumor growth. To address the critical question of how MSCs loaded with oncolytic viruses affect virotherapy outcomes and tumor growth patterns in a tumor microenvironment, we developed and analyzed an integrated mathematical-experimental model. We used the model to describe both the growth dynamics in our experiments of firefly luciferase-expressing Hep3B tumor xenografts and the effects of the immune response during the MSCs-based virotherapy. We further employed it to explore the conceptual clinical feasibility, particularly, in evaluating the relative significance of potential immune promotive/suppressive mechanisms induced by MSCs loaded with oncolytic viruses. We were able to delineate conditions which may significantly contribute to the success or failure of MSC-based virotherapy as well as generate new hypotheses. In fact, one of the most impactful outcomes shown by this investigation, not inferred from the experiments alone, was the initially counter-intuitive fact that using tumor-promoting MSCs as carriers is not only helpful but necessary in achieving tumor control. Considering the fact that it is still currently a controversial debate whether MSCs exert a pro- or anti-tumor action, mathematical models such as this one help to quantitatively predict the consequences of using MSCs for delivering virotherapeutic agents in vivo. Taken together, our results show that MSC-mediated systemic delivery of oncolytic viruses is a promising strategy for achieving synergistic anti-tumor efficacy with improved safety profiles.The National Research Foundation of Korea and Korea Drug Development Fund (KDDF) funded by MSIP, MOTIE, and MOHW, Republic of Korea as well as the DST/NRF SARChI Chair in Mathematical Models and Methods in Biosciences and Bioengineering at the University of Pretoria.http://www.nature.com/srepam2020Mathematics and Applied Mathematic

Mesenchymal stem cells used as carrier cells of oncolytic adenovirus results in enhanced oncolytic virotherapy

CITATION: Mahasa, K. J. et al. 2020. Mesenchymal stem cells used as carrier cells of oncolytic adenovirus results in enhanced oncolytic virotherapy. Nature Scientific Reports, 10:425, doi:10.1038/s41598-019-57240-x.The original publication is available at https://www.nature.comMesenchymal stem cells (MSCs) loaded with oncolytic viruses are presently being investigated as a new modality of advanced/metastatic tumors treatment and enhancement of virotherapy. MSCs can, however, either promote or suppress tumor growth. To address the critical question of how MSCs loaded with oncolytic viruses affect virotherapy outcomes and tumor growth patterns in a tumor microenvironment, we developed and analyzed an integrated mathematical-experimental model. We used the model to describe both the growth dynamics in our experiments of firefly luciferase-expressing Hep3B tumor xenografts and the effects of the immune response during the MSCs-based virotherapy. We further employed it to explore the conceptual clinical feasibility, particularly, in evaluating the relative significance of potential immune promotive/suppressive mechanisms induced by MSCs loaded with oncolytic viruses. We were able to delineate conditions which may significantly contribute to the success or failure of MSC-based virotherapy as well as generate new hypotheses. In fact, one of the most impactful outcomes shown by this investigation, not inferred from the experiments alone, was the initially counter-intuitive fact that using tumor-promoting MSCs as carriers is not only helpful but necessary in achieving tumor control. Considering the fact that it is still currently a controversial debate whether MSCs exert a pro- or anti-tumor action, mathematical models such as this one help to quantitatively predict the consequences of using MSCs for delivering virotherapeutic agents in vivo. Taken together, our results show that MSC-mediated systemic delivery of oncolytic viruses is a promising strategy for achieving synergistic anti-tumor efficacy with improved safety profiles.National Research Foundation of KoreaKorea Drug Development FundDST/NRF SARChI Chair in Mathematical Models and Methods in Biosciences and Bioengineering at the University of Pretoriahttps://www.nature.com/articles/s41598-019-57240-x#citeasPublisher's versio