Uninfected Tumor Cells Research Articles

An optimal solution for tumor growth model using generalized Bessel polynomials

In this paper, a mathematical model is given that depicts the interactions between cancer cells and viruses in the setting of oncolytic virotherapy. The model is separated into three classes, namely, concentrations of uninfected tumor cells in the population “ ”, free virus “ ”, and cancerous cells infected “ ”. Applying Caputo fractional derivative, the model is fractionalized, and using generalized Bessel polynomials, an optimal problem is solved utilizing Lagrange multipliers method. The results show that the presented method has high accuracy and is suitable for solving the nonlinear systems based on partial differential equations especially tumors models.

Mathematical analysis on a diffusion model describing the compatibility between two types of tumor cells

Cancer caused by malignant tumor is a very common and serious disease which can lead to people towards death. However, sometimes, cancer may be controlled if the cancer cells can be infected and split by particular virus with weak pathogenicity. To give a better understanding on tumor dynamics, in this paper, we deal with a reaction–diffusion tumor model, which comes from the process of tumor therapy with oncolytic virus. Our main objective is to analyze the biological compatibility of uninfected and infected tumor cells. In addition, we are concerned with the long‐time behavior, stability, and a priori estimates for the model. The compatibility conditions show that under certain range of parameters control, the infected tumor cells can coexist with normal tumor cells or be eliminated by oncolytic virus as time goes on; in the elimination case, it implies that the organism's complete recovery is highly possible as a result of the attack of oncolytic virus. An indirect idea in calculating fixed point index is proposed; correspondingly, a new condition on coexistence is presented.

Abstract 5746: Flexible tumor-specific cytokine and antigen delivery through the T-SIGn vector platform enables effective CAR-T cell therapy against solid tumors

Abstract Efficacy of Chimeric Antigen Receptor (CAR) T cell therapy against solid tumors is hampered by multiple barriers, including tumor-associated immunosuppression, poor CAR-T cell trafficking into solid tumor masses and shortage of highly expressed cancer-specific target antigens. The T-SIGn (Tumor Specific ImmunoGene) platform generates viral vectors that can produce combinations of transgenes selectively within the tumor microenvironment (TME). T-SIGn is clinically validated for intravenous (i.v.) delivery, enabling vectors to reach primary and metastatic sites to produce their therapeutic payloads specifically in malignant epithelial cells. Using an A549 human tumor xenograft and metastasis model, we previously demonstrated that i.v. administration of a T-SIGn vector encoding IFNα, MIP1α and CD80 results into potentiated CAR-T cell activation and therapy efficacy (Sonzogni et al. 2022). Here, we further evaluated the potential of T-SIGn combination with Cell Therapy by investigating the impact on CAR-T cell activity of vectors encoding different arrays of cytokines and chemokines. Using an in vivo A549 model and anti-HER2 CAR-T cells in NSG mice, we demonstrated that T-SIGn vectors can enable effective CAR-T cell therapy against solid tumors by providing diverse localized cytokine/chemokine-mediated T cell boosting, with IL-12-encoding vectors resulting in complete and durable tumor clearance. Furthermore, we explored the use of the T-SIGn platform to encode secreted bispecific “adaptor” molecules able to simultaneously bind to a tumor surface antigen and to a CAR specific for an antigen not naturally expressed by the tumor, allowing the redirection of CAR-T cells against desired tumor types. We designed a vector (NG-1125) encoding an anti-HER2 ScFv_CD19 bispecific construct as a model “adaptor” molecule, together with IFNα and CXCL9, and we showed that this construct can effectively redirect anti-CD19 CAR-T cell against HER2+CD19− tumor cells. In vitro X-CELLigence-based cytotoxicity assays demonstrated killing of both HER2+CD19− A549 and SKOV3 cells by anti-CD19 CAR-T cells in presence of vector-derived anti-HER2 ScFv_CD19. Following i.v. NG-1125 dosing of A549 tumor-bearing mice, ex vivo flow cytometry analysis of tumor masses revealed binding of the encoded adaptor molecule to both vector-infected and uninfected tumor cells. Furthermore, in vivo NG-1125 administration together with anti-CD19 CAR-T cells resulted into increased intra-tumoral densities of transferred T cells. Collectively, these data show the potential of T-SIGn vectors in overcoming solid tumor resistance mechanisms to CAR-T and pave the way for the development of other immunotherapeutics to be expressed within the TME via T-SIGn vectors in combination with CAR or TCR-based therapies. Citation Format: Maria Stella Sasso, Rachel Bergin, Rochelle Lear, Darren Plumb, Manuela Zonca, Eva Vainiute, Meg Snowden, Tae Hyun Jang, Alice Muntzer, Carla C. Cerqueira, Katy West, Samantha Bucktrout, Brian R. Champion. Flexible tumor-specific cytokine and antigen delivery through the T-SIGn vector platform enables effective CAR-T cell therapy against solid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5746.

In Vivo Oncolytic Virotherapy in Murine Models of Hepatocellular Carcinoma: A Systematic Review.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Current therapies often provide marginal survival benefits at the expense of undesirable side effects. Oncolytic viruses represent a novel strategy for the treatment of HCC due to their inherent ability to cause direct tumor cell lysis while sparing normal tissue and their capacity to stimulate potent immune responses directed against uninfected tumor cells and distant metastases. Oncolytic virotherapy (OVT) is a promising cancer treatment, but before it can become a standard option in practice, several challenges—systemic viral delivery optimization/enhancement, inter-tumoral virus dispersion, anti-cancer immunity cross-priming, and lack of artificial model systems—need to be addressed. Addressing these will require an in vivo model that accurately mimics the tumor microenvironment and allows the scientific community to design a more precise and accurate OVT. Due to their close physiologic resemblance to humans, murine cancer models are the likely preferred candidates. To provide an accurate assessment of the current state of in vivo OVT in HCC, we have reviewed a comprehensively searched body of work using murine in vivo HCC models for OVT.

Bifurcations and multistability in a virotherapy model with two time delays

In this paper, we establish a delayed virotherapy model including infected tumor cells, uninfected tumor cells and free virus. In this model, both infected and uninfected tumor cells have special growth patterns, and there are at most two positive equilibria. We mainly analyze the stability and Hopf bifurcation of the model under different time delays. For the model without delay, we study the Hopf and Bogdanov–Takens bifurcations. For the delayed model, by center manifold theorem and normal form theory of functional differential equation, we study the direction of Hopf bifurcation and stability of the bifurcated periodic solution. Moreover, we prove the existence of Zero-Hopf bifurcation. Finally, some numerical simulations show the results of our theoretical calculations, and the dynamic behaviors near Zero-Hopf and Bogdanov–Takens point of the system are also observed in the simulations, such as bistability, periodic coexistence and chaotic behavior.

Dynamic analysis of an age structure model for oncolytic virus therapy.

Cancer is recognized as one of the serious diseases threatening human health. Oncolytic therapy is a safe and effective new cancer treatment method. Considering the limited ability of uninfected tumor cells to infect and the age of infected tumor cells have a significant effect on oncolytic therapy, an age-structured model of oncolytic therapy involving Holling-Ⅱ functional response is proposed to investigate the theoretical significance of oncolytic therapy. First, the existence and uniqueness of the solution is obtained. Furthermore, the stability of the system is confirmed. Then, the local stability and global stability of infection-free homeostasis are studied. The uniform persistence and local stability of the infected state are studied. The global stability of the infected state is proved by constructing the Lyapunov function. Finally, the theoretical results are verified by numerical simulation. The results show that when the tumor cells are at the appropriate age, injection of the right amount of oncolytic virus can achieve the purpose of tumor treatment.

Combination of virotherapy and chemotherapy with optimal control for combating cancer

The purpose of this paper is to study the behaviors shown by a modified mathematical model representing interactions between immune cells, un-infected tumor cells, infected tumor cells, and normal cells when subjected initially to chemotherapy and virotherapy alone and subsequently a combination of both. Stability analysis is carried out for all steady states in each treatment model. Conditions are derived under which recurrence of tumors can be prevented when the amount of applied drugs are reduced. Analysis of the model shows that the tumor can be eliminated with a lower dose of chemotherapy if it is combined with virotherapy. The existence of an optimal control set, and optimality of the model are discussed. The optimal control problem relative to the model is designed in a way to reduce the number of tumor cells and the amount of chemotherapeutic drugs and at the same time to increase the positive effect of virotherapy to improve the immune system, thereby causing a reduction in patient’s recovery time.

An Analysis of Virus Amplification and Antitumor Responses in T-Cell Lymphoma Patients Treated with Voyager-V1 ( VSV-IFNβ-NIS)

An Analysis of Virus Amplification and Antitumor Responses in T-Cell Lymphoma Patients Treated with Voyager-V1 ( VSV-IFNβ-NIS)

Specificity, Safety, Efficacy of EGFRvIII-Retargeted Oncolytic HSV for Xenotransplanted Human Glioblastoma.

Glioblastoma is a lethal primary brain tumor lacking effective therapy. The secluded onset site, combined with the infiltrative properties of this tumor, require novel targeted therapies. In this scenario, the use of oncolytic viruses retargeted to glioblastoma cells and able to spread across the tumor cells represent an intriguing treatment strategy. Here, we tested the specificity, safety and efficacy of R-613, the first oncolytic HSV fully retargeted to EGFRvIII, a variant of the epidermal growth factor receptor carrying a mutation typically found in glioblastoma. An early treatment with R-613 on orthotopically transplanted EGFRvIII-expressing human glioblastoma significantly increased the median survival time of mice. In this setting, the growth of human glioblastoma xenotransplants was monitored by a secreted luciferase reporter and showed that R-613 is able to substantially delay the development of the tumor masses. When administered as late treatment to a well-established glioblastomas, R-613 appeared to be less effective. Notably the uninfected tumor cells derived from the explanted tumor masses were still susceptible to R-613 infection ex vivo, thus suggesting that multiple treatments could enhance R-613 therapeutic efficacy, making R-613 a promising oncolytic HSV candidate for glioblastoma treatment.

Oncolytic parainfluenza virus combines with NK cells to mediate killing of infected and non-infected lung cancer cells within 3D spheroids: role of type I and type III interferon signaling

BackgroundThere is intense interest in developing novel oncolytic viruses, which can be used in cancer therapies along with immune cells such as natural killer (NK) cells. We have previously developed...

Hopf bifurcation analysis in a delayed model of tumor therapy with oncolytic viruses

The stability and Hopf bifurcation of a nonlinear mathematical model are described by the delay differential equation proposed by Wodarz for interaction between uninfected tumor cells and infected tumor cells with the virus. By choosing τ as a bifurcation parameter, we show that the Hopf bifurcation can occur for a critical value τ. Using the normal form theory and the center manifold theory, formulas are given to determine the stability and the direction of bifurcation and other properties of bifurcating periodic solutions. Then, by changing the infection rate to two nonlinear infection rates, we investigate the stability and existence of a limit cycle for the appropriate value of τ, numerically. Lastly, we present some numerical simulations to justify our theoretical results.

Modeling dynamics of cancer virotherapy with immune response

Virotherapy is a therapeutic treatment for cancer. It uses genetically engineered viruses to selectively infect, replicate in, and destroy cancer cells without damaging normal cells. In this paper, we present a modified model to include, within the dynamics of virotherapy, the interaction between uninfected tumor cells and immune response. The model is analyzed qualitatively to produce five equilibrium points. One of these equilibriums demonstrates the effect observed in virotherapy, where the immune system demolishes infected cells as well as viruses. Moreover, the existence and stability of the equilibrium points are established under certain criteria. Numerical simulations are performed to display the agreement with the analytical results. Finally, parameter analysis is carried out to illustrate which parameters in the model affect the outcome of virotherapy.

Ultimate tumor dynamics and eradication using oncolytic virotherapy

In this paper we study ultimate dynamics of one three-dimensional model for tumor growth under oncolytic virotherapy which describes interactions between cytotoxic T-cells, uninfected tumor cells and infected tumor cells. Using the localization theorem of compact invariant sets we derive ultimate upper bounds for all cell populations and establish the property of the existence of the attracting set. Next, we find several conditions under which our system demonstrates convergence dynamics to equilibrium points located in invariant planes corresponding cases of the absence of uninfected or infected tumor cells. These assertions mean global eradication of uninfected or infected tumor cell populations and are presented as algebraic inequalities respecting virus replication rate θ. In particular, we find in Theorems 4 and 5the following curious phenomenon. Namely, when we vary θ from the instability range of the infected tumor free equilibrium point to the stability range we obtain in the latter range convergence dynamics to one of tumor free equilibrium points; this means that the local eradication of infected tumor cells implies their global eradication. Besides, we give conditions under which the infected tumor cell population persists. Our theoretical studies are supplied by results of numerical simulation.

Oncolytic measles virus therapy enhances tumor antigen-specific T-cell responses in patients with multiple myeloma

Oncolytic virus therapy leads to immunogenic death of virus-infected tumor cells and this has been shown in preclinical models to enhance the cytotoxic T-lymphocyte response against tumor-associated antigens (TAAs), leading to killing of uninfected tumor cells. To investigate whether oncolytic virotherapy can increase immune responses to tumor antigens in human subjects, we studied T-cell responses against a panel of known myeloma TAAs using PBMC samples obtained from ten myeloma patients before and after systemic administration of an oncolytic measles virus encoding sodium iodide symporter (MV-NIS). Despite their prior exposures to multiple immunosuppressive antimyeloma treatment regimens, T-cell responses to some of the TAAs were detectable even before measles virotherapy. Measurable baseline T-cell responses against MAGE-C1 and hTERT were present. Furthermore, MV-NIS treatment significantly (P < 0.05) increased T-cell responses against MAGE-C1 and MAGE-A3. Interestingly, one patient who achieved complete remission after MV-NIS therapy had strong baseline T-cell responses both to measles virus proteins and to eight of the ten tested TAAs. Our data demonstrate that oncolytic virotherapy can function as an antigen agnostic vaccine, increasing cytotoxic T-lymphocyte responses against TAAs in patients with multiple myeloma, providing a basis for continued exploration of this modality in combination with immune checkpoint blockade.

Modeling treatment of cancer using oncolytic virotherapy with saturated incidence

Oncolytic virotherapy is emerging as a promising new method for cancer treatment. In the present study, we propose and analyze a mathematical model for treatment of cancer by using oncolytic virotherapy. Here, it is assumed that the growth of tumor cells follows logistic growth and the interaction between tumor cells and viruses is of saturation type. Additionally, the removal rates of uninfected and virus-infected tumor cells due to CTL’s are also of saturation type. The basic reproduction numbers and different equilibria of the model are computed. The local stability of the equilibria is also discussed. Numerical simulation is also performed and it is found that for some set of parameters model system exhibits periodic oscillations. In this case it is not easy to predict the success of virotherapy. Finally, the model is extended to stochastic model and numerical simulation is performed to compare the results of deterministic and stochastic model.

Global classical solutions to a doubly haptotactic cross-diffusion system modeling oncolytic virotherapy

This work studies a haptotaxis system proposed as a model for oncolytic virotherapy, accounting for interaction between uninfected cancer cells, infected cancer cells, extracellular matrix (ECM) and oncolytic virus. In addition to random movement, both uninfected and infected tumor cells migrate haptotactically toward higher ECM densities; moreover, besides degrading the non-diffusible ECM upon contact the two cancer cell populations are subject to an infection-induced transition mechanism driven by virus particles which are released by infected cancer cells, and which assault the uninfected part of the tumor.The main results assert global classical solvability in an associated initial-boundary value problem posed in one- or two-dimensional domains with any given suitably regular initial data. This is achieved by discovering a quasi-Lyapunov functional structure that allows to appropriately cope with the presence of nonlinear zero-order interaction terms which apparently form the most significant additional mathematical challenge of the considered system in comparison to previously studied haptotaxis models.

Model of virus therapy and chemotherapy for cancer

This article discusses the mathematical model of changes in the number of cancer cells as a result of the intervention. Here the effect of combination treatment, in the form of virus injection and chemotherapy on tumor cells, is presented in detail. There are two different tumor cells, uninfected tumor cells and infected tumor cells. Model simulations with different parameters were performed for 700 d. The initial values for the population of virus-infected tumor cells are divided into two categories. The number of tumor cells injected with the virus is ½ (half) and all tumor cells that are not infected. Based on the simulation results, it was concluded that the more the number of tumor cells injected with the virus, the faster the decrease in the number of tumor cell populations. It was also concluded that the reduced population of tumor cells reduces the amount of chemotherapy concentration used.

Dynamic Analysis of a Tumor Treatment Model Using Oncolytic Virus and Chemotherapy with Saturated Infection Rate

Virotherapy is one of the most promising therapies in the treatment of tumors which may be further combined with chemotherapy to accelerate the healing rate. In this article, we propose a mathematical model for the treatment of tumors using oncolytic virus and chemotherapy. This model takes the form of nonlinear ordinary differential equations describing the interactions between uninfected tumor cells, infected tumor cells, an oncolytic virus, and chemotherapy. It is assumed that the rate of infection between uninfected tumor cells and infected tumor cells is in a saturated form. The saturation effect takes into account the fact that the number of contacts between them reaches the maximum value when the immune system works to stop the virus. The dynamical analysis, which includes the existence of equilibrium points, and its stability analysis is investigated. The analysis result shows that the system has three equilibrium points: tumor-free equilibrium point, virus-free equilibrium point and endemic equilibrium point. It is proven that these equilibrium points are conditionally stable. The numerical simulations show the successful combination of chemotherapy and virotherapy using an oncolytic virus in eliminating the tumor cells.

For the Success of Oncolytic Viruses: Single Cycle Cures or Repeat Treatments? (One Cycle Should Be Enough).

For the Success of Oncolytic Viruses: Single Cycle Cures or Repeat Treatments? (One Cycle Should Be Enough).

A mathematical model for tumor growth and treatment using virotherapy

We present a system of four nonlinear differential equations to model the use of virotherapy as a treatment for cancer. This model describes interactions among infected tumor cells, uninfected tumor cells, effector T-cells, and virions. We establish a necessary and sufficient treatment condition to ensure a globally stable cure state, and we additionally show the existence of a cancer persistence state when this condition is violated. We provide numerical evidence of a Hopf bifurcation under estimated parameter values from the literature, and we conclude with a discussion on the biological implications of our results.