生物医药

The goal of cancer immunotherapy is to boost a patient's immune response to a tumor. Yet, the design of an effective immunotherapy is complicated by various factors, including a potentially immunosuppressive tumor microenvironment, immune-modulating effects of conventional treatments, and therapy-related toxicities. These complexities can be incorporated into mathematical and computational models of cancer immunotherapy that can then be used to aid in rational therapy design. In this review, we survey modeling approaches under the umbrella of the major challenges facing immunotherapy development, which encompass tumor classification, optimal treatment scheduling, and combination therapy design. Although overlapping, each challenge has presented unique opportunities for modelers to make contributions using analytical and numerical analysis of model outcomes, as well as optimization algorithms. We discuss several examples of models that have grown in complexity as more biological information has become available, showcasing how model development is a dynamic process interlinked with the rapid advances in tumor-immune biology. We conclude the review with recommendations for modelers b

Regulatory T cells (Treg) have recently been identified as playing a central role in allergy and during allergen-specific immunotherapy. We have extended our previous mathematical model describing the nonlinear dynamics of Th1-Th2 regulation by including Treg cells and their major cytokines. We hypothesize that immunotherapy mainly acts on the T cell level and that the decisive process can be regarded as a dynamical phenomenon. The model consists of nonlinear differential equations which describe the proliferation and mutual suppression of different T cell subsets. The old version of the model was based upon the Th1-Th2 paradigm and is successful in describing the "Th1-Th2 switch" which was considered the decisive event during specific immunotherapy. In recent years, however, the Th1-Th2 paradigm has been questioned and therefore, we have investigated a modified model in order to account for the influence of a regulatory T cell type. We examined the extended model by means of numerical simulations and analytical methods. As the modified model is more complex, we had to develop new methods to portray its characteristics. The concept of stable manifolds of fixed points of a strobosco

In this article, a well-known mathematical model of cancer immunotherapy is discussed and used to represent therapeutic protocols for cancer treatment. The optimal control problem is formulated based on the Pontryagin maximum principle to deal with adoptive cellular immunotherapy, then the problem has been solved by the application of particle swarm optimization (PSO) in combination with regular methods of solutions to optimal control problems. The results are compared with those of other researchers. It is explained how the PSO algorithm could be enlisted to obtain the optimal controls, then the obtained optimal controls are demonstrated to be more appropriate to the elimination of cancer cells by using fewer amounts of external sources of medicine.

Antibodies, a prominent class of approved biologics, play a crucial role in detecting foreign antigens. The effectiveness of antigen neutralisation and elimination hinges upon the strength, sensitivity, and specificity of the paratope-epitope interaction, which demands resource-intensive experimental techniques for characterisation. In recent years, artificial intelligence and machine learning methods have made significant strides, revolutionising the prediction of protein structures and their complexes. The past decade has also witnessed the evolution of computational approaches aiming to support immunotherapy design. This review focuses on the progress of machine learning-based tools and their frameworks in the domain of B-cell immunotherapy design, encompassing linear and conformational epitope prediction, paratope prediction, and antibody design. We mapped the most commonly used data sources, evaluation metrics, and method availability and thoroughly assessed their significance and limitations, discussing the main challenges ahead.

This work presents a new mathematical model to depict the effect of obesity on cancerous tumor growth when chemotherapy as well as immunotherapy have been administered. We consider an optimal control problem to destroy the tumor population and minimize the drug dose over a finite time interval. The constraint is a model including tumor cells, immune cells, fat cells, chemotherapeutic and immunotherapeutic drug concentrations with Caputo time fractional derivative. We investigate the existence and stability of the equilibrium points namely, tumor free equilibrium and coexisting equilibrium, analytically. We discretize the cancer-obesity model using L1-method. Simulation results of the proposed model are presented to compare three different treatment strategies: chemotherapy, immunotherapy and their combination. In addition, we investigate the effect of the differentiation order $α$ and the value of the decay rate of the amount of chemotherapeutic drug to the value of the cost functional. We find out the optimal treatment schedule in case of chemotherapy and immunotherapy applied.

Immunotherapy constitutes a paradigm shift in cancer treatment. Its FDA approval for several indications has yielded improved prognosis for cases where traditional therapy has shown limited efficiencey. However, many patients still fail to benefit from this treatment modality, and the exact mechanisms responsible for tumor response are unknown. Noninvasive treatment monitoring is crucial for longitudinal tumor characterization and the early detection of non-responders. While various medical imaging techniques can provide a morphological picture of the lesion and its surrounding tissue, a molecular-oriented imaging approach holds the key to unraveling biological effects that occur much earlier in the immunotherapy timeline. Magnetic resonance imaging (MRI) is a highly versatile imaging modality, where the image contrast can be tailored to emphasize a particular biophysical property of interest using advanced engineering of the imaging pipeline. In this review, recent advances in molecular-MRI based cancer immunotherapy monitoring are described. Next, the presentation of the underlying physics, computational, and biological features are complemented by a critical analysis of the resu

Achieving effective synergy between radiotherapy and immunotherapy is critical for optimizing tumor control and treatment outcomes. To explore the underlying mechanisms of this synergy, we have investigated a novel treatment approach known as personalized ultra-fractionated stereotactic adaptive radiation therapy (PULSAR), which emphasizes the impact of radiation timing on treatment efficacy. However, the precise mechanism remains unclear. Building on insights from small animal PULSAR studies, we developed a mathematical framework consisting of multiple ordinary differential equations to elucidate the temporal dynamics of tumor control resulting from radiation and the adaptive immune response. The model accounts for the migration and infiltration of T-cells within the tumor microenvironment. This proposed model establishes a causal and quantitative link between radiation therapy and immunotherapy, providing a valuable in-silico analysis tool for designing future PULSAR trials.

Despite ongoing efforts in cancer research, a fully effective treatment for glioblastoma multiforme (GBM) is still unknown. Since adoptive cell transfer immunotherapy is one of the potential cure candidates, efforts have been made to assess its effectiveness using mathematical modeling. In this paper, we consider a model of GBM immunotherapy proposed by Abernathy and Burke (2016), which also takes into account the dynamics of cancer stem cells, i.e., the type of cancer cells that are hypothesized to be largely responsible for cancer recurrence. We modify the initial ODE system by applying simplifying assumptions and analyze the existence and stability of steady states of the obtained simplified model depending on the treatment levels.

Purpose: Immunotherapies have revolutionized the landscape of cancer treatments. However, our understanding of response patterns in advanced cancers treated with immunotherapy remains limited. By leveraging routinely collected noninvasive longitudinal and multimodal data with artificial intelligence, we could unlock the potential to transform immunotherapy for cancer patients, paving the way for personalized treatment approaches. Methods: In this study, we developed a novel artificial neural network architecture, multimodal transformer-based simple temporal attention (MMTSimTA) network, building upon a combination of recent successful developments. We integrated pre- and on-treatment blood measurements, prescribed medications and CT-based volumes of organs from a large pan-cancer cohort of 694 patients treated with immunotherapy to predict mortality at three, six, nine and twelve months. Different variants of our extended MMTSimTA network were implemented and compared to baseline methods incorporating intermediate and late fusion based integration methods. Results: The strongest prognostic performance was demonstrated using a variant of the MMTSimTA model with area under the curves

Immunotherapy plays a major role in tumour treatment, in comparison with other methods of dealing with cancer. The Kirschner-Panetta (KP) model of cancer immunotherapy describes the interaction between tumour cells, effector cells and interleukin-2 which are clinically utilized as medical treatment. The model selects a rich concept of immune-tumour dynamics. In this paper, approximate analytical solutions to KP model are represented by using the differential transform and Adomian decomposition. The complicated nonlinearity of the KP system causes the application of these two methods to require more involved calculations. The approximate analytical solutions to the model are compared with the results obtained by numerical fourth order Runge-Kutta method.

Cancer immunotherapy provides durable clinical benefit in only a small fraction of patients, particularly due to a lack of reliable biomarkers for accurate prediction of treatment outcomes and evaluation of response. Here, we demonstrate the first application of label-free Raman spectroscopy for elucidating biochemical changes induced by immunotherapy in the tumor microenvironment. We used CT26 murine colorectal cancer cells to grow tumor xenografts and subjected them to treatment with anti-CTLA-4 and anti-PD-L1 antibodies. Multivariate curve resolution - alternating least squares (MCR-ALS) decomposition of Raman spectral dataset obtained from the treated and control tumors revealed subtle differences in lipid, nucleic acid, and collagen content due to therapy. Our supervised classification analysis using support vector machines and random forests provided excellent prediction accuracies for both immune checkpoint inhibitors and delineated important spectral markers specific to each therapy, consistent with their differential mechanisms of action. Our findings pave the way for in vivo studies of response to immunotherapy in clinical patients using label-free Raman spectroscopy and

In this paper, we investigate a mathematical model describing the interactions between effector cells (E), cancer cells (T), and the IL-2 compound (IL). The model considered here is a generalization, taking into account some cross-diffusion effects, of a spatial cancer immunotherapy model proposed by S. Suddin et al in 2021. These modifications allow us to describe two biologically relevant scenarios: a patient treated with Adoptive Cell Immunotherapy (ACI) and a patient not receiving any treatment/therapy. Cross-diffusion effects are particularly relevant in the interactions between tumor cells and the immune system, in fact they play a key role in immune response dynamics and cannot be neglected. We analyze the equilibrium points of the homogeneous system, along with their stability and bifurcation mechanisms. Furthermore, adopting the Turing approach for reaction-diffusion systems, we investigate the diffusion-driven instability and the emergence of spatial regular structures (stationary in time), i.e. the patterns. Finally, numerical simulations based on the Finite Difference Method (FDM) are presented for the two previously mentioned scenarios.

We propose an extension of a standard stochastic individual-based model in population dynamics which broadens the range of biological applications. Our primary motivation is modelling of immunotherapy of malignant tumours. In this context the different actors, T-cells, cytokines or cancer cells, are modelled as single particles (individuals) in the stochastic system. The main expansions of the model are distinguishing cancer cells by phenotype and genotype, including environment-dependent phenotypic plasticity that does not affect the genotype, taking into account the effects of therapy and introducing a competition term which lowers the reproduction rate of an individual in addition to the usual term that increases its death rate. We illustrate the new setup by using it to model various phenomena arising in immunotherapy. Our aim is twofold: on the one hand, we show that the interplay of genetic mutations and phenotypic switches on different timescales as well as the occurrence of metastability phenomena raise new mathematical challenges. On the other hand, we argue why understanding purely stochastic events (which cannot be obtained with deterministic models) may help to understa

Accurately predicting immunotherapy response in Non-Small Cell Lung Cancer (NSCLC) remains a critical unmet need. Existing radiomics and deep learning-based predictive models rely primarily on pre-treatment imaging to predict categorical response outcomes, limiting their ability to capture the complex morphological and textural transformations induced by immunotherapy. This study introduces ImmunoDiff, an anatomy-aware diffusion model designed to synthesize post-treatment CT scans from baseline imaging while incorporating clinically relevant constraints. The proposed framework integrates anatomical priors, specifically lobar and vascular structures, to enhance fidelity in CT synthesis. Additionally, we introduce a novel cbi-Adapter, a conditioning module that ensures pairwise-consistent multimodal integration of imaging and clinical data embeddings, to refine the generative process. Additionally, a clinical variable conditioning mechanism is introduced, leveraging demographic data, blood-based biomarkers, and PD-L1 expression to refine the generative process. Evaluations on an in-house NSCLC cohort treated with immune checkpoint inhibitors demonstrate a 21.24% improvement in balanc

Datasets used in immunotherapy response prediction are typically small in size, as well as diverse in cancer type, drug administered, and sequencer used. Models often drop in performance when tested on patient cohorts that are not included in the training process. Recent work has shown that transformer-based models along with self-supervised learning show better generalisation performance than threshold-based biomarkers, but is still suboptimal. We present BioCOMPASS, an extension of a transformer-based model called COMPASS, that integrates biomarkers and treatment information to further improve its generalisability. Instead of feeding biomarker data as input, we built loss components to align them with the model's intermediate representations. We found that components such as treatment gating and pathway consistency loss improved generalisability when evaluated with Leave-one-cohort-out, Leave-one-cancer-type-out and Leave-one-treatment-out strategies. Results show that building components that exploit biomarker and treatment information can help in generalisability of immunotherapy response prediction. Careful curation of additional components that leverage complementary clinical

Immunotherapy is an effective precision medicine treatment for several cancers. Imaging signatures of the underlying genome (radiogenomics) in glioblastoma patients may serve as preoperative biomarkers of the tumor-host immune apparatus. Validated biomarkers would have the potential to stratify patients during immunotherapy clinical trials, and if trials are beneficial, facilitate personalized neo-adjuvant treatment. The increased use of whole genome sequencing data, and the advances in bioinformatics and machine learning make such developments plausible. We performed a systematic review to determine the extent of development and validation of immune-related radiogenomic biomarkers for glioblastoma. A systematic review was performed following PRISMA guidelines using the PubMed, Medline, and Embase databases. Qualitative analysis was performed by incorporating the QUADAS 2 tool and CLAIM checklist. PROSPERO registered CRD42022340968. Extracted data were insufficiently homogenous to perform a meta-analysis. Results Nine studies, all retrospective, were included. Biomarkers extracted from magnetic resonance imaging volumes of interest included apparent diffusion coefficient values, re

Glioblastoma Multiforme (GBM) is a highly aggressive brain tumour with limited therapeutic options and poor prognosis. This study presents a mathematical framework to investigate the efficacy of immunotherapy strategies based on cytotoxic T-lymphocyte (CTL) infusion. The model couples tumour and immune dynamics through a system of partial differential equations (PDEs), incorporating cell proliferation, diffusion, and chemotactic migration in response to TGF-$β$, a tumour-secreted signalling molecule. A reduced ordinary differential equation (ODE) model is first analysed to derive threshold conditions for tumour eradication, identifying critical infusion levels consistent with clinical data. Numerical bifurcation analysis explores the impact of parameter variations. The full PDE model is solved using the finite element method on simplified 2D domains, followed by sensitivity analyses to quantify parameter influence on tumour mass and volume. The model is then applied to a realistic 3D brain geometry reconstructed from patient-specific MRI and DTI data, accounting for anatomical anisotropy and tissue heterogeneity. Therapeutic scenarios are simulated with spatially localised lymphocy

Formulating tumor models that predict growth under therapy is vital for improving patient-specific treatment plans. In this context, we present our recent work on simulating non-small-scale cell lung cancer (NSCLC) in a simple, deterministic setting for two different patients receiving an immunotherapeutic treatment. At its core, our model consists of a Cahn-Hilliard-based phase-field model describing the evolution of proliferative and necrotic tumor cells. These are coupled to a simplified nutrient model that drives the growth of the proliferative cells and their decay into necrotic cells. The applied immunotherapy decreases the proliferative cell concentration. Here, we model the immunotherapeutic agent concentration in the entire lung over time by an ordinary differential equation (ODE). Finally, reaction terms provide a coupling between all these equations. By assuming spherical, symmetric tumor growth and constant nutrient inflow, we simplify this full 3D cancer simulation model to a reduced 1D model. We can then resort to patient data gathered from computed tomography (CT) scans over several years to calibrate our model. For the reduced 1D model, we show that our model can qu

Progress in immunotherapy revolutionized the treatment landscape for advanced lung cancer, raising survival expectations beyond those that were historically anticipated with this disease. In the present study, we describe the methods for the adjustment of mixture parametric models of two populations for survival analysis in the presence of long survivors. A methodology is proposed in several five steps: first, it is proposed to use the multimodality test to decide the number of subpopulations to be considered in the model, second to adjust simple parametric survival models and mixture distribution models, to estimate the parameters and to select the best model fitted the data, finally, to test the hypotheses to compare the effectiveness of immunotherapies in the context of randomized clinical trials. The methodology is illustrated with data from a clinical trial that evaluates the effectiveness of the therapeutic vaccine CIMAvaxEGF vs the best supportive care for the treatment of advanced lung cancer. The mixture survival model allows estimating the presence of a subpopulation of long survivors that is 44% for vaccinated patients. The differences between the treated and control gro

This paper deals with the estimation of regions of attraction (RoAs) under parametric uncertainties for a cancer growth model with combined therapies. We propose a framework of probabilistic certification, based on the randomized methods, in order to derive probabilistically certified RoAs of a cancer growth model. The model that we consider in this paper describes the interaction between tumor and immune system in presence of a combined chemo- and immunotherapy. Furthermore, we model the concentration of the chemotherapy agent in the body via a pharmacokinetic equation.