scholarly journals Mathematical Modelling for the Role of CD4+T Cells in Tumor-Immune Interactions

2020 ◽  
Vol 2020 ◽  
pp. 1-16 ◽  
Author(s):  
Ahmed M. Makhlouf ◽  
Lamiaa El-Shennawy ◽  
Hesham A. Elkaranshawy
Keyword(s):  
Mathematical Model ◽  
T Cells ◽  
T Cell ◽  
Natural Killer Cells ◽  
Cell Therapy ◽  
Mathematical Modelling ◽  
Equilibrium Points ◽  
T Cell Therapy ◽  
Circulating Lymphocytes

Mathematical modelling has been used to study tumor-immune cell interaction. Some models were proposed to examine the effect of circulating lymphocytes, natural killer cells, and CD8+T cells, but they neglected the role of CD4+T cells. Other models were constructed to study the role of CD4+T cells but did not consider the role of other immune cells. In this study, we propose a mathematical model, in the form of a system of nonlinear ordinary differential equations, that predicts the interaction between tumor cells and natural killer cells, CD4+T cells, CD8+T cells, and circulating lymphocytes with or without immunotherapy and/or chemotherapy. This system is stiff, and the Runge–Kutta method failed to solve it. Consequently, the “Adams predictor-corrector” method is used. The results reveal that the patient’s immune system can overcome small tumors; however, if the tumor is large, adoptive therapy with CD4+T cells can be an alternative to both CD8+T cell therapy and cytokines in some cases. Moreover, CD4+T cell therapy could replace chemotherapy depending upon tumor size. Even if a combination of chemotherapy and immunotherapy is necessary, using CD4+T cell therapy can better reduce the dose of the associated chemotherapy compared to using combined CD8+T cells and cytokine therapy. Stability analysis is performed for the studied patients. It has been found that all equilibrium points are unstable, and a condition for preventing tumor recurrence after treatment has been deduced. Finally, a bifurcation analysis is performed to study the effect of varying system parameters on the stability, and bifurcation points are specified. New equilibrium points are created or demolished at some bifurcation points, and stability is changed at some others. Hence, for systems turning to be stable, tumors can be eradicated without the possibility of recurrence. The proposed mathematical model provides a valuable tool for designing patients’ treatment intervention strategies.

scholarly journals Toxicity Management in CAR T cell therapy for B-ALL: Mathematical modelling as a new avenue for improvement

2016 ◽  
Author(s):  
Shalla Hanson ◽  
David Robert Grimes ◽  
Jake P. Taylor-King ◽  
Benedikt Bauer ◽  
Pravnam I. Warman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Mathematical Modelling ◽  
Mechanism Of Action ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

AbstractAdvances in genetic engineering have made it possible to reprogram individual immune cells to express receptors that recognise markers on tumour cell surfaces. The process of re-engineering T cell lymphocytes to express Chimeric Antigen Receptors (CARs), and then re-infusing the CAR-modified T cells into patients to treat various cancers is referred to as CAR T cell therapy. This therapy is being explored in clinical trials - most prominently for B Cell Acute Lymphoblastic Leukaemia (B-ALL), a common B cell malignancy, for which CAR T cell therapy has led to remission in up to 90% of patients. Despite this extraordinary response rate, however, potentially fatal inflammatory side effects occur in up to 10% of patients who have positive responses. Further, approximately 50% of patients who initially respond to the therapy relapse. Significant improvement is thus necessary before the therapy can be made widely available for use in the clinic.To inform future development, we develop a mathematical model to explore interactions between CAR T cells, inflammatory toxicity, and individual patients’ tumour burdens in silico. This paper outlines the underlying system of coupled ordinary differential equations designed based on well-known immunological principles and widely accepted views on the mechanism of toxicity development in CAR T cell therapy for B-ALL - and reports in silico outcomes in relationship to standard and recently conjectured predictors of toxicity in a heterogeneous, randomly generated patient population. Our initial results and analyses are consistent with and connect immunological mechanisms to the clinically observed, counterintuitive hypothesis that initial tumour burden is a stronger predictor of toxicity than is the dose of CAR T cells administered to patients.We outline how the mechanism of action in CAR T cell therapy can give rise to such non-standard trends in toxicity development, and demonstrate the utility of mathematical modelling in understanding the relationship between predictors of toxicity, mechanism of action, and patient outcomes.

ROLE OF REGULATORY T CELLS IN ADOPTIVE CMV-SPECIFIC T-CELL THERAPY

2008 ◽  
Vol 86 (Supplement) ◽  
pp. 716
Author(s):  
A Fischer ◽  
S Zwinger ◽  
G Brestrich ◽  
A Roemhild ◽  
J P. Maciejewski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Therapy ◽  
T Cell Therapy

scholarly journals Anti-Mesothelin CAR T cell therapy for malignant mesothelioma

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Laura Castelletti ◽  
Dannel Yeo ◽  
Nico van Zandwijk ◽  
John E. J. Rasko
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Malignant Mesothelioma ◽  
Oncolytic Viruses ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

AbstractMalignant mesothelioma (MM) is a treatment-resistant tumor originating in the mesothelial lining of the pleura or the abdominal cavity with very limited treatment options. More effective therapeutic approaches are urgently needed to improve the poor prognosis of MM patients. Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a novel potential treatment for this incurable solid tumor. The tumor-associated antigen mesothelin (MSLN) is an attractive target for cell therapy in MM, as this antigen is expressed at high levels in the diseased pleura or peritoneum in the majority of MM patients and not (or very modestly) present in healthy tissues. Clinical trials using anti-MSLN CAR T cells in MM have shown that this potential therapeutic is relatively safe. However, efficacy remains modest, likely due to the MM tumor microenvironment (TME), which creates strong immunosuppressive conditions and thus reduces anti-MSLN CAR T cell tumor infiltration, efficacy and persistence. Various approaches to overcome these challenges are reviewed here. They include local (intratumoral) delivery of anti-MSLN CAR T cells, improved CAR design and co-stimulation, and measures to avoid T cell exhaustion. Combination therapies with checkpoint inhibitors as well as oncolytic viruses are also discussed. Preclinical studies have confirmed that increased efficacy of anti-MSLN CAR T cells is within reach and offer hope that this form of cellular immunotherapy may soon improve the prognosis of MM patients.

scholarly journals Metabolic and Mitochondrial Functioning in Chimeric Antigen Receptor (CAR)—T Cells

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1229
Author(s):  
Ali Hosseini Rad S. M. ◽  
Joshua Colin Halpin ◽  
Mojtaba Mollaei ◽  
Samuel W. J. Smith Bell ◽  
Nattiya Hirankarn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Metabolic State ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized adoptive cell therapy with impressive therapeutic outcomes of >80% complete remission (CR) rates in some haematological malignancies. Despite this, CAR T cell therapy for the treatment of solid tumours has invariably been unsuccessful in the clinic. Immunosuppressive factors and metabolic stresses in the tumour microenvironment (TME) result in the dysfunction and exhaustion of CAR T cells. A growing body of evidence demonstrates the importance of the mitochondrial and metabolic state of CAR T cells prior to infusion into patients. The different T cell subtypes utilise distinct metabolic pathways to fulfil their energy demands associated with their function. The reprogramming of CAR T cell metabolism is a viable approach to manufacture CAR T cells with superior antitumour functions and increased longevity, whilst also facilitating their adaptation to the nutrient restricted TME. This review discusses the mitochondrial and metabolic state of T cells, and describes the potential of the latest metabolic interventions to maximise CAR T cell efficacy for solid tumours.

scholarly journals A modular and controllable T cell therapy platform for acute myeloid leukemia

Leukemia ◽  
2021 ◽  
Author(s):  
Mohamed-Reda Benmebarek ◽  
Bruno L. Cadilha ◽  
Monika Herrmann ◽  
Stefanie Lesch ◽  
Saskia Schmitt ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Cell Therapy ◽  
Myeloid Leukemia ◽  
Tumor Antigens ◽  
Adoptive T Cell Therapy ◽  
Single Chain ◽  
T Cell Therapy ◽  
Acute Myeloid

AbstractTargeted T cell therapy is highly effective in disease settings where tumor antigens are uniformly expressed on malignant cells and where off-tumor on-target-associated toxicity is manageable. Although acute myeloid leukemia (AML) has in principle been shown to be a T cell-sensitive disease by the graft-versus-leukemia activity of allogeneic stem cell transplantation, T cell therapy has so far failed in this setting. This is largely due to the lack of target structures both sufficiently selective and uniformly expressed on AML, causing unacceptable myeloid cell toxicity. To address this, we developed a modular and controllable MHC-unrestricted adoptive T cell therapy platform tailored to AML. This platform combines synthetic agonistic receptor (SAR) -transduced T cells with AML-targeting tandem single chain variable fragment (scFv) constructs. Construct exchange allows SAR T cells to be redirected toward alternative targets, a process enabled by the short half-life and controllability of these antibody fragments. Combining SAR-transduced T cells with the scFv constructs resulted in selective killing of CD33+ and CD123+ AML cell lines, as well as of patient-derived AML blasts. Durable responses and persistence of SAR-transduced T cells could also be demonstrated in AML xenograft models. Together these results warrant further translation of this novel platform for AML treatment.

158 Inhibition of PI3Kδ improves tumor specific T cell immunity and metabolic fitness

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A172-A172
Author(s):  
Guillermo Rangel Rivera ◽  
Guillermo Rangel RIvera ◽  
Connor Dwyer ◽  
Dimitrios Arhontoulis ◽  
Hannah Knochelmann ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cell Therapy ◽  
Tumor Immunity ◽  
Mitochondrial Function ◽  
T Cell Differentiation ◽  
Tumor Control ◽  
T Cell Therapy

BackgroundDurable responses have been observed with adoptive T cell therapy (ACT) in some patients. However, current protocols used to expand T cells often exhibit suboptimal tumor control. Failure in these therapies has been attributed to premature differentiation and impaired metabolism of the infused T cells. Previous work done in our lab showed that reduced PI3Kδ signaling improved ACT. Because PI3Kγ and PI3Kδ have critical regulatory roles in T cell differentiation and function, we tested whether inhibiting PI3Kγ could recapitulate or synergize PI3Kδ blockade.MethodsTo test this, we primed melanoma specific CD8+ pmel-1 T cells, which are specific to the glycoprotein 100 epitope, in the presence of PI3Kγ (IPI-459), PI3Kδ (CAL101 or TGR-1202) or PI3Kγ/δ (IPI-145) inhibitors following antigen stimulation with hgp100, and then infused them into 5Gy total body irradiated B16F10 tumor bearing mice. We characterized the phenotype of the transferred product by flow cytometry and then assessed their tumor control by measuring the tumor area every other day with clippers. For metabolic assays we utilized the 2-NBDG glucose uptake dye and the real time energy flux analysis by seahorse.ResultsSole inhibition of PI3Kδ or PI3Kγ in vitro promoted greater tumor immunity and survival compared to dual inhibition. To understand how PI3Kδ or PI3Kγ blockade improved T cell therapy, we assessed their phenotype. CAL101 treatment produced more CD62LhiCD44lo T cells compared to IPI-459, while TGR-1202 enriched mostly CD62LhiCD44hi T cells. Because decreased T cell differentiation is associated with mitochondrial metabolism, we focused on CAL101 treated T cells to study their metabolism. We found that CAL101 decreased glucose uptake and increased mitochondrial respiration in vitro, indicating augmented mitochondrial function.ConclusionsThese findings indicate that blocking PI3Kδ is sufficient to mediate lasting tumor immunity of adoptively transferred T cells by preventing premature differentiation and improving mitochondrial fitness. Our data suggest that addition of CAL101 to ACT expansion protocols could greatly improve T cell therapies for solid tumors by preventing T cell differentiation and improving mitochondrial function.

IMMU-45. COMBINATION OF EGFRVIII CAR T-CELL THERAPY AND PARACRINE GAM MODULATION FOR THE TREATMENT OF GBM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi102-vi103
Author(s):  
Tomás A Martins ◽  
Marie-Françoise Ritz ◽  
Tala Shekarian ◽  
Philip Schmassmann ◽  
Deniz Kaymak ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Differential Expression Analysis ◽  
Dependent Manner ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract The GBM immune tumor microenvironment mainly consists of protumoral glioma-associated microglia and macrophages (GAMs). We have previously shown that blockade of CD47, a ‘don't eat me’-signal overexpressed by GBM cells, rescued GAMs' phagocytic function in mice. However, monotherapy with CD47 blockade has been ineffective in treating human solid tumors to date. Thus, we propose a combinatorial approach of local CAR T cell therapy with paracrine GAM modulation for a synergistic elimination of GBM. We generated humanized EGFRvIII CAR T-cells by lentiviral transduction of healthy donor human T-cells and engineered them to constitutively release a soluble SIRPγ-related protein (SGRP) with high affinity towards CD47. Tumor viability and CAR T-cell proliferation were assessed by timelapse imaging analysis in co-cultures with endogenous EGFRvIII-expressing BS153 cells. Tumor-induced CAR T-cell activation and degranulation were confirmed by flow cytometry. CAR T-cell secretomes were analyzed by liquid chromatography-mass spectrometry. Immunocompromised mice were orthotopically implanted with EGFRvIII+ BS153 cells and treated intratumorally with a single CAR T-cell injection. EGFRvIII and EGFRvIII-SGRP CAR T-cells killed tumor cells in a dose-dependent manner (72h-timepoint; complete cytotoxicity at effector-target ratio 1:1) compared to CD19 controls. CAR T-cells proliferated and specifically co-expressed CD25 and CD107a in the presence of tumor antigen (24h-timepoint; EGFRvIII: 59.3±3.00%, EGFRvIII-SGRP: 52.6±1.42%, CD19: 0.1±0.07%). Differential expression analysis of CAR T-cell secretomes identified SGRP from EGFRvIII-SGRP CAR T-cell supernatants (-Log10qValue/Log2fold-change= 3.84/6.15). Consistent with studies of systemic EGFRvIII CAR T-cell therapy, our data suggest that intratumoral EGFRvIII CAR T-cells were insufficient to eliminate BS153 tumors with homogeneous EGFRvIII expression in mice (Overall survival; EGFRvIII-treated: 20%, CD19-treated: 0%, n= 5 per group). Our current work focuses on the functional characterization of SGRP binding, SGRP-mediated phagocytosis, and on the development of a translational preclinical model of heterogeneous EGFRvIII expression to investigate an additive effect of CAR T-cell therapy and GAM modulation.

scholarly journals First-in-Human Study of ET019003, a Next Generation Anti-CD19 T-Cell Therapy, in Patients with Relapsed/Refractory Diffuse Large B Cell Lymphoma (r/r DLBCL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2870-2870 ◽  
Author(s):  
Pengcheng He ◽  
Hong Liu ◽  
Haibo Liu ◽  
Mina Luo ◽  
Hui Feng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cell Expansion ◽  
T Cell Therapy ◽  
Car T ◽  
Equity Ownership ◽  
T Cell Expansion ◽  
The Absolute

Background : CD19-targeted CAR-T therapies have shown promising efficacy in treating B-cell malignancies. However, treatment-related toxicities, such as cytokine-release syndrome (CRS) and CAR T-cell-related encephalopathy syndrome (CRES), have been one of the major obstacles limiting the use of CAR-T therapies. How to minimize occurrence and severity of toxicity while maintaining efficacy is a major focus for T-cell therapies in development. ET019003 is a next generation CD19-targeted T-cell therapy developed by Eureka Therapeutics, built on the proprietary ARTEMISTM T-cell platform. The ET019003 construct is optimized with the co-expression of an ET190L1 Antibody-TCR (Xu et al, 2018) and novel co-stimulation molecule. We are conducting a First-in-human (FIH) study of ET019003 T cells in CD19+ r/r DLBCL patients. Methods: This FIH study aims to evaluate the safety and efficacy of ET019003 T-cell therapy in CD19+ patients with r/r DLBCL. As of July 2019, six subjects were administered ET019003 T cells. These subjects were pathologically confirmed with DLBCL that is CD19+ (by immunohistochemistry), whose disease have progressed or relapsed after 2-5 lines of prior therapies. All were high-risk patients with rapid tumor progression and heavy tumor burden. Each subject had a Ki67 proliferative index over 60%, 2/6 of the subjects had a Ki67 proliferative index over 90%. Moreover, 5/6 of the subjects had extra-nodal involvement. Following a 3-day preconditioning treatment with Fludarabine (25mg/m2/day)/ Cyclophosphamide (250mg/m2/day), patients received i.v. infusions of ET019003 T cells at an initial dose of 2-3×106 cells/kg. Additional doses at 3×106 cells/kg were administered at 14 to 30-day intervals. Adverse events were monitored and assessed based on CTCAE 5.0. Clinical responses were assessed based on Lugano 2014 criteria. Results: As of July 2019, six subjects have received at least one ET019003 T-cell infusion, and four subjects have received two or more ET019003 T-cell infusions. No Grade 2 or higher CRS was observed in the six subjects. One subject developed convulsions and cognitive disturbance. This subject had lymphoma invasion in the central nervous system before ET019003 T-cell therapy. The subject was treated with glucocorticoid and the symptoms resolved within 24 hours. Other adverse events included fever (6/6, 100%), fatigue (3/6, 50%), thrombocytopenia (3/6, 50%), diarrhea (2/6, 33%), and herpes zoster (1/6, 17%). ET019003 T-cell expansion in vivo (monitored by flow cytometry and qPCR) was observed in all six subjects after first infusion. The absolute peak value of detected ET019003 T cells ranged between 26,000 - 348,240 (median 235,500) per ml of peripheral blood. Tmax (time to reach the absolute peak value) was 6 - 14 days (median 7.5 days). For the four subjects who received multiple ET019003 T-cell infusions, the absolute peak values of detected ET019003 T cells after the second infusion were significantly lower than the absolute peak values achieved after the first infusion. For the two subjects who received three or more infusions of ET019003 T cells, no significant ET019003 T-cell expansion in vivo was observed after the third infusion. All six subjects completed the evaluation of clinical responses at 1 month after ET019003 T-cell therapy. All subjects responded to ET019003 T cells and achieved either a partial remission (PR) or complete response (CR). Conclusions: Preliminary results from six CD19+ r/r DLBCL patients in a FIH study show that ET019003 T-cell therapy is safe with robust in vivo T-cell expansion. The clinical study is on-going and we are monitoring safety as well as duration of response in longer follow-up. Reference: Xu et al. Nature Cell Discovery, 2018 Disclosures Liu: Eureka Therapeutics: Employment, Equity Ownership. Chang:Eureka Therapeutics: Equity Ownership. Liu:Eureka Therapeutics: Employment, Equity Ownership.

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