scholarly journals A Mathematical Model for Controlling Exchanged Spinor Waves between Hemoglobin, Tumor and T-Cells

Mathematics ◽  
2021 ◽  
Vol 9 (24) ◽  
pp. 3310
Author(s):  
Massimo Fioranelli ◽  
Alireza Sepehri ◽  
Maria Grazia Roccia ◽  
Aroonkumar Beesham ◽  
Dana Flavin
Keyword(s):  
Mathematical Model ◽  
T Cells ◽  
Blood Vessels ◽  
Tumor Cells ◽  
Large Distance ◽  
Blood Cells ◽  
Electronic Devices ◽  
Brain Cells ◽  
Heart Cells ◽  
Biological Cells

To date, it is known that tumor cells respond to attacks of T-cells by producing some PD-1/PD-L1 and other connections. Unfortunately, medical methods for preventing these connections are expensive and sometimes non-effective. In this study, we suggest a new way for reducing these connections by producing some noise in the exchanged information between tumor cells, T-cells, hemoglobin, and controller cells such as those of the heart or brain. In this model, we assume that human cells use spinor waves for exchanging information because the velocity of exchanged information between two spinors, which are located a large distance apart, exceeds the velocity of light. In fact, two spinors could send and receive information from each other instantaneously. In this hypothesis, the DNAs within heart cells, brain cells or any controller are built from some spinors such as electrons, and by their motion, some waves are generated. These spinor waves are received by iron atoms and multi-gonal molecules within hemoglobin and other spinors within the blood vessels. The hemoglobin molecules are located on some blood cells, move along the blood vessels and pass on their information to cells, proteins and RNAs. The spins of the spinors within the hemoglobin and also the spins of the charges and ions within the blood vessels are entangled and could transmit any information between cells. Thus, when a tumor is formed, its spinor waves change, and are transmitted rapidly into the heart cells, brain cells and other controller cells. The heart, brain or other controller cells diagnose these quantum waves, and by using the entanglement between the spinors within the blood vessels and the hemoglobin, send some messages to the T-cells. These messages are received by tumor cells and they become ready to respond to attacks. To prevent the reception of information by tumor cells, we can make use of some extra cells or hemoglobin, which interact with spinors and hemoglobin around tumor cells and produce some noise. Science quantum spinor waves are minute and have minor power and intensity; we cannot detect them by our present electronic devices and for this reason, we suggest using biological cells. This is a hypothesis; however, if experiments show its validity, some types of cancers could be cured or controlled by this method. We formulate the model by considering quantum entanglement between spinors within biological systems. By changing any spin within this system, all spins change and consequently, information is transmitted immediately. Then, we add new spinors to this system mathematically, and show that this causes the correlations between the initial spinors to reduce. Thus, the spinors of the extra hemoglobin or cells could act like noise, and prevent reception of real information by tumor cells.

scholarly journals Clonal origin of a T cell lymphoproliferative malignancy

Blood ◽  
1978 ◽  
Vol 52 (1) ◽  
pp. 69-76 ◽  
Author(s):  
PA Stryckmans ◽  
L Debusscher ◽  
C Heyder-Bruckner ◽  
R Heimann ◽  
IM Mandelbaum ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Red Blood Cells ◽  
Tumor Cells ◽  
Blood Cells ◽  
Mononuclear Cells ◽  
Polymorphonuclear Cells ◽  
Clonal Origin ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Cell Malignancy

Abstract A woman with a T cell lymphoproliferative malignacy and heterozhgosity at the X chromosome-linked locus for glucose-6-phosphate dehydrogenase (G-6PD) isoenzymes was studied to find the clonal origin of her circulating neoplastic T cells. The red blood cells, polymorphonuclear cells, whole mononuclear cells, and T cell-depleted mononuclear cells contained both A and B isoenzymes of G-6-PD. In contrast, the tumor cells, separated by using their capacity to form rosettes with sheep red blood cells, contained only the B isoenzyme of G-6-PD. This observation strongly suggests the monoclonality of this T cell malignancy.

scholarly journals Clonal origin of a T cell lymphoproliferative malignancy

Blood ◽  
1978 ◽  
Vol 52 (1) ◽  
pp. 69-76
Author(s):  
PA Stryckmans ◽  
L Debusscher ◽  
C Heyder-Bruckner ◽  
R Heimann ◽  
IM Mandelbaum ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Red Blood Cells ◽  
Tumor Cells ◽  
Blood Cells ◽  
Mononuclear Cells ◽  
Polymorphonuclear Cells ◽  
Clonal Origin ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Cell Malignancy

A woman with a T cell lymphoproliferative malignacy and heterozhgosity at the X chromosome-linked locus for glucose-6-phosphate dehydrogenase (G-6PD) isoenzymes was studied to find the clonal origin of her circulating neoplastic T cells. The red blood cells, polymorphonuclear cells, whole mononuclear cells, and T cell-depleted mononuclear cells contained both A and B isoenzymes of G-6-PD. In contrast, the tumor cells, separated by using their capacity to form rosettes with sheep red blood cells, contained only the B isoenzyme of G-6-PD. This observation strongly suggests the monoclonality of this T cell malignancy.

Receptor Mediated Binding of the Fibrinolytic Components, Plasminogen and Urokinase, to Peripheral Blood Cells

1987 ◽  
Vol 58 (03) ◽  
pp. 936-942 ◽  
Author(s):  
Lindsey A Miles ◽  
Edward F Plow
Keyword(s):  
T Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Binding Sites ◽  
Blood Cells ◽  
High Capacity ◽  
Red Cells ◽  
Peripheral Blood Cells ◽  
Cellular Functions ◽  
Fibrinolytic Proteins

SummaryGlu-plasminogen binds to platelets; the monocytoid line, U937, and the human fetal fibroblast line, GM1380 bind both plasminogen and its activator, urokinase. This study assesses the interaction of these fibrinolytic proteins with circulating human blood cells. Plasminogen bound minimally to red cells but bound saturably and reversibly to monocytes, granulocytes and lymphocytes with apparent Kd values of 0.9-1.4 μM. The interactions were of high capacity with 1.6 to 49 × 105 sites/cell and involved the lysine binding sites of plasminogen. Both T cells and non-rosetting lymphocytes and two B cell lines saturably bound plasminogen. Urokinase bound saturably to gianulocytes, monocytes, non-rosetting lymphocytes and a B cell line, but minimally to T cells, platelets and red cells. Therefore, plasminogen binding sites of high capacity, of similar affinities, and with common recognition specificities are expressed by many peripheral blood cells. Urokinase receptors are also widely distributed, but less so than plasminogen binding sites. The binding ol plasminogen and/ or urokinase to these cells may lead to generation of cell- associated proteolytic activity which contributes to a variety of cellular functions.

scholarly journals Deep immune profiling reveals targetable mechanisms of immune evasion in immune checkpoint inhibitor-refractory glioblastoma

2021 ◽  
Vol 9 (6) ◽  
pp. e002181
Author(s):  
Erin F Simonds ◽  
Edbert D Lu ◽  
Oscar Badillo ◽  
Shokoufeh Karimi ◽  
Eric V Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Immune Evasion ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Prolonged Survival ◽  
Tumor Associated Macrophages ◽  
The Brain ◽  
Immune Profiling

BackgroundGlioblastoma (GBM) is refractory to immune checkpoint inhibitor (ICI) therapy. We sought to determine to what extent this immune evasion is due to intrinsic properties of the tumor cells versus the specialized immune context of the brain, and if it can be reversed.MethodsWe used CyTOF mass cytometry to compare the tumor immune microenvironments (TIME) of human tumors that are generally ICI-refractory (GBM and sarcoma) or ICI-responsive (renal cell carcinoma), as well as mouse models of GBM that are ICI-responsive (GL261) or ICI-refractory (SB28). We further compared SB28 tumors grown intracerebrally versus subcutaneously to determine how tumor site affects TIME and responsiveness to dual CTLA-4/PD-1 blockade. Informed by these data, we explored rational immunotherapeutic combinations.ResultsICI-sensitivity in human and mouse tumors was associated with increased T cells and dendritic cells (DCs), and fewer myeloid cells, in particular PD-L1+ tumor-associated macrophages. The SB28 mouse model of GBM responded to ICI when grown subcutaneously but not intracerebrally, providing a system to explore mechanisms underlying ICI resistance in GBM. The response to ICI in the subcutaneous SB28 model required CD4 T cells and NK cells, but not CD8 T cells. Recombinant FLT3L expanded DCs, improved antigen-specific T cell priming, and prolonged survival of mice with intracerebral SB28 tumors, but at the cost of increased Tregs. Targeting PD-L1 also prolonged survival, especially when combined with stereotactic radiation.ConclusionsOur data suggest that a major obstacle for effective immunotherapy of GBM is poor antigen presentation in the brain, rather than intrinsic immunosuppressive properties of GBM tumor cells. Deep immune profiling identified DCs and PD-L1+ tumor-associated macrophages as promising targetable cell populations, which was confirmed using therapeutic interventions in vivo.

scholarly journals Immunomodulating nano-adaptors potentiate antibody-based cancer immunotherapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Cheng-Tao Jiang ◽  
Kai-Ge Chen ◽  
An Liu ◽  
Hua Huang ◽  
Ya-Nan Fan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cancer Immunotherapy ◽  
Tumor Cells ◽  
Noncovalent Interactions ◽  
Killer Cell ◽  
Antibody Immobilization ◽  
Effector Cells ◽  
Nanoparticle Surface

AbstractModulating effector immune cells via monoclonal antibodies (mAbs) and facilitating the co-engagement of T cells and tumor cells via chimeric antigen receptor- T cells or bispecific T cell-engaging antibodies are two typical cancer immunotherapy approaches. We speculated that immobilizing two types of mAbs against effector cells and tumor cells on a single nanoparticle could integrate the functions of these two approaches, as the engineered formulation (immunomodulating nano-adaptor, imNA) could potentially associate with both cells and bridge them together like an ‘adaptor’ while maintaining the immunomodulatory properties of the parental mAbs. However, existing mAbs-immobilization strategies mainly rely on a chemical reaction, a process that is rough and difficult to control. Here, we build up a versatile antibody immobilization platform by conjugating anti-IgG (Fc specific) antibody (αFc) onto the nanoparticle surface (αFc-NP), and confirm that αFc-NP could conveniently and efficiently immobilize two types of mAbs through Fc-specific noncovalent interactions to form imNAs. Finally, we validate the superiority of imNAs over the mixture of parental mAbs in T cell-, natural killer cell- and macrophage-mediated antitumor immune responses in multiple murine tumor models.

108 MCY-M11, a CAR-PBMC cell product transiently expressing a mesothelin targeted mRNA CAR, exhibits desirable functional and immune phenotype attributed to sustained antitumor immunity in vitro

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A120-A120
Author(s):  
Sashi Kasimsetty ◽  
Himavanth Gatla ◽  
Dhana Chinnasamy
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Antitumor Immunity ◽  
Memory T Cells ◽  
Cell Populations ◽  
Epitope Spreading ◽  
Antitumor Response ◽  
Cell Product

BackgroundMCY-M11, an anti-mesothelin CAR (Meso-CAR) mRNA transfected PBMC cell product manufactured through <1 day-process is under clinical evaluation for the treatment of advanced ovarian cancer and peritoneal mesothelioma. In this in-vitro study, we characterized the phenotypic and functional status of immune cell populations in MCY-M11 and their possible role in antitumor immunity.MethodsMCY-M11 cell product were generated using unmanipulated healthy donor PBMCs (n=5) by transfection of Meso-CAR mRNA using MaxCyte’s proprietary Flow Electroporation® system. Frozen MCY-M11 cell product was thawed and cultured for 18 hours, then co-cultured with hMSLNneg or hMSLNpos human mesothelioma cell line, MSTO-211H, or stimulated with anti-CD3/anti-CD28 antibodies in vitro for 8 days. Distinct cell populations in MCY-M11 were evaluated for kinetics and duration of CAR expression, differentiation, activation, exhaustion, and their ability to secrete various immunomodulatory molecules during in vitro stimulation. Antigen-specific proliferation and cytotoxicity of MCY-M11 against hMSLNpos tumor cells as well as their ability to mount long-term antitumor immunity through epitope spreading mechanisms were studied.ResultsIndividual cell populations in MCY-M11 exhibited a consistent but transient Meso-CAR expression persisting for about 7 days. Cell subsets in MCY-M11 acquired early signs of activation and differentiation within 18–24 hours post-culture, but only attained full activation and lineage-specific differentiation upon specific response to hMSLNpos tumor cells. hMSLN antigen experienced MCY-M11 retained significant fractions of Naïve and Central Memory T cells and increased percentage of Effector Memory T cells along with increased expression of CD62L, CD27, and chemokine receptors (CCR5, CCR7, and CXCR3). MCY-M11 exhibited strong antigen-specific cytotoxicity against hMSLNpos tumor cells with corresponding increase in activation and proliferation of CD4+ and CD8+ T cell subsets and displayed low or no acquisition of known exhaustion markers. NK cells also exhibited a functionally superior molecular signature exhibiting increased levels of NKG2D, NKp44, NKp46, FAS, and TRAIL. The Monocytes and B cells in MCY-M11 also acquired an activated, differentiated, and mature phenotype, expressing molecules required for antigen presentation (HLA-DR, HLA-ABC, and CD205) and T cell co-stimulation (CD80 and CD86) to mount a strong antitumor response. These phenotypic changes in cell subsets of MCY-M11 transpired with simultaneous secretion of potent immunostimulatory molecules and chemokines facilitating an extended antitumor response through epitope spreading.ConclusionsWe demonstrated that MCY-M11 is a unique cell product possessing a complete built-in immune cellular machinery with favorable phenotype and enhanced functions specialized in mediating an effective and long-term antitumor response.Trial RegistrationNCT03608618

scholarly journals CARTmath—A Mathematical Model of CAR-T Immunotherapy in Preclinical Studies of Hematological Cancers

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2941
Author(s):  
Luciana R. C. Barros ◽  
Emanuelle A. Paixão ◽  
Andrea M. P. Valli ◽  
Gustavo T. Naozuka ◽  
Artur C. Fassoni ◽  
...  
Keyword(s):  
Mathematical Model ◽  
T Cells ◽  
T Cell ◽  
Mouse Models ◽  
In Silico ◽  
Car T Cells ◽  
Car T Cell ◽  
Cell Immunotherapy ◽  
Car T ◽  
T Cell Immunotherapy

Immunotherapy has gained great momentum with chimeric antigen receptor T cell (CAR-T) therapy, in which patient’s T lymphocytes are genetically manipulated to recognize tumor-specific antigens, increasing tumor elimination efficiency. In recent years, CAR-T cell immunotherapy for hematological malignancies achieved a great response rate in patients and is a very promising therapy for several other malignancies. Each new CAR design requires a preclinical proof-of-concept experiment using immunodeficient mouse models. The absence of a functional immune system in these mice makes them simple and suitable for use as mathematical models. In this work, we develop a three-population mathematical model to describe tumor response to CAR-T cell immunotherapy in immunodeficient mouse models, encompassing interactions between a non-solid tumor and CAR-T cells (effector and long-term memory). We account for several phenomena, such as tumor-induced immunosuppression, memory pool formation, and conversion of memory into effector CAR-T cells in the presence of new tumor cells. Individual donor and tumor specificities are considered uncertainties in the model parameters. Our model is able to reproduce several CAR-T cell immunotherapy scenarios, with different CAR receptors and tumor targets reported in the literature. We found that therapy effectiveness mostly depends on specific parameters such as the differentiation of effector to memory CAR-T cells, CAR-T cytotoxic capacity, tumor growth rate, and tumor-induced immunosuppression. In summary, our model can contribute to reducing and optimizing the number of in vivo experiments with in silico tests to select specific scenarios that could be tested in experimental research. Such an in silico laboratory is an easy-to-run open-source simulator, built on a Shiny R-based platform called CARTmath. It contains the results of this manuscript as examples and documentation. The developed model together with the CARTmath platform have potential use in assessing different CAR-T cell immunotherapy protocols and its associated efficacy, becoming an accessory for in silico trials.

scholarly journals Beyond the Lactate Paradox: How Lactate and Acidity Impact T Cell Therapies against Cancer

Antibodies ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 25
Author(s):  
Violet Y. Tu ◽  
Asma Ayari ◽  
Roddy S. O’Connor
Keyword(s):  
T Cells ◽  
Lactic Acid ◽  
T Cell ◽  
Tumor Cells ◽  
Cell Biology ◽  
Redox Balance ◽  
Hematologic Malignancies ◽  
Activated T Cells ◽  
Unique Challenge ◽  
Cell Therapies

T cell therapies, including CAR T cells, have proven more effective in hematologic malignancies than solid tumors, where the local metabolic environment is distinctly immunosuppressive. In particular, the acidic and hypoxic features of the tumor microenvironment (TME) present a unique challenge for T cells. Local metabolism is an important consideration for activated T cells as they undergo bursts of migration, proliferation and differentiation in hostile soil. Tumor cells and activated T cells both produce lactic acid at high rates. The role of lactic acid in T cell biology is complex, as lactate is an often-neglected carbon source that can fuel TCA anaplerosis. Circulating lactate is also an important means to regulate redox balance. In hypoxic tumors, lactate is immune-suppressive. Here, we discuss how intrinsic- (T cells) as well as extrinsic (tumor cells and micro-environmental)-derived metabolic factors, including lactate, suppress the ability of antigen-specific T cells to eradicate tumors. Finally, we introduce recent discoveries that target the TME in order to potentiate T cell-based therapies against cancer.

12 Development of an in vitro assay to assess bispecific T cell engager using T cells from CD3e humanized mice

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A12-A12
Author(s):  
Jun Zhou ◽  
Shuang Zhu ◽  
Hongjuan Zhang ◽  
Lei Zheng ◽  
Mingfa Zang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Lymphoblastic Leukemia ◽  
Humanized Mice ◽  
Activation Markers ◽  
In Vivo Models ◽  
Vitro Assay ◽  
Bite Antibody

BackgroundBispecific T cell engagers (BiTE) is a fast-growing class of immunotherapies. They are bispecific antibody that bind to T cell-surface protein (for example, CD3e) and a specific tumor associate antigen (TAA) on tumor cells, by which to redirect T cells against tumor cells in a MHC-independent manner. A successful example in the clinical is Blinatumomab, a BiTE antibody against CD3/CD19 approved in 2014 to treat acute lymphoblastic leukemia. Currently, many CD3-based BiTE are in clinical trials, including BCMAxCD3, Her2xCD3, CEAxCD3, and PSMAxCD3. To evaluate the efficacy of BiTE in vitro, human peripheral blood monocyte cells (hPBMC) are commonly being used as a source of T cells to co-culture with tumor cells. The disadvantage of using hPBMC is donor-to-donor variability and the availability of the original donor if a study needs to be repeated.MethodsTo overcome this, we proposed to replace hPBMC with T cells from human CD3e (hCD3) genetically engineered mouse models mice (GEMM) for in in vitro coculture assay. T cells were isolated from hCD3 GEMM mice using negative selection mouse T cell isolation kit. Conventional tumor cell lines or luciferase-engineered patient-derived-xenograft (PDX)-derived organoids (PDXO) expressing specific antigens are co-cultured with hCD3 T cells in 96-well plates in the presence of BiTE antibody.ResultsWe measured the killing of tumor cells using either flow cytometry or luciferase activity as readouts. To analyze tumor-reactivity of T cells to cancer cell line or organoids, IFN-gamma in the culture medium was measured and activation markers on T cells was assessed.ConclusionsOur data showed the feasibility of using humanized mice T cells as a replacement for hPBMCs to assess BiTE antibody in vitro. We are further validating the application of murine hCD3 T cells for in vivo models to test bispecific T cell engagers.

scholarly journals Single-cell evaluation reveals shifts in the tumor-immune niches that shape and maintain aggressive lesions in the breast

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Vidya C. Sinha ◽  
Amanda L. Rinkenbaugh ◽  
Mingchu Xu ◽  
Xinhui Zhou ◽  
Xiaomei Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Mouse Model ◽  
Transition State ◽  
Tumor Cell ◽  
Single Cell ◽  
Tumor Cells ◽  
Breast Lesions ◽  
Aggressive Tumor ◽  
Insight Into

AbstractThere is an unmet clinical need for stratification of breast lesions as indolent or aggressive to tailor treatment. Here, single-cell transcriptomics and multiparametric imaging applied to a mouse model of breast cancer reveals that the aggressive tumor niche is characterized by an expanded basal-like population, specialization of tumor subpopulations, and mixed-lineage tumor cells potentially serving as a transition state between luminal and basal phenotypes. Despite vast tumor cell-intrinsic differences, aggressive and indolent tumor cells are functionally indistinguishable once isolated from their local niche, suggesting a role for non-tumor collaborators in determining aggressiveness. Aggressive lesions harbor fewer total but more suppressed-like T cells, and elevated tumor-promoting neutrophils and IL-17 signaling, disruption of which increase tumor latency and reduce the number of aggressive lesions. Our study provides insight into tumor-immune features distinguishing indolent from aggressive lesions, identifies heterogeneous populations comprising these lesions, and supports a role for IL-17 signaling in aggressive progression.

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