scholarly journals 139 Chimeric antigen receptor macrophages (CAR-M) elicit a systemic anti-tumor immune response and synergize with PD1 blockade in immunocompetent mouse models of HER2+ solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A148-A148
Author(s):  
Stefano Pierini ◽  
Michael Klichinsky ◽  
Rashid Gabbasov ◽  
Alison Worth ◽  
Ilyssa Ramos ◽  
...  
Keyword(s):  
Immune Response ◽  
Overall Survival ◽  
Immune System ◽  
Solid Tumors ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Adaptive Immune System ◽  
List Type ◽  
Epitope Spreading ◽  
Adaptive Immune

BackgroundDespite the remarkable efficacy achieved by CAR-T therapy in hematologic malignancies, application in solid tumors has been challenging. We previously developed human CAR-M and demonstrated that adoptive transfer of CAR-M into xenograft models of human cancer controls tumor progression and improves overall survival.1 Given that CAR-M are M1-polarized macrophages with the potential to remodel the tumor microenvironment (TME) and act as professional antigen presenting cells, we developed an immunocompetent animal model to evaluate the interaction of CAR-M with the TME and the adaptive immune system.MethodsMurine bone marrow-derived macrophages were engineered to express an anti-HER2 CAR using the chimeric adenoviral vector Ad5f35. To evaluate the safety and efficacy of CAR-M therapy, immunocompetent mice were engrafted with HER2+ tumors and treated with syngeneic CAR-M monotherapy or in combination with a PD1 blocking antibody. Tumors were collected at various time points and dynamic changes in the TME were assessed using flow cytometry, immunohistochemistry, and gene expression analysis.ResultsIn addition to efficient gene delivery, Ad5f35 transduction promoted a pro-inflammatory (M1) phenotype in murine macrophages. CAR-M, but not control macrophages, phagocytosed and killed HER2-overexpressing tumor cell lines. CAR-M induced MHC-I expression on tumor cells and enhanced the cytotoxicity of CD8+ T cells. In vivo, CAR-M led to significant tumor regression and improved overall survival in multiple syngeneic models. Analysis of the TME showed that CAR-M led to increased infiltration of intratumoral CD4+ and CD8+ T, NK, and dendritic cells – as well as an increase in T cell responsiveness to tumor-associated antigens, indicating enhanced epitope spreading. Given the impact of CAR-M on the endogenous adaptive immune system, we evaluated the combination of CAR-M with anti-PD1 in the CT26-HER2 model, which is resistant to anti-PD1 monotherapy, and found that the combination further reprogrammed the TME, enhanced tumor control, and improved overall survival compared to monotherapy with either agent. Mice that achieved complete responses (CRs) after CAR-M therapy were protected against antigen-negative relapse, indicating long-term anti-tumor immunity. Finally, the combination of CAR-M with anti-PD1 did not trigger sustained elevations of any serum analyte associated with cytokine release syndrome (CRS) and was well tolerated across numerous safety assessmentsConclusionsThese results demonstrate that CAR-M reprogram the TME, induce epitope spreading, and orchestrate a systemic immune response against solid tumors. Moreover, our findings provide rationale for the combination of CAR-M with immune checkpoint inhibitors for the treatment of solid tumors.ReferenceKlichinsky M, Ruella M, Shestova O, et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat Biotechnol 2020;38(8):947–953

132 CAR macrophages (CAR-M) elicit a systemic anti-tumor immune response and synergize with PD1 blockade in immunocompetent mouse models of HER2+ solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A145-A145
Author(s):  
Stefano Pierini ◽  
Rashid Gabbasov ◽  
Linara Gabitova ◽  
Yumi Ohtani ◽  
Michael Klichinsky
Keyword(s):  
Immune Response ◽  
Overall Survival ◽  
Animal Model ◽  
T Cell ◽  
Cancer Cells ◽  
Solid Tumors ◽  
Tumor Model ◽  
Epitope Spreading ◽  
Mhc I ◽  
Single Tumor

BackgroundDespite the remarkable efficacy achieved by CAR-T therapy in hematologic malignancies, application in solid tumors has been challenging. We previously developed human CAR-M and demonstrated that adoptive cell transfer of CAR-M into xenograft models of human cancer controls tumor progression and improves overall survival [1]. Given that CAR-M are professional antigen presenting cells, we developed an immunocompetent animal model to evaluate the potential for induction of a systemic anti-tumor immune response.MethodsMurine bone marrow-derived macrophages were engineered to express an anti-HER2 CAR using the chimeric adenoviral vector Ad5f35. CAR-M were phenotypically and functionally evaluated in vitro and in syngeneic models. To evaluate CAR-M efficacy in an immunocompetent animal model, BALB/c mice were engrafted with CT26-HER2+ tumors (single-tumor model) and were treated with intratumoral CAR-HER2 or untransduced (UTD) macrophages. To evaluate epitope spreading, we simultaneously engrafted BALB/c mice with CT26-HER2+ and CT26-Wt tumors on opposite flanks (dual-tumor model), and treated mice with CAR-M or controls into the CT26-HER2+ tumor only. Peripheral and tumor-infiltrating immune cells were phenotypically and functionally characterized.ResultsIn addition to efficient gene delivery, Ad5f35 transduction promoted a pro-inflammatory (M1) phenotype in murine macrophages. CAR-M, but not control UTD macrophages, phagocytosed HER2+ target cancer cells. Anti-HER2 CAR-M eradicated HER2+ murine CT26 colorectal and human AU-565 breast cancer cells in a dose-dependent manner. CAR-M increased MHC-I and MHC-II expression on tumor cells and promoted tumor-associated antigen presentation and T cell activation. In vivo, CAR-M treatment led to tumor regression and improved overall survival in the CT26-HER2+ single-tumor model. In the dual-tumor model, CAR-M treatment cleared 75% of CT26-HER2+ tumors and inhibited the growth rate of contralateral CT26-WT tumors, demonstrating an abscopal effect. CAR-M treatment led to increased infiltration of intratumoral CD4+ and CD8+ T, NK, and dendritic cells – as well as an increase in T cell responsiveness to the CT26 MHC-I antigen gp70, indicating enhanced epitope spreading. Given the impact CAR-M had on endogenous T-cell immunity, we evaluated the combination of CAR-M and anti-PD1 in the CT26-HER2 model and found that the combination further enhanced tumor control and overall survival.ConclusionsThese results demonstrate that CAR-M therapy induces epitope spreading via activation of endogenous T cells, orchestrating a systemic immune response against solid tumors. Moreover, our findings provide rationale for the combination of CAR-M with immune checkpoint inhibitors. The anti-HER2 CAR-M CT-0508 will be evaluated in an upcoming Phase I clinical trial.ReferenceKlichinsky M, Ruella M, Shestova O, et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat Biotechnol 2020;38(8):947–953.

scholarly journals Suppression of the Peripheral Immune System Limits the Central Immune Response Following Cuprizone-Feeding: Relevance to Modelling Multiple Sclerosis

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1314 ◽  
Author(s):  
Sen ◽  
Almuslehi ◽  
Gyengesi ◽  
Myers ◽  
Shortland ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune Response ◽  
Immune System ◽  
Adaptive Immune System ◽  
Synaptic Function ◽  
Adaptive Immune ◽  
Splenic Atrophy ◽  
The Impact ◽  
The Brain ◽  
Inside Out

Cuprizone (CPZ) preferentially affects oligodendrocytes (OLG), resulting in demyelination. To investigate whether central oligodendrocytosis and gliosis triggered an adaptive immune response, the impact of combining a standard (0.2%) or low (0.1%) dose of ingested CPZ with disruption of the blood brain barrier (BBB), using pertussis toxin (PT), was assessed in mice. 0.2% CPZ(±PT) for 5 weeks produced oligodendrocytosis, demyelination and gliosis plus marked splenic atrophy (37%) and reduced levels of CD4 (44%) and CD8 (61%). Conversely, 0.1% CPZ(±PT) produced a similar oligodendrocytosis, demyelination and gliosis but a smaller reduction in splenic CD4 (11%) and CD8 (14%) levels and no splenic atrophy. Long-term feeding of 0.1% CPZ(±PT) for 12 weeks produced similar reductions in CD4 (27%) and CD8 (43%), as well as splenic atrophy (33%), as seen with 0.2% CPZ(±PT) for 5 weeks. Collectively, these results suggest that 0.1% CPZ for 5 weeks may be a more promising model to study the ‘inside-out’ theory of Multiple Sclerosis (MS). However, neither CD4 nor CD8 were detected in the brain in CPZ±PT groups, indicating that CPZ-mediated suppression of peripheral immune organs is a major impediment to studying the ‘inside-out’ role of the adaptive immune system in this model over long time periods. Notably, CPZ(±PT)-feeding induced changes in the brain proteome related to the suppression of immune function, cellular metabolism, synaptic function and cellular structure/organization, indicating that demyelinating conditions, such as MS, can be initiated in the absence of adaptive immune system involvement.

scholarly journals Immune Regulation of Cancer

2010 ◽  
Vol 28 (29) ◽  
pp. 4531-4538 ◽  
Author(s):  
Mary L. Disis
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Adaptive Immune System ◽  
Tumor Stroma ◽  
Tissue Destruction ◽  
Cancer Proliferation ◽  
Patients With Cancer ◽  
Adaptive Immune ◽  
Improved Outcomes ◽  
Tumor Types

Innate and adaptive immune system cells play a major role in regulating the growth of cancer. Although it is commonly thought that an immune response localized to the tumor will inhibit cancer growth, it is clear that some types of inflammation induced in a tumor may also lead to cancer proliferation, invasion, and dissemination. Recent evidence suggests, however, that some patients with cancer can mount an antitumor immune response that has the potential to control or eliminate cancer. Indeed, a so-called “immune response” signature has been described in malignancy that is associated with improved outcomes in several tumor types. Moreover, the presence of specific subsets of T cells, which have the capability to penetrate tumor stroma and infiltrate deep into the parenchyma, identifies patients with an improved prognosis. Immune-based therapies have the potential to modulate the tumor microenvironment by eliciting immune system cells that will initiate acute inflammation that leads to tissue destruction.

scholarly journals Fierce selection and interference in B-cell repertoire response to chronic HIV-1

2018 ◽  
Author(s):  
Armita Nourmohammad ◽  
Jakub Otwinowski ◽  
Marta Łuksza ◽  
Thierry Mora ◽  
Aleksandra M Walczak
Keyword(s):  
Immune Response ◽  
Population Genetics ◽  
Immune System ◽  
B Cell ◽  
Adaptive Immune System ◽  
Clonal Interference ◽  
Cell Repertoire ◽  
Beneficial Mutations ◽  
Adaptive Immune ◽  
Hiv 1

AbstractDuring chronic infection, HIV-1 engages in a rapid coevolutionary arms race with the host’s adaptive immune system. While it is clear that HIV exerts strong selection on the adaptive immune system, the characteristics of the somatic evolution that shape the immune response are still unknown. Traditional population genetics methods fail to distinguish chronic immune response from healthy repertoire evolution. Here, we infer the evolutionary modes of B-cell repertoires and identify complex dynamics with a constant production of better B-cell receptor mutants that compete, maintaining large clonal diversity and potentially slowing down adaptation. A substantial fraction of mutations that rise to high frequencies in pathogen engaging CDRs of B-cell receptors (BCRs) are beneficial, in contrast to many such changes in structurally relevant frameworks that are deleterious and circulate by hitchhiking. We identify a pattern where BCRs in patients who experience larger viral expansions undergo stronger selection with a rapid turnover of beneficial mutations due to clonal interference in their CDR3 regions. Using population genetics modeling, we show that the extinction of these beneficial mutations can be attributed to the rise of competing beneficial alleles and clonal interference. The picture is of a dynamic repertoire, where better clones may be outcompeted by new mutants before they fix.

scholarly journals Quantitative Immunology for Physicists

2019 ◽  
Author(s):  
Grégoire Altan-Bonnet ◽  
Thierry Mora ◽  
Aleksandra M. Walczak
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Adaptive Immune System ◽  
Adaptive Immune ◽  
Self Organized

AbstractThe adaptive immune system is a dynamical, self-organized multiscale system that protects vertebrates from both pathogens and internal irregularities, such as tumours. For these reason it fascinates physicists, yet the multitude of different cells, molecules and sub-systems is often also petrifying. Despite this complexity, as experiments on different scales of the adaptive immune system become more quantitative, many physicists have made both theoretical and experimental contributions that help predict the behaviour of ensembles of cells and molecules that participate in an immune response. Here we review some recent contributions with an emphasis on quantitative questions and methodologies. We also provide a more general methods section that presents some of the wide array of theoretical tools used in the field.

scholarly journals Snippets of virus integrated into human genome suggests possibility of CRISPR-like adaptive immune system in human cells

2019 ◽  
Author(s):  
Wenfa Ng
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Human Genome ◽  
Adaptive Immune Response ◽  
Adaptive Immune System ◽  
Human Cells ◽  
Rna Seq ◽  
Viral Dna ◽  
Adaptive Immune ◽  
Foreign Dna

Snippets of virus that infect humans have been shown to be incorporated into the human genome. Could such virus snippets provide a form of adaptive immunity similar to that offered by CRISPR to bacterial cells? To answer the question, RNA-seq could be used to provide a broad view of the RNA transcribed from DNA in the genome. Using known genome sequence of viruses that infect humans as template, reads obtained from RNA-seq would be profiled for virus snippets integrated into human genome and subsequently transcribed as part of an adaptive immune system. Subsequently, viruses corresponding to the virus snippets in human genome would be used to infect human cell lines to obtain direct evidence of how virus snippets mediate an adaptive immune response at the cellular level. Specifically, successful defence of the cell by virus snippets triggering an adaptive immune response would manifest as viable cells compared to lysed cells unable to mount an immune response. Following demonstration of cell viability under viral challenge, in vitro biochemical assays using cell lysate would interrogate the specific proteins and enzymes that mediate possible cutting of the foreign DNA or RNA. To this end, beads immobilized with virus snippets would serve as bait for binding to complementary viral DNA or RNA as well as potential endogenous endonuclease protein. Following precipitation and recovery of beads, possible endonuclease that bind to both viral DNA or RNA and virus snippets immobilized on beads would be isolated through gel electrophoresis and subsequently purified. Purified endonuclease would be assayed for activity against a variety of nucleic acids (both DNA and RNA) from various sources with and without added virus snippets. This provides important information on substrate range and specificity of the potential endonuclease. Amino acid sequencing of the purified endonuclease would help downstream bioinformatic search for candidate protein in the human genome. Finally, cryo-electron microscopy could help determine the structure of the endonuclease in complex with viral nucleic acids and virus snippets. Such structural information would provide more insights into mechanistic details describing the binding and cleavage of viral DNA or RNA in a CRISPR-like adaptive immune response in human cells. Overall, tantalizing clues have emerged that a CRISPR-like adaptive immune response may exist in human cells for defending against viral attack. Combination of cell biological, biochemical and structural tools could lend insights into the potential endonuclease that mediate double strand break of foreign DNA or RNA using virus snippets transcribed from the human genome as guide RNA. If demonstrated to be true for a variety of human viruses across different cell lines, the newly discovered viral defence mechanism in human cells hold important implications for understanding the adoption and evolution of CRISPR in eukaryotic cells.

Role of non-resident subpopulations of mucosal and adaptive immune systems in patients with chronic periodontitis

2021 ◽  
Vol 1 (30) ◽  
pp. 61-66
Author(s):  
V. P. Mudrov ◽  
N. V. Davidova ◽  
S. P. Kazakov ◽  
T. E. Mishina
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Chronic Periodontitis ◽  
Periodontal Diseases ◽  
Single Cells ◽  
Adaptive Immune Response ◽  
Adaptive Immune System ◽  
Quantitative Composition ◽  
Adaptive Immune ◽  
Hla Dr

Periodontal bacterial bioflm causes an innate and adaptive immune response of the host mucosa, leading to inflammation and destruction of the tissues supporting the periodontal. The progression of periodontitis depends not only on bacteria, since an inadequate immune response to microorganisms can accelerate the development of periodontitis. However, the exact mechanisms of the development of immune reactions remain unclear. Recent studies emphasize the existence of a typical innate response of resident and extravasated immune cells.Objective. To investigate the quantitative composition of non-resident subpopulations of lymphocytes in salivary fluid and to study the mechanisms of interaction of the cellular link of the innate and adaptive immune system in chronic generalized periodontitis of varying severity.Materials and methods. 49 people aged 26–67 years of both sexes were examined with a diagnosis of chronic periodontitis. The comparison group consisted of 17 people aged 26–44 years with no periodontal diseases. The state of the cellular link of the adaptive and local immune system of the oral cavity was assessed by the following phenotypes: CD3–CD16+56+; CD3+CD16+56+; CD3+; CD3+HLA-DR+; CD19+, CD19+HLA-DR+; CD19+CD5+CD27–; CD19+CD5–СD 27–; CD19+СD5–CD27+.Results. The number of T-NK cells decreased with a mild degree of periodontitis and increased with a severe degree. Similarly, CD3+HLA-DR+ decreased with mild periodontitis [Me = 0.148 cells/µl] and increased with moderate [Me = 0.247 cells/µl] and severe [Me = 0.448 cells/µl]. The number of B-lymphocytes with the CD19+, CD19+CD5+, CD19+CD5–CD27+ phenotype decreased to single cells per microliter during the development of the disease.Conclusion. The imbalance of the immune system caused by pathogenic colonization of the periodontium, at different degrees of severity, is an important factor in the occurrence and development of periodontitis, in which various subsets of B cells of the adaptive immune system play a certain role, closely interacting with the cellular link of the innate mucosal immune system

Basic Immunology

2019 ◽  
Author(s):  
Jonathan Lambourne ◽  
Ruaridh Buchanan
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Epithelial Cells ◽  
Immune Cells ◽  
Innate Immune System ◽  
Adaptive Immune System ◽  
Lymphoid Organs ◽  
Innate Immune ◽  
Adaptive Immune ◽  
Pathogen Entry

There are four major components of the immune system. These include: 1. mechanical barriers to pathogen entry. 2. the innate immune system. 3. the adaptive immune system. 4. the lymphoid organs. Mechanical barriers include skin and mucous membranes and tight junctions between epithelial cells prevent pathogen entry. Breaches can be iatrogenic, for example, IV lines, surgical wounds, and mucositis, and are a large source of healthcare- associated infections. The innate immune system provides the first internal line of defence, as well as initiating and shaping the adaptive immune response. The innate system comprises a range of responses: phagocytosis by neutrophils and macrophages (guided in part by the adaptive immune system), the complement cascade, and the release of antimicrobial peptides by epithelial cells (e.g. defensins, cathelicidin). The adaptive immune system includes both humoral (antibody- mediated) and cell-mediated responses. It is capable of greater diversity and specificity than the innate immune system, and can develop memory to pathogens and provide increased protection on re-exposure. Immune cells are divided into myeloid cells (neutrophils, eosinophils, basophils, mast cells, and monocytes/macrophages) and lymphoid cells (B, T, and NK cells). These all originate in the bone marrow from pluripotent haematopoietic stem cells. The lymphoid organs include the spleen, the lymph nodes, and mucosal-associated lymphoid tissues—which respond to antigens in the blood, tissues, and epithelial surfaces respectively. The three main ‘professional’ phagocytes are macrophages, dendritic cells, and neutrophils. They are similar with respect to how they recognize pathogens, but differ in their principal location and effector functions. Phagocytes express an array of Pattern Recognition Receptors (PRRs) e.g. Toll-like receptors and lectins (proteins that bind carbohydrates). PRRs recognize Pathogen- Associated Molecular Patterns (PAMPs)— elements which are conserved across species, such as cell-surface glycoproteins and nucleic acid sequences. Though limited in number, PRRs have evolved to recognize a huge array of pathogens. Binding of PRRs to PAMPs enhances phagocytosis. Macrophages are tissue-resident phagocytes, initiating and co-ordinating the local immune response. The cytokines and chemokines they produce cause vasodilation and alter the expression of endothelial cell adhesion factors, recruiting circulating immune cells.

Polymer Nanoparticles Regulate Macrophage Repolarization for Antitumor Treatment

2021 ◽  
Author(s):  
Xuancheng Fu ◽  
Jiamu Yu ◽  
Anran Yuan ◽  
Libing Liu ◽  
Hao Zhao ◽  
...  
Keyword(s):  
Immune System ◽  
Cancer Cells ◽  
Solid Tumors ◽  
Therapeutic Strategy ◽  
Adaptive Immune System ◽  
Polymer Nanoparticles ◽  
Next Generation ◽  
Adaptive Immune ◽  
Immunosuppressive Microenvironment

Immunotherapy regarded as the next generation cancer therapeutic strategy could activate the innate or adaptive immune system for specific eliminating cancer cells, but limited by immunosuppressive microenvironment inside solid tumors....

Graphene Oxide Modulates B Cell Surface Phenotype and Impairs Immunoglobulin Secretion in Plasma Cell

2016 ◽  
Vol 16 (4) ◽  
pp. 4205-4215 ◽  
Author(s):  
Shaohai Xu ◽  
Shengmin Xu ◽  
Shaopeng Chen ◽  
Huadong Fan ◽  
Xun Luo ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Graphene Oxide ◽  
Immune System ◽  
Cell Surface ◽  
B Cell ◽  
Plasma Cell ◽  
Adaptive Immune System ◽  
Surface Phenotype ◽  
Adaptive Immune

Since discovery, graphene oxide (GO) has been used in all aspects of human life and revealed promising applications in biomedicine. Nevertheless, the potential risks of GO were always being revealed. Although GO was found to induce immune cell death and innate immune response, little is known regarding its toxicity to the specific adaptive immune system that is crucial for protecting against exotic invasion. The B-cell mediated adaptive immune system, which composed of highly specialized cells (B and plasma cell) and specific immune response (antibody response) is the focus in our present study. Using diverse standard immunological techniques, we found that GO modulated B cell surface phenotype, both costimulatory molecules (CD80, CD86 and especially CD40) and antigen presenting molecules (both classical and nonclassical) under the condition without causing cell death. Meanwhile, the terminal differentiated immunoglobulin (Ig) secreting plasma cell was affected by GO, which displayed a less secretion of Ig and more severe ER stress caused by the retention of the secreted form of Ig in cell compartment. The combined data reveal that GO has a particular adverse effect to B cell and the humoral immunity, directly demonstrating the potential risk of GO to the specific adaptive immunity.

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