scholarly journals INTRODUCTION: Immune Relevant Animal Models: Opportunities and Challenges

ILAR Journal ◽  
2018 ◽  
Vol 59 (3) ◽  
pp. 209-210
Author(s):  
Gregers Jungersen ◽  
Jorge Piedrahita
Keyword(s):  
Immune System ◽  
T Cell ◽  
Animal Models ◽  
Infectious Diseases ◽  
Tissue Specific ◽  
Car T Cell ◽  
Car T ◽  
Preclinical Animal Models

Abstract Valid interpretation of preclinical animal models in immunology-related clinical challenges is important to solve outstanding clinical needs. Given the overall complexity of the immune system and both species- and tissue-specific immune peculiarities, the selection and design of appropriate immune-relevant animal models is, however, not following a straightforward path. The topics in this issue of the ILAR Journal provide assessments of immune-relevant animal models used in oncology, hematopoietic-, CAR-T cell- and xenotransplantation, adjuvants and infectious diseases, and immune privileged inflammation that are providing key insights into unmet human clinical needs.

scholarly journals Multifaceted Role of the Transforming Growth Factor β on Effector T Cells and the Implication for CAR-T Cell Therapy

Immuno ◽  
2021 ◽  
Vol 1 (3) ◽  
pp. 160-173
Author(s):  
Apolline de Folmont ◽  
Jean-Henri Bourhis ◽  
Salem Chouaib ◽  
Stéphane Terry
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Cell Therapy ◽  
Host Immune System ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Evading the immune system is one of the hallmarks of cancer. Tumors escape anti-tumor immunity through cell-intrinsic means and the assembly of an immunosuppressive tumor microenvironment. By significantly boosting the host immune system, cancer immunotherapies targeting immune checkpoint receptors (CTLA-4 and PD-1) improved survival in patients even with cancers previously considered rapidly fatal. Nevertheless, an important group of patients is refractory or relapse rapidly. The factors involved in the heterogeneous responses observed are still poorly understood. Other immunotherapeutic approaches are being developed that may widen the options, including adoptive cell therapy using CAR-T cells alone or in combination. Despite impressive results in B cell malignancies, many caveats and unanswered questions remain in other cancers, thus limiting the potential of this approach to treat aggressive diseases. In particular, a complex TME could impair the survival, proliferation, and effector functions of CAR-T cells. Recent reports highlight the potential of targeting TGF-β signaling to improve CAR-T cell therapy. TGF-β is a well-known regulatory cytokine with pleiotropic effects in the TME, including immunosuppression. This review summarizes recent work investigating the potential effects of TGF-β within the TME, with a focus on CAR-T behavior and efficacy. We also discuss several key questions to be addressed to accelerate clinical translation of this approach.

scholarly journals Changes of T Lymphocyte Subsets after CAR-T Cell Therapy and Its Clinical Significance

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1423-1423
Author(s):  
Lijuan Ding ◽  
Jiazhen Cui ◽  
Yongxian Hu ◽  
Huijun Xu ◽  
Yanlei Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
T Lymphocyte ◽  
The Body ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Introduction: In tumor cell immunity, T cells play a central regulatory role. T cells are divided into several major subsets based on different cell surface molecules to maintain the body's immune balance. Detection of T lymphocyte expression levels can assist in the dynamic analysis of changes in cellular immune function during treatment. CAR-T cell therapy is one of the most promising immune therapies in recent years. The current research focuses on the immune function of CAR-T cells, while ignoring the changes in the body immune system itself. In fact, the body's immune function plays an important role in the anti-tumor immune response, and the changes in the body immune system are likely to be the main reason of long-term maintenance of remission after CAR-T cells exhausted. In our study, we detect the changes of T lymphocyte subsets after CAR-T cell infusion, to explore the effect of CAR-T cell therapy on body immune system and its possible mechanism. Methods: Peripheral blood of 10 patients after CAR-T cell therapy at different time points were collected. Flow cytometry was used to detect lymphocyte surface molecules including CD3, CAR, CD4, CD8, CD45RA and CCR7 in the scatter plot. T lymphocyte populations were isolated and the ratio of CAR+ and CAR- cells was labeled, and cell subpopulations were labeled in CAR+ and CAR-cells, respectively. Statistical analysis was performed using the R-Studio software package. When comparing the proportion of T cell subsets at different time points, repeated measures of variance analysis were used. Results: 10 patients with good clinical response and complete data were analyzed and summarized. The proportion of CD8+ cells in CAR+ cell population was (61.4±32.5) % at the initial of CRS, and went up to (74.1±24.5) % as CAR-T cells proliferated to a peak level. After that, CD8+ cells began to decline as CAR-T cells decreased (F= 0.647, P= 0.531). The changes of CD4+ cells went the opposite way (F= 2.678, P= 0.087). The same change patterns of CD8+ and CD4+ cells were shared in CAR- cell population. In CAR+, CAR+CD4+, CAR+CD8+ cell populations, CD45RA+CCR7- cells (effector T cells) have decreased before CAR-T cell peak level. We assumed that effector T cells began to decrease as tumor cells were completely cleared. CD45RA-CCR7-, CD45RA-CCR7+, CD45RA+CCR7+ cells (effector memory T cells, central memory T cells, naïve T cells) gradually increased as the body immune system began to recover. ALL the change patterns were shared in CAR- cells. Conclusion: The above results suggest that the expansion of CAR-T cells in vivo are mainly CD8+ cells, and are mainly effector T cells that directly exercising killing function. The CAR- cell population shared the same changes of cell subsets with the CAR+ cell population, suggesting that CAR-T cells have certain optimization effects on the body immune system. Disclosures No relevant conflicts of interest to declare.

scholarly journals Approaches of the Innate Immune System to Ameliorate Adaptive Immunotherapy for B-Cell Non-Hodgkin Lymphoma in Their Microenvironment

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 141
Author(s):  
Takashi Watanabe
Keyword(s):  
Immune System ◽  
T Cell ◽  
B Cell ◽  
Innate Immune System ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Response ◽  
Innate Immune ◽  
Car T Cell ◽  
Car T

A dominant paradigm being developed in immunotherapy for hematologic malignancies is of adaptive immunotherapy that involves chimeric antigen receptor (CAR) T cells and bispecific T-cell engagers. CAR T-cell therapy has yielded results that surpass those of the existing salvage immunochemotherapy for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) after first-line immunochemotherapy, while offering a therapeutic option for patients with follicular lymphoma (FL) and mantle cell lymphoma (MCL). However, the role of the innate immune system has been shown to prolong CAR T-cell persistence. Cluster of differentiation (CD) 47-blocking antibodies, which are a promising therapeutic armamentarium for DLBCL, are novel innate immune checkpoint inhibitors that allow macrophages to phagocytose tumor cells. Intratumoral Toll-like receptor 9 agonist CpG oligodeoxynucleotide plays a pivotal role in FL, and vaccination may be required in MCL. Additionally, local stimulator of interferon gene agonists, which induce a systemic anti-lymphoma CD8+ T-cell response, and the costimulatory molecule 4-1BB/CD137 or OX40/CD134 agonistic antibodies represent attractive agents for dendritic cell activations, which subsequently, facilitates initiation of productive T-cell priming and NK cells. This review describes the exploitation of approaches that trigger innate immune activation for adaptive immune cells to operate maximally in the tumor microenvironment of these lymphomas.

scholarly journals CRISPR/Cas9-mediated TGFβRII disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells in vitro

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Khadijeh Alishah ◽  
Matthias Birtel ◽  
Elham Masoumi ◽  
Leila Jafarzadeh ◽  
Hamid Reza Mirzaee ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Solid Tumors ◽  
Target Cells ◽  
Cell Functions ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Abstract Background CAR T-cell therapy has been recently unveiled as one of the most promising cancer therapies in hematological malignancies. However, solid tumors mount a profound line of defense to escape immunosurveillance by CAR T-cells. Among them, cytokines with an inhibitory impact on the immune system such as IL-10 and TGFβ are of great importance: TGFβ is a pleiotropic cytokine, which potently suppresses the immune system and is secreted by a couple of TME resident and tumor cells. Methods In this study, we hypothesized that knocking out the TGFβ receptor II gene, could improve CAR T-cell functions in vitro and in vivo. Hereby, we used the CRISPR/Cas9 system, to knockout the TGFβRII gene in T-cells and could monitor the efficient gene knock out by genome analysis techniques. Next, Mesothelin or Claudin 6 specific CAR constructs were overexpressed via IVT-RNA electroporation or retroviral transduction and the poly-functionality of these TGFβRII KO CAR T-cells in terms of proliferation, cytokine secretion and cytotoxicity were assessed and compared with parental CAR T-cells. Results Our experiments demonstrated that TGFβRII KO CAR T-cells fully retained their capabilities in killing tumor antigen positive target cells and more intriguingly, could resist the anti-proliferative effect of exogenous TGFβ in vitro outperforming wild type CAR T-cells. Noteworthy, no antigen or growth factor-independent proliferation of these TGFβRII KO CAR T-cells has been recorded. TGFβRII KO CAR T-cells also resisted the suppressive effect of induced regulatory T-cells in vitro to a larger extent. Repetitive antigen stimulation demonstrated that these TGFβRII KO CAR T-cells will experience less activation induced exhaustion in comparison to the WT counterpart. Conclusion The TGFβRII KO approach may become an indispensable tool in immunotherapy of solid tumors, as it may surmount one of the key negative regulatory signaling pathways in T-cells.

Quarterly picks from the editors

2020 ◽  
Vol 12 (574) ◽  
pp. eabg0485
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Infectious Diseases ◽  
Translational Medicine ◽  
Host Immune Response ◽  
Cell Engineering ◽  
Intestinal Microbiome ◽  
Car T Cell ◽  
Car T ◽  
T Cell Engineering

Four times a year, the Science Translational Medicine editors select recently published articles across the Science family of journals and highlight interesting translational ties. These short write-ups identify common links between disparate diseases; technologies and research approaches that could prove complementary; and biomedical insights that may inform therapies or treatments. This quarter’s articles cover flexible biosensors, SARS-CoV-2 transmission from a genomics perspective, advances in CAR T cell engineering, the intestinal microbiome, the host immune response to SARS-CoV-2, and strategies for treating infectious diseases.

scholarly journals A Deep Insight Into CAR-T Cell Therapy in Non-Hodgkin Lymphoma: Application, Opportunities, and Future Directions

2021 ◽  
Vol 12 ◽  
Author(s):  
Faroogh Marofi ◽  
Heshu Sulaiman Rahman ◽  
Muhammad Harun Achmad ◽  
Klunko Nataliya Sergeevna ◽  
Wanich Suksatan ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
B Cell ◽  
Molecular Mechanisms ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Anti Cancer ◽  
Car T

Non-Hodgkin’s lymphoma (NHL) is a cancer that starts in the lymphatic system. In NHL, the important part of the immune system, a type of white blood cells called lymphocytes become cancerous. NHL subtypes include marginal zone lymphoma, small lymphocytic lymphoma, follicular lymphoma (FL), and lymphoplasmacytic lymphoma. The disease can emerge in either aggressive or indolent form. 5-year survival duration after diagnosis is poor among patients with aggressive/relapsing form of NHL. Therefore, it is necessary to understand the molecular mechanisms of pathogenesis involved in NHL establishment and progression. In the next step, we can develop innovative therapies for NHL based on our knowledge in signaling pathways, surface antigens, and tumor milieu of NHL. In the recent few decades, several treatment solutions of NHL mainly based on targeted/directed therapies have been evaluated. These approaches include B-cell receptor (BCR) signaling inhibitors, immunomodulatory agents, monoclonal antibodies (mAbs), epigenetic modulators, Bcl-2 inhibitors, checkpoint inhibitors, and T-cell therapy. In recent years, methods based on T cell immunotherapy have been considered as a novel promising anti-cancer strategy in the treatment of various types of cancers, and particularly in blood cancers. These methods could significantly increase the capacity of the immune system to induce durable anti-cancer responses in patients with chemotherapy-resistant lymphoma. One of the promising therapy methods involved in the triumph of immunotherapy is the chimeric antigen receptor (CAR) T cells with dramatically improved killing activity against tumor cells. The CAR-T cell-based anti-cancer therapy targeting a pan–B-cell marker, CD19 is recently approved by the US Food and Drug Administration (FDA) for the treatment of chemotherapy-resistant B-cell NHL. In this review, we will discuss the structure, molecular mechanisms, results of clinical trials, and the toxicity of CAR-T cell-based therapies. Also, we will criticize the clinical aspects, the treatment considerations, and the challenges and possible drawbacks of the application of CAR-T cells in the treatment of NHL.

scholarly journals The Role of Immune Checkpoints after Cellular Therapy

2020 ◽  
Vol 21 (10) ◽  
pp. 3650 ◽  
Author(s):  
Friederike Schmitz ◽  
Dominik Wolf ◽  
Tobias A.W. Holderried
Keyword(s):  
Immune System ◽  
T Cell ◽  
Cellular Therapy ◽  
Immune Checkpoints ◽  
Malignant Cells ◽  
Malignant Diseases ◽  
Cell Therapies ◽  
Car T Cell ◽  
Anti Cancer ◽  
Car T

Cellular therapies utilize the powerful force of the human immune system to target malignant cells. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the most established cellular therapy, but chimeric antigen receptor (CAR) T cell therapies have gained attention in recent years. While in allo-HCT an entirely novel allogeneic immune system facilitates a so-called Graft-versus-tumor, respectively, Graft-versus-leukemia (GvT/GvL) effect against high-risk hematologic malignancies, in CAR T cell therapies genetically modified autologous T cells specifically attack target molecules on malignant cells. These therapies have achieved high success rates, offering potential cures in otherwise detrimental diseases. However, relapse after cellular therapy remains a serious clinical obstacle. Checkpoint Inhibition (CI), which was recently designated as breakthrough in cancer treatment and consequently awarded with the Nobel prize in 2018, is a different way to increase anti-tumor immunity. Here, inhibitory immune checkpoints are blocked on immune cells in order to restore the immunological force against malignant diseases. Disease relapse after CAR T cell therapy or allo-HCT has been linked to up-regulation of immune checkpoints that render cancer cells resistant to the cell-mediated anti-cancer immune effects. Thus, enhancing immune cell function after cellular therapies using CI is an important treatment option that might re-activate the anti-cancer effect upon cell therapy. In this review, we will summarize current data on this topic with the focus on immune checkpoints after cellular therapy for malignant diseases and balance efficacy versus potential side effects.

The Current and Future Role of Radiation Therapy in the Era of CAR T-cell Salvage

2021 ◽  
pp. 20210098
Author(s):  
Carl DeSelm
Keyword(s):  
T Cells ◽  
Radiation Therapy ◽  
Immune System ◽  
T Cell ◽  
Cellular Therapies ◽  
Car T Cells ◽  
Car T Cell ◽  
Number Of Patients ◽  
Car T

Radiation therapy has the potential to modulate the immune system in a variety of ways, and given the critical role of the immune system in cancer elimination, it is becoming increasingly important to understand how radiation can be strategically implemented in conjunction with approved immunotherapies to improve the cancer patient’s chance of cure and/or quality of life. Current successful, approved cancer immunotherapies fall into two broad classes: antibodies and cellular therapies. Approved cellular therapies thus far consist of Chimeric Antigen Receptor (CAR) T-cells targeting CD19 for refractory non-Hodgkin lymphoma and relapsed or refractory acute lymphoblastic leukemia. Part of the ardor surrounding CAR T-cells stems from the fact that the survival curve of treated patients has a clear plateau, meaning that a number of patients with aggressive, disseminated disease who would have otherwise died rather rapidly appear to now be cured, commonly after just one dose. Despite an encouraging number of these durable remissions, the majority do still relapse. In this review, we discuss the potential for strategically utilizing radiation to further improve CAR T-cell patient outcomes. Given that there are currently over 750 cellular therapies in development, half of which are now in clinical trial, CAR T-cell usage will inevitably expand; as the field grows in importance and effectiveness, radiation oncology has the opportunity to coevolve symbiotically and steer these novel, exciting live therapies to new depths.

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