scholarly journals Expanding the Role of CAR-T Cell Therapy to Systemic Lupus Erythematosus

2020 ◽  
pp. 105-112
Author(s):  
Shreya Patel ◽  
Kelly Brassil ◽  
Paiboon Jungsuwadee
Keyword(s):  
T Cell ◽  
B Cells ◽  
Lupus Erythematosus ◽  
Treatment Options ◽  
Current Treatment ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Immune Effector ◽  
Car T Cell Therapy ◽  
Car T

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disorder resulting from autoantibodies produced by B-cell derived plasma cells. Clinical presentation ranges from mild skin rash to multiorgan failure. Regardless of the clinical presentation or severity of the disease, patients with SLE often require life-long treatment. Current treatment recommendations for SLE include hydroxychloroquine, glucocorticoids, immunomodulatory agents, cyclophosphamide, and biologic agents. Despite availability of these agents, the condition of some patients with SLE progressively worsens. With limited treatment options, new and novel therapeutic approaches are needed. Given the active role of B cells in the pathophysiology of SLE, they present an attractive target for therapies evolving in the oncology field. Amongst these, immune effector cell therapies, including chimeric antigen receptor (CAR)-T cell therapy, have proven beneficial in targeting B cells. The eradication of B cells, along with the potential for T cell persistence, has resulted in prolonged remission or stable disease. This review provides an overview of the pathophysiology of SLE; current treatment options, including monoclonal antibodies targeting cluster of differentiation-20 (CD20), CD22, and B cell-activating factor (BAFF); and explores why and how immune effector cell therapies may prove a promising therapeutic option for this patient population, particularly for individuals with refractory disease. Clinical implications from currently approved U.S. Food and Drug Administration (FDA) agents for haematologic malignancies are discussed and provide insight into considerations for applying this therapy to the patient population with SLE in the context of clinical trials.

scholarly journals Potential strategies against resistance to CAR T-cell therapy in haematological malignancies

2020 ◽  
Vol 12 ◽  
pp. 175883592096296
Author(s):  
Qing Cai ◽  
Mingzhi Zhang ◽  
Zhaoming Li
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Haematological Malignancies ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Chimeric antigen receptor (CAR) T-cell therapy is a rapidly developing method for adoptive immunotherapy of tumours in recent years. CAR T-cell therapies have demonstrated unprecedented efficacy in the treatment of patients with haematological malignancies. A 90% complete response (CR) rate has been reported in patients with advanced relapse or refractory acute lymphoblastic leukaemia, while >50% CR rates have been reported in cases of chronic lymphocytic leukaemia and partial B-cell lymphoma. Despite the high CR rates, a subset of the patients with complete remission still relapse. The mechanism of development of resistance is not clearly understood. Some patients have been reported to demonstrate antigen-positive relapse, whereas others show antigen-negative relapses. Patients who relapse following CAR T-cell therapy, have very poor prognosis and novel approaches to overcome resistance are required urgently. Herein, we have reviewed current literature and research that have investigated the strategies to overcome resistance to CAR T-cell therapy.

scholarly journals Identification of the risks in CAR T-cell therapy clinical trials in China: a Delphi study

2020 ◽  
Vol 12 ◽  
pp. 175883592096657
Author(s):  
Weijia Wu ◽  
Yan Huo ◽  
Xueying Ding ◽  
Yuhong Zhou ◽  
Shengying Gu ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cell ◽  
Cell Therapy ◽  
Delphi Method ◽  
Delphi Study ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Aims: Within the past few years, there has been tremendous growth in clinical trials of chimeric antigen receptor (CAR) T-cell therapies. Unlike those of many small-molecule pharmaceuticals, CAR T-cell therapy clinical trials are fraught with risks due to the use of live cell products. The aim of this study is to reach a consensus with experts on the most relevant set of risks that practically occur in CAR T-cell therapy clinical trials. Methods: A Delphi method of consensus development was used to identify the risks in CAR T-cell therapy clinical trials, comprising three survey rounds. The expert panel consisted of principal investigators, clinical research physicians, members of institutional ethics committees, and Good Clinical Practice managers. Results: Of the 24 experts invited to participate in this Delphi study, 20 participants completed Round 1, Round 2, and Round 3. Finally, consensus (defined as >80% agreement) was achieved for 54 risks relating to CAR T-cell clinical trials. Effective interventions related to these risks are needed to ensure the proper protection of subject health and safety. Conclusion: The Delphi method was successful in gaining a consensus on risks relevant to CAR T-cell clinical trials in a geographically diverse expert association. It is hoped that this work can benefit future risk-based quality management in clinical trials and can potentially promote the better development of CAR T-cell therapy products.

scholarly journals Chimeric Antigen Receptor Cell Therapy: Overcoming Obstacles to Battle Cancer

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 842 ◽  
Author(s):  
Amy J. Petty ◽  
Benjamin Heyman ◽  
Yiping Yang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Clinical Success ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Local Immunosuppression ◽  
Car T

Chimeric antigen receptors (CAR) are fusion proteins engineered from antigen recognition, signaling, and costimulatory domains that can be used to reprogram T cells to specifically target tumor cells expressing specific antigens. Current CAR-T cell technology utilizes the patient’s own T cells to stably express CARs and has achieved exciting clinical success in the past few years. However, current CAR-T cell therapy still faces several challenges, including suboptimal persistence and potency, impaired trafficking to solid tumors, local immunosuppression within the tumor microenvironment and intrinsic toxicity associated with CAR-T cells. This review focuses on recent strategies to improve the clinical efficacy of CAR-T cell therapy and other exciting CAR approaches currently under investigation, including CAR natural killer (NK) and NKT cell therapies.

scholarly journals CAR-T Cell Therapy: Mechanism, Management, and Mitigation of Inflammatory Toxicities

2021 ◽  
Vol 12 ◽  
Author(s):  
Joseph W. Fischer ◽  
Nirjal Bhattarai
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Future Research ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Car T Cell ◽  
Safety Risks ◽  
Car T Cell Therapy ◽  
Car T

Engineered T cell therapies such as chimeric antigen receptor (CAR) expressing T cells (CAR-T cells) have great potential to treat many human diseases; however, inflammatory toxicities associated with these therapies present safety risks and can greatly limit its widespread use. This article briefly reviews our current understanding of mechanisms for inflammatory toxicities during CAR T-cell therapy, current strategies for management and mitigation of these risks and highlights key areas of knowledge gap for future research.

scholarly journals Prevalence and variation of CHIP in patients with aggressive lymphomas undergoing CD19-directed CAR-T-cell treatment

2022 ◽  
Author(s):  
Raphael Teipel ◽  
Frank P Kroschinsky ◽  
Michael Kramer ◽  
Theresa Kretschmann ◽  
Katharina Egger-Heidrich ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Immune Effector ◽  
Car T Cell ◽  
Markers Of Inflammation ◽  
Car T Cell Therapy ◽  
Significant Difference ◽  
Car T ◽  
Before And After

Inflammation plays an important role in CAR-T-cell therapy, especially in the pathophysiology of cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Clonal hematopoiesis of indetermined potential (CHIP) has also been associated with chronic inflammation. The relevance of CHIP in the context of CAR-T-cell treatment is currently widely unknown. We longitudinally evaluated the prevalence of CHIP, using a targeted deep sequencing approach in a cohort of patients with r/r B-NHL before and after CAR-T-cell treatment. The aim was to define the prevalence and variation of CHIP over time and to assess the influence on clinical inflammation syndromes (CRS/ICANS), cytopenia and outcome. Overall, 32 patients were included. CHIP was found in 11 of 32 patients (34 %) before CAR-T-cell therapy. CHIP progression was commonly detected in the later course. Patients with CHIP showed a comparable response rate to CAR-T-cell treatment but had an improved OS (not reached vs. 265 days, p=0.003). No significant difference was observed in terms of the occurrence and severity of CRS/ICANS, therapeutic usage of tocilizumab and glucocorticosteroids, paraclinical markers of inflammation (except ferritin) or dynamics of hematopoietic recovery. CHIP is commonly observed in patients undergoing CD19-directed CAR-T-cell therapy and is not associated with an inferior outcome.

scholarly journals Chimeric antigen receptor T cell therapy in cancer: Advances and challenges

2021 ◽  
Vol 3 (3) ◽  
pp. 46-47
Author(s):  
Yuanzheng Liang ◽  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Number Of Patients ◽  
Car T

Chimeric antigen receptor (CAR) T-cell therapy has drawn the most attention ever in the treatment of hematologic malignancies due to its impressive efficacy in heavily pretreated patients. However, the use of CAR T-cell therapy has just started in the field of solid tumor. Till now, four CAR T-cell therapies have been approved in the world, and an increasing number of patients will receive this expensive treatment. Thus, we will briefly talk about the advances and challenges in the adventure of CAR T-cell therapy

scholarly journals Point mutation in CD19 facilitates immune escape of B cell lymphoma from CAR-T cell therapy

2020 ◽  
Vol 8 (2) ◽  
pp. e001150 ◽  
Author(s):  
Zhen Zhang ◽  
Xinfeng Chen ◽  
Yonggui Tian ◽  
Feng Li ◽  
Xuan Zhao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Cell Therapy ◽  
Point Mutation ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

BackgroundTumor relapse due to mutation in CD19 can hinder the efficacy of chimeric antigen receptor (CAR)-T cell therapy. Herein, we focused on lymphoma patients whose B cells exhibited a point mutation in CD19 of B cells after CAR-T cell infusion.MethodsThe CAR-T and CD19+ B cells from peripheral blood or bone marrow were assessed using flow cytometry. Genome sequencing was conducted to identify the molecular characteristics of CAR-T and CD19+ B cells from pre-relapse and postrelapse samples. CD19 in CARs comprising single chain fragments variable (scFV) antibody with FMC63 or 21D4 was constructed. The cytotoxic efficacy of CAR-T cells was also evaluated via in vitro and in vivo experiments.ResultsA patient with high-grade B cell lymphoma exhibited complete response, but the lymphoma relapsed in her left breast at 6 months after CD19 CAR (FMC63)-T cell infusion. A mutation was found in exon 3 of CD19 (p.163. R-L) in malignant B cells of the patient. In two lymphoma patients who exhibited resistance to CAR-T cell therapy, a mutation was detected in exon 3 of CD19 (p.174. L-V). Functional analysis revealed that FMC63 CAR-T cells exhibited antitumor ability against wild-type CD19+ cells but were unable to eradicate these two types of mutated CD19+ cells. Interestingly, 21D4 CAR-T cells were potentially capable of eradicating these mutated CD19+ cells and exhibiting high antitumor capacity against CD19+ cells with loss of exon 1, 2, or 3.ConclusionsThese findings suggest that point mutation can facilitate immune escape from CAR-T cell therapy and that alternative CAR-T cells can effectively eradicate the mutated B cells, providing an individualized therapeutic approach for lymphoma patients showing relapse.

What is CAR T-cell therapy?

2021 ◽  
Vol 59 (5) ◽  
pp. 73-76
Author(s):  
Kayleigh Kew
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Healthcare Professionals ◽  
Cancer Therapeutics ◽  
Current Evidence ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

The emergence of targeted and precision therapies has increased treatment options for people living with cancer. Of particular note is the development and approval of chimeric antigen receptor (CAR) T-cell therapies that involve the use of a patient’s own immune system to treat cancers that have proven resistant to other approaches. Keeping abreast of treatment changes and practice guidelines is a challenge for all healthcare professionals, and the pressure of doing so becomes most acute with innovations in cancer therapeutics that have the potential to extend or save lives. Though uncommon, step changes like CAR T-cell therapy pose a challenge, often requiring completely new ways of thinking about efficacy evidence, basic science, ethics and service delivery. At a time when patients are able and empowered to readily access information about novel and exploratory treatments, healthcare professionals need to feel informed enough to help patients with life-changing or life-limiting cancers who approach them for advice. This article gives an overview of the basic principles of CAR T-cell therapy including how it is delivered, who is eligible to receive it in the UK, and a brief outline of current evidence of its efficacy and safety. The information is intended to provide healthcare professionals with an introduction to CAR T-cell therapy to help them advise potentially eligible patients or those already undergoing treatment about what to expect.

scholarly journals The role of axicabtagene ciloleucel as a treatment option for patients with follicular/marginal zone lymphoma

2021 ◽  
Vol 12 ◽  
pp. 204062072110177
Author(s):  
Jose Sandoval-Sus ◽  
Julio C. Chavez
Keyword(s):  
Treatment Options ◽  
Current Treatment ◽  
Clinical Activity ◽  
Phosphatidylinositol 3 Kinase ◽  
T Cell Therapy ◽  
Pi3k Inhibitors ◽  
Car T Cell Therapy ◽  
Car T ◽  
Long Term Follow Up ◽  
Poor Outcomes

Chimeric antigen receptor (CAR) T-cell therapy with axicabtagene ciloleucel (axi-cel) continues to make its way in the treatment of B-cell lymphomas. Follicular lymphoma (FL) is the second most common non-Hodgkin’s lymphoma. While its prognosis is usually good, the disease is considered incurable and patients still relapse. High-risk subgroups such as high FLIPI score or early relapses (POD24) face poor outcomes. Current treatment options with phosphatidylinositol 3-kinase (Pi3K) inhibitors or other novel agents have clinical activity but short remission with cures remaining elusive. The ZUMA-5 study of axi-cel has shown high response rates with durable remissions with manageable toxicities, particularly in poor risk FL, replicating the outcomes in smaller and earlier studies. Long-term follow up will demonstrate the real impact of axi-cel in relapsed FL.

scholarly journals Reactions Related to CAR-T Cell Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Lele Miao ◽  
Zhengchao Zhang ◽  
Zhijian Ren ◽  
Yumin Li
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Adverse Reactions ◽  
Tumor Lysis Syndrome ◽  
T Cell Therapy ◽  
Immune Effector ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Life Threatening

The application of chimeric antigen receptor (CAR) T-cell therapy as a tumor immunotherapy has received great interest in recent years. This therapeutic approach has been used to treat hematological malignancies solid tumors. However, it is associated with adverse reactions such as, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), off-target effects, anaphylaxis, infections associated with CAR-T-cell infusion (CTI), tumor lysis syndrome (TLS), B-cell dysplasia, hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) and coagulation disorders. These adverse reactions can be life-threatening, and thus they should be identified early and treated effectively. In this paper, we review the adverse reactions associated with CAR-T cells, the mechanisms driving such adverse reactions, and strategies to subvert them. This review will provide important reference data to guide clinical application of CAR-T cell therapy.

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