scholarly journals Managing therapy-associated neurotoxicity in children with ALL

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 376-383
Author(s):  
Deepa Bhojwani ◽  
Ravi Bansal ◽  
Alan S. Wayne
Keyword(s):  
T Cells ◽  
Chemotherapeutic Agents ◽  
Low Grade ◽  
Immune Effector ◽  
Neurologic Recovery ◽  
Car T Cells ◽  
Car T ◽  
Life Threatening ◽  
Excellent Control ◽  
Almost All

Abstract Several chemotherapeutic agents and novel immunotherapies provide excellent control of systemic and central nervous system (CNS) leukemia but can be highly neurotoxic. The manifestations of subacute methotrexate neurotoxicity are diverse and require vigilant management; nonetheless, symptoms are transient in almost all patients. As methotrexate is a crucial drug to prevent CNS relapse, it is important to aim to resume it after full neurologic recovery. Most children tolerate methotrexate rechallenge without significant delays or prophylactic medications. Neurotoxicity is more frequent with newer immunotherapies such as CD19– chimeric antigen receptor T (CAR T) cells and blinatumomab. A uniform grading system for immune effector cell–associated neurotoxicity syndrome (ICANS) and algorithms for management based on severity have been developed. Low-grade ICANS usually resolves within a few days with supportive measures, but severe ICANS requires multispecialty care in the intensive care unit for life-threatening seizures and cerebral edema. Pharmacologic interventions include anticonvulsants for seizure control and glucocorticoids to reduce neuroinflammation. Anticytokine therapies targeted to the pathophysiology of ICANS are in development. By using illustrative patient cases, we discuss the management of neurotoxicity from methotrexate, CAR T cells, and blinatumomab in this review.

scholarly journals Conventional CARs versus modular CARs

2019 ◽  
Vol 68 (10) ◽  
pp. 1713-1719 ◽  
Author(s):  
Anja Feldmann ◽  
Claudia Arndt ◽  
Stefanie Koristka ◽  
Nicole Berndt ◽  
Ralf Bergmann ◽  
...  
Keyword(s):  
T Cells ◽  
Side Effects ◽  
Tumor Lysis Syndrome ◽  
Antigen Receptors ◽  
Immune Effector ◽  
Effector Cells ◽  
Car T Cells ◽  
Car T ◽  
Immune Effector Cells ◽  
Life Threatening

Abstract The clinical application of immune effector cells genetically modified to express chimeric antigen receptors (CARs) has shown impressive results including complete remissions of certain malignant hematological diseases. However, their application can also cause severe side effects such as cytokine release syndrome (CRS) or tumor lysis syndrome (TLS). One limitation of currently applied CAR T cells is their lack of regulation. Especially, an emergency shutdown of CAR T cells in case of life-threatening side effects is missing. Moreover, targeting of tumor-associated antigens (TAAs) that are not only expressed on tumor cells but also on vital tissues requires the possibility of a switch allowing to repeatedly turn the activity of CAR T cells on and off. Here we summarize the development of a modular CAR variant termed universal CAR (UniCAR) system that promises to overcome these limitations of conventional CARs.

scholarly journals Engineering Next-Generation CAR-T Cells for Better Toxicity Management

2020 ◽  
Vol 21 (22) ◽  
pp. 8620
Author(s):  
Alain E. Andrea ◽  
Andrada Chiron ◽  
Stéphanie Bessoles ◽  
Salima Hacein-Bey-Abina
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Receptors ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Safety Strategies ◽  
Life Threatening ◽  
Preclinical And Clinical Studies

Immunoadoptive therapy with genetically modified T lymphocytes expressing chimeric antigen receptors (CARs) has revolutionized the treatment of patients with hematologic cancers. Although clinical outcomes in B-cell malignancies are impressive, researchers are seeking to enhance the activity, persistence, and also safety of CAR-T cell therapy—notably with a view to mitigating potentially serious or even life-threatening adverse events like on-target/off-tumor toxicity and (in particular) cytokine release syndrome. A variety of safety strategies have been developed by replacing or adding various components (such as OFF- and ON-switch CARs) or by combining multi-antigen-targeting OR-, AND- and NOT-gate CAR-T cells. This research has laid the foundations for a whole new generation of therapeutic CAR-T cells. Here, we review the most promising CAR-T cell safety strategies and the corresponding preclinical and clinical studies.

Strategies to improve the safety profile of CAR-T therapy

2021 ◽  
Vol 8 ◽  
pp. 48-60
Author(s):  
Agnieszka Graczyk-Jarzynka
Keyword(s):  
T Cells ◽  
Adverse Effects ◽  
Safety Profile ◽  
Logic Gates ◽  
Immune Effector ◽  
Effector Cells ◽  
Protein Levels ◽  
Car T Cells ◽  
Car T ◽  
Different Types

The chimeric antigen receptor (CAR) technology has become one of the greatest breakthroughs in immunotherapy in recent years. CARs facilitate the attack of immune effector cells such as T cells or NK cells being directed at virtually any molecule presented on the surface of a cancer cell. The exceptional efficacy of CAR receptors has been demonstrated for the CD19 molecule found on B cell-derived tumors. However, the efficacy of CAR-T therapy targeting other antigens is less satisfactory while being quite frequently associated with a number of adverse effects. The adverse effects are mainly due to the effector cells being activated in a simplified manner; the most serious effect consists in the antigen being detected on healthy cells (“the on-target, off-tumor” effect). A number of ongoing studies aim at enhancing the safety profile of therapies making use of CAR--modified effector cells. In part, this can be achieved by optimizing the structure of the CAR receptor itself or by using transient transfection to modify the effector cells. A more complex solution consists in obtaining remote control over CAR-T lymphocytes within the patient’s body. This approach makes use of different types of systems that limit the functionality of CAR-T cells in the patient, such as suicide genes, regulation at the transcriptional and protein levels, different types of adapters being used to activate the CAR-T cells. The most advanced system consists in the use of logic gates which make it possible for CAR-T cells to recognize and „understand” incoming signals from the environment, allowing for a certain degree of autonomy in the activation of the cells’ cytotoxic potential. This study presents key strategies to improve the safety profiles of CAR-T therapies.

scholarly journals Engineering better chimeric antigen receptor T cells

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Hao Zhang ◽  
Pu Zhao ◽  
He Huang
Keyword(s):  
T Cells ◽  
Intracellular Signaling ◽  
Influence Factors ◽  
Target Antigen ◽  
Car T Cells ◽  
Car T ◽  
Underlying Mechanisms ◽  
Almost All

AbstractCD19-targeted CAR T cells therapy has shown remarkable efficacy in treatment of B cell malignancies. However, relapse of primary disease remains a major obstacle after CAR T cells therapy, and the majority of relapses present a tumor phenotype with retention of target antigen (antigen-positive relapse), which highly correlate with poor CAR T cells persistence. Therefore, study on factors and mechanisms that limit the in vivo persistence of CAR T cells is crucial for developing strategies to overcome these limitations. In this review, we summarize the rapidly developing knowledge regarding the factors that influence CAR T cells in vivo persistence and the underlying mechanisms. The factors involve the CAR constructs (extracellular structures, transmembrane and intracellular signaling domains, as well as the accessory structures), activation signaling (CAR signaling and TCR engagement), methods for in vitro culture (T cells collection, purification, activation, gene transduction and cells expansion), epigenetic regulations, tumor environment, CD4/CD8 subsets, CAR T cells differentiation and exhaustion. Of note, among these influence factors, CAR T cells differentiation and exhaustion are identified as the central part due to the fact that almost all factors eventually alter the state of cells differentiation and exhaustion. Moreover, we review the potential coping strategies aiming at these limitations throughout this study.

scholarly journals Limitations in the Design of Chimeric Antigen Receptors for Cancer Therapy

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 472 ◽  
Author(s):  
Stefan Stoiber ◽  
Bruno L. Cadilha ◽  
Mohamed-Reda Benmebarek ◽  
Stefanie Lesch ◽  
Stefan Endres ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Therapy ◽  
Rational Design ◽  
Chemotherapeutic Agents ◽  
Therapeutic Modality ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Cancer therapy has entered a new era, transitioning from unspecific chemotherapeutic agents to increasingly specific immune-based therapeutic strategies. Among these, chimeric antigen receptor (CAR) T cells have shown unparalleled therapeutic potential in treating refractory hematological malignancies. In contrast, solid tumors pose a much greater challenge to CAR T cell therapy, which has yet to be overcome. As this novel therapeutic modality matures, increasing effort is being invested to determine the optimal structure and properties of CARs to facilitate the transition from empirical testing to the rational design of CAR T cells. In this review, we highlight how individual CAR domains contribute to the success and failure of this promising treatment modality and provide an insight into the most notable advances in the field of CAR T cell engineering.

Hematologic Malignancies: Plasma Cell Disorders

2017 ◽  
pp. 561-568 ◽  
Author(s):  
Madhav V. Dhodapkar ◽  
Ivan Borrello ◽  
Adam D. Cohen ◽  
Edward A. Stadtmauer
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
Cell Surface ◽  
Plasma Cell ◽  
Antigen Specificity ◽  
Immune Effector ◽  
Car T Cells ◽  
Car T

Multiple myeloma (MM) is a plasma cell malignancy characterized by the growth of tumor cells in the bone marrow. Properties of the tumor microenvironment provide both potential tumor-promoting and tumor-restricting properties. Targeting underlying immune triggers for evolution of tumors as well as direct attack of malignant plasma cells is an emerging focus of therapy for MM. The monoclonal antibodies daratumumab and elotuzumab, which target the plasma cell surface proteins CD38 and SLAMF7/CS1, respectively, particularly when used in combination with immunomodulatory agents and proteasome inhibitors, have resulted in high response rates and improved survival for patients with relapsed and refractory MM. A number of other monoclonal antibodies are in various stages of clinical development, including those targeting MM cell surface antigens, the bone marrow microenvironment, and immune effector T cells such as antiprogrammed cell death protein 1 antibodies. Bispecific preparations seek to simultaneously target MM cells and activate endogenous T cells to enhance efficacy. Cellular immunotherapy seeks to overcome the limitations of the endogenous antimyeloma immune response through adoptive transfer of immune effector cells with MM specificity. Allogeneic donor lymphocyte infusion can be effective but can cause graft-versus-host disease. The most promising approach appears to be genetically modified cellular therapy, in which T cells are given novel antigen specificity through expression of transgenic T-cell receptors (TCRs) or chimeric antigen receptors (CARs). CAR T cells against several different targets are under investigation in MM. Infusion of CD19-targeted CAR T cells following salvage autologous stem cell transplantation (SCT) was safe and extended remission duration in a subset of patients with relapsed/refractory MM. CAR T cells targeting B-cell maturation antigen (BCMA) appear most promising, with dramatic remissions seen in patients with highly refractory disease in three ongoing trials. Responses are associated with degree of CAR T-cell expansion/persistence and often toxicity, including cytokine release syndrome (CRS) and neurotoxicity. Ongoing and future studies are exploring correlates of response, ways to mitigate toxicity, and “universal” CAR T cells.

scholarly journals Strategies to Circumvent the Side-Effects of Immunotherapy Using Allogeneic CAR-T Cells and Boost Its Efficacy: Results of Recent Clinical Trials

2021 ◽  
Vol 12 ◽  
Author(s):  
Sergei Smirnov ◽  
Alexey Petukhov ◽  
Ksenia Levchuk ◽  
Sergey Kulemzin ◽  
Alena Staliarova ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Hematological Malignancies ◽  
Host Immune System ◽  
Extensive Area ◽  
Graft Versus Host ◽  
Car T Cells ◽  
Results Of Treatment ◽  
Car T ◽  
Life Threatening

Despite the outstanding results of treatment using autologous chimeric antigen receptor T cells (CAR-T cells) in hematological malignancies, this approach is endowed with several constraints. In particular, profound lymphopenia in some patients and the inability to manufacture products with predefined properties or set of cryopreserved batches of cells directed to different antigens in advance. Allogeneic CAR-T cells have the potential to address these issues but they can cause life-threatening graft-versus-host disease or have shorter persistence due to elimination by the host immune system. Novel strategies to create an “off the shelf” allogeneic product that would circumvent these limitations are an extensive area of research. Here we review CAR-T cell products pioneering an allogeneic approach in clinical trials.

scholarly journals Infections following CAR-T cells therapy: current state-of-the-art review and recommendations

2020 ◽  
Vol 51 (1) ◽  
pp. 11-16 ◽  
Author(s):  
Jan Styczyński
Keyword(s):  
T Cells ◽  
Hematopoietic Cell Transplantation ◽  
Current Knowledge ◽  
Tumor Lysis Syndrome ◽  
Infectious Complications ◽  
Related Factors ◽  
Immune Effector ◽  
Car T Cells ◽  
Increased Risk ◽  
Car T

AbstractThe most frequent and severe complications after chimeric antigen receptor T-cells (CAR-T cells) therapy include cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH), tumor lysis syndrome (TLS), followed by B-cell aplasia and hypogammaglobulinemia. With these immunologically related events, cytokine storm and immunosuppression, there is a high risk of sepsis and infectious complications. The objective of this review was to present current knowledge on incidence, risk factors, clinical characteristics, and outcome of infections in patients following CAR-T cells therapy, as well as to present current recommendations on prophylaxis of infections after CAR-T cells therapy. Comparable to hematopoietic cell transplantation setting, specific pre- and post-CAR-T cells infusion phases can be determined as early (from 0 to +30 days), intermediate (from +31 to +100 days), and late (beyond day +100). These phases are characterized by CAR-T cells therapy-related factors and immune system defects contributing to an increased risk of infections. It is recommended that in case of active infection, CAR-T cells infusion should be delayed until infection has been successfully treated. After CAR-T cells therapy, prophylaxis should be implemented (anti-bacterial, anti-viral, anti-fungal, anti-pneumocystis), as well as treatment of neutropenia and immunoglobulin replacement should be considered. No recommendations so far can be given on revaccinations after CAR-T cells therapy.

scholarly journals A BAFF ligand-based CAR-T cell targeting three receptors and multiple B cell cancers

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Derek P. Wong ◽  
Nand K. Roy ◽  
Keman Zhang ◽  
Anusha Anukanth ◽  
Abhishek Asthana ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Viral Gene ◽  
Car T Cells ◽  
Car T ◽  
Almost All ◽  
Viral Gene Delivery

AbstractB cell-activating factor (BAFF) binds the three receptors BAFF-R, BCMA, and TACI, predominantly expressed on mature B cells. Almost all B cell cancers are reported to express at least one of these receptors. Here we develop a BAFF ligand-based chimeric antigen receptor (CAR) and generate BAFF CAR-T cells using a non-viral gene delivery method. We show that BAFF CAR-T cells bind specifically to each of the three BAFF receptors and are effective at killing multiple B cell cancers, including mantle cell lymphoma (MCL), multiple myeloma (MM), and acute lymphoblastic leukemia (ALL), in vitro and in vivo using different xenograft models. Co-culture of BAFF CAR-T cells with these tumor cells results in induction of activation marker CD69, degranulation marker CD107a, and multiple proinflammatory cytokines. In summary, we report a ligand-based BAFF CAR-T capable of binding three different receptors, minimizing the potential for antigen escape in the treatment of B cell cancers.

scholarly journals Enhanced Solid Tumor Recognition and T cell Stemness with SynNotch CAR Circuits

2021 ◽  
Author(s):  
Axel Hyrenius-Wittsten ◽  
Yang Su ◽  
Minhee Park ◽  
Julie M Garcia ◽  
Nathaniel Perry ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Specific Antigen ◽  
Tumor Control ◽  
Car T Cells ◽  
Therapeutic Benefits ◽  
Car T ◽  
Tumor Recognition ◽  
Life Threatening

The lack of highly tumor-specific antigens limits the development of engineered T cell therapeutics because of life-threatening on-target/off-tumor toxicities. Here we identify ALPPL2 as a tumor-specific antigen expressed in a spectrum of solid tumors, including mesothelioma. ALPPL2 can act as a sole target for chimeric antigen receptor (CAR) therapy or be combined with tumor-associated antigens such as MCAM or mesothelin in synthetic Notch (synNotch) CAR combinatorial antigen circuits. SynNotch CAR T cells display superior tumor control when compared to CAR T cells to the same antigens by prevention of CAR-mediated tonic signaling allowing T cells to maintain a long-lived memory and non-exhausted phenotype. Collectively, we establish ALPPL2 as a clinically viable target for multiple solid tumors and demonstrate the multi-faceted therapeutic benefits of synNotch CAR T cells.

Sign in / Sign up

Export Citation Format

Share Document