Conventional CARs versus modular CARs

AbstractIn recent decades, a new method of cellular immunotherapy was introduced based on engineering and empowering the immune effector cells. In this type of immunotherapy, the immune effector cells are equipped with chimeric antigen receptor (CAR) to specifically target cancer cells. In much of the trials and experiments, CAR-modified T cell immunotherapy has achieved very promising therapeutic results in the treatment of some types of cancers and infectious diseases. However, there are also some considerable drawbacks in the clinical application of CAR-T cells although much effort is in progress to rectify the issues. In some conditions, CAR-T cells initiate over-activated and strong immune responses, therefore, causing unexpected side-effects such as systemic cytokine toxicity (i.e., cytokine release syndrome), neurotoxicity, on-target, off-tumor toxicity, and graft-versus-host disease (GvHD). To overcome these limitations in CAR-T cell immunotherapy, NK cells as an alternative source of immune effector cells have been utilized for CAR-engineering. Natural killer cells are key players of the innate immune system that can destroy virus-infected cells, tumor cells, or other aberrant cells with their efficient recognizing capability. Compared to T cells, CAR-transduced NK cells (CAR-NK) have several advantages, such as safety in clinical use, non-MHC-restricted recognition of tumor cells, and renewable and easy cell sources for their preparation. In this review, we will discuss the recent preclinical and clinical studies, different sources of NK cells, transduction methods, possible limitations and challenges, and clinical considerations.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21228620 ◽

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.

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Next-generation cell therapies: the emerging role of CAR-NK cells

Hematology ◽

10.1182/hematology.2020002547 ◽

2020 ◽

Vol 2020 (1) ◽

pp. 570-578

Author(s):

Rafet Basar ◽

May Daher ◽

Katayoun Rezvani

Keyword(s):

T Cells ◽

Cell Therapy ◽

Natural Killer ◽

Γδ T Cells ◽

Antigen Receptors ◽

T Cell Therapy ◽

Cell Therapies ◽

Immune Effector ◽

Effector Cells ◽

Immune Effector Cells

Abstract T cells engineered with chimeric antigen receptors (CARs) have revolutionized the field of cell therapy and changed the paradigm of treatment for many patients with relapsed or refractory B-cell malignancies. Despite this progress, there are limitations to CAR-T cell therapy in both the autologous and allogeneic settings, including practical, logistical, and toxicity issues. Given these concerns, there is a rapidly growing interest in natural killer cells as alternative vehicles for CAR engineering, given their unique biological features and their established safety profile in the allogeneic setting. Other immune effector cells, such as invariant natural killer T cells, γδ T cells, and macrophages, are attracting interest as well and eventually may be added to the repertoire of engineered cell therapies against cancer. The pace of these developments will undoubtedly benefit from multiple innovative technologies, such as the CRISPR-Cas gene editing system, which offers great potential to enhance the natural ability of immune effector cells to eliminate refractory cancers.

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Strategies to improve the safety profile of CAR-T therapy

Postępy Polskiej Medycyny i Farmacji ◽

10.5604/01.3001.0014.9200 ◽

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.

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

Acta Haematologica Polonica ◽

10.2478/ahp-2020-0004 ◽

2020 ◽

Vol 51 (1) ◽

pp. 11-16 ◽

Cited By ~ 1

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.

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Fast off-rate CD229 chimeric antigen receptor T cells efficiently target multiple myeloma, spare T cells, and exhibit reduced trogocytosis

10.1101/2021.12.06.471279 ◽

2021 ◽

Author(s):

Erica R. Vander Mause ◽

Jillian M. Baker ◽

Sabarinath V. Radhakrishnan ◽

Patricia Davis ◽

Jens Panse ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

T Cell ◽

Antigen Receptors ◽

Car T Cells ◽

Car T Cell ◽

Car T ◽

Life Threatening ◽

Low Levels ◽

Anti Tumor Activity

ABSTRACTT cells expressing chimeric antigen receptors have shown remarkable therapeutic activity against different types of cancer. However, their wider use has been hampered by the potential for life-threatening toxicities due to the unintended targeting of healthy cells expressing low levels of the targeted antigen. We have now developed an affinity-tuning approach for the generation of minimally modified, low-affinity antibody variants derived from existing high-affinity antibodies. Using this approach, we engineered low affinity variants of the fully human CD229-specific antibody 2D3. Parental 2D3 originally efficiently targeted multiple myeloma cells but also healthy T cells expressing low levels of CD229. We demonstrate that CAR T cells based on a low affinity variant of 2D3 maintain the parental antibody’s anti-tumor activity, but lack its targeting of healthy T cells. In addition, variant CD229 CAR T cells show reduced trogocytosis potentially augmenting CAR T cell persistence. The fast off-rate CAR produced using our affinity tuning approach eliminates a key liability of CD229 CAR T cells and paves the way for the effective and safe treatment of patients with multiple myeloma.One sentence summaryAffinity tuning approach yields low affinity CD229 CAR binding domain maintaining the parental clone’s anti-tumor activity while eliminating killing of healthy T cells, increasing CAR T cell expansion, and decreasing trogocytosis.

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Managing therapy-associated neurotoxicity in children with ALL

Hematology ◽

10.1182/hematology.2021000269 ◽

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.

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Next-generation cell therapies: the emerging role of CAR-NK cells

Blood Advances ◽

10.1182/bloodadvances.2020002547 ◽

2020 ◽

Vol 4 (22) ◽

pp. 5868-5876

Author(s):

Rafet Basar ◽

May Daher ◽

Katayoun Rezvani

Keyword(s):

T Cells ◽

Cell Therapy ◽

Natural Killer ◽

Γδ T Cells ◽

Antigen Receptors ◽

T Cell Therapy ◽

Cell Therapies ◽

Immune Effector ◽

Effector Cells ◽

Immune Effector Cells

Abstract T cells engineered with chimeric antigen receptors (CARs) have revolutionized the field of cell therapy and changed the paradigm of treatment for many patients with relapsed or refractory B-cell malignancies. Despite this progress, there are limitations to CAR-T cell therapy in both the autologous and allogeneic settings, including practical, logistical, and toxicity issues. Given these concerns, there is a rapidly growing interest in natural killer cells as alternative vehicles for CAR engineering, given their unique biological features and their established safety profile in the allogeneic setting. Other immune effector cells, such as invariant natural killer T cells, γδ T cells, and macrophages, are attracting interest as well and eventually may be added to the repertoire of engineered cell therapies against cancer. The pace of these developments will undoubtedly benefit from multiple innovative technologies, such as the CRISPR-Cas gene editing system, which offers great potential to enhance the natural ability of immune effector cells to eliminate refractory cancers.

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Soluble CD70: a novel immunotherapeutic agent for experimental glioblastoma

Journal of Neurosurgery ◽

10.3171/2009.11.jns09901 ◽

2010 ◽

Vol 113 (2) ◽

pp. 280-285 ◽

Cited By ~ 18

Author(s):

James Miller ◽

Guenter Eisele ◽

Ghazaleh Tabatabai ◽

Steffen Aulwurm ◽

Gabriele von Kürthy ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

Malignant Gliomas ◽

Ectopic Expression ◽

Glioma Cells ◽

Interferon Γ ◽

Soluble Form ◽

Immune Effector ◽

Effector Cells ◽

Immune Effector Cells

Object Given the overall poor outcome with current treatment strategies in malignant gliomas, immunotherapy has been considered a promising experimental approach to glioblastoma for more than 2 decades. A cell surface molecule, CD70, may induce potent antitumor immune responses via activation of the costimulatory receptor CD27 expressed on immune effector cells. There is evidence that a soluble form of CD70 (sCD70) may exhibit biological activity, too. A soluble costimulatory ligand is attractive because it may facilitate immune activation and may achieve a superior tissue distribution. Methods To test the antiglioma effect of sCD70, the authors genetically modified SMA-560 mouse glioma cells to secrete the extracellular domain of CD70. They assessed the immunogenicity of the transfected cells in cocultures with immune effector cells by the determination of immune cell proliferation and the release of interferon-γ. Syngeneic VM/Dk mice were implanted orthotopically with control or sCD70-releasing glioma cells to determine a survival benefit mediated by sCD70. Depletion studies were performed to identify the cellular mediators of prolonged survival of sCD70-releasing glioma-bearing mice. Results The authors found that ectopic expression of sCD70 enhanced the proliferation and interferon-γ release of syngeneic splenocytes in vitro. More importantly, sCD70 prolonged the survival of syngeneic VM/Dk mice bearing intracranial SMA-560 gliomas. The survival rate at 60 days increased from 5 to 45%. Antibody-mediated depletion of CD8-positive T cells abrogates the survival advantage conferred by sCD70. Conclusions These data suggest that sCD70 is a potent stimulator of antiglioma immune responses that depend critically on CD8-positive T cells. Soluble CD70 could be a powerful adjuvant for future immunotherapy trials for glioblastoma.

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