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 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 Renaissance of armored immune effector cells, CAR-NK cells, brings the higher hope for successful cancer therapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Faroogh Marofi ◽  
Heshu Sulaiman Rahman ◽  
Lakshmi Thangavelu ◽  
Aleksey Dorofeev ◽  
Favian Bayas-Morejón ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Tumor Cells ◽  
Immune Effector ◽  
Effector Cells ◽  
Car T Cells ◽  
Cell Immunotherapy ◽  
Car T ◽  
Immune Effector Cells ◽  
T Cell Immunotherapy

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.

scholarly journals Melanoma cell-derived exosomes in plasma of melanoma patients suppress functions of immune effector cells

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Priyanka Sharma ◽  
Brenda Diergaarde ◽  
Soldano Ferrone ◽  
John M. Kirkwood ◽  
Theresa L. Whiteside
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Melanoma Cell ◽  
Disease Stage ◽  
Immune Effector ◽  
Effector Cells ◽  
Major Mechanism ◽  
Protein Levels ◽  
Melanoma Patients ◽  
Induced Apoptosis

AbstractMelanoma patients’ plasma contains exosomes produced by malignant and normal cells. Plasma exosomes were isolated and separated by immunocapture into two fractions: melanoma cell-derived exosomes (MTEX) and normal cell-derived exosomes (non-MTEX). Immunosuppressive effects of MTEX on primary human immune cells were evaluated. Exosomes were isolated from plasma of 12 melanoma patients and six healthy donors (HDs). Expression levels of 19 immunoregulatory proteins in MTEX, non-MTEX and HDs exosomes were evaluated by on-bead flow cytometry. Functional/phenotypic changes induced in CD8+ T or natural killer (NK) cells by MTEX or non-MTEX were compared. Plasma protein levels were higher in patients than HDs (P < 0.0009). In patients, MTEX accounted for 23–66% of total exosomes. MTEX were enriched in immunosuppressive proteins (P = 0.03). MTEX, but not HDs exosomes, inhibited CD69 expression (P ≤ 0.0008), induced apoptosis (P ≤ 0.0009) and suppressed proliferation (P ≤ 0.002) in CD8+ T cells and downregulated NKG2D expression in NK cells (P = 0.001). Non-MTEX were enriched in immunostimulatory proteins (P = 0.002) and were only weakly immunosuppressive. Elevated MTEX/total exosome ratios and, surprisingly, non-MTEX ability to induce apoptosis of CD8+ T cells emerged as positive correlates of disease stage. MTEX emerge as the major mechanism of tumor-induced immune suppression and as an underestimated barrier to successful melanoma immunotherapy.

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 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 Multi-antigen-targeted chimeric antigen receptor T cells for cancer therapy

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiao Han ◽  
Yao Wang ◽  
Jianshu Wei ◽  
Weidong Han
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Logic Gates ◽  
Cell Types ◽  
Boolean Logic ◽  
Therapeutic Window ◽  
Car T Cells ◽  
Car T

AbstractThe approval of two chimeric antigen receptor-modified T cell types by the US Food and Drug Administration (FDA) for the treatment of hematologic malignancies is a milestone in immunotherapy; however, the application of CAR-T cells has been limited by antigen escape and on-target, off-tumor toxicities. Therefore, it may be a potentially effective strategy to select appropriate targets and to combine multi-antigen-targeted CAR-T cells with “OR”, “AND” and “NOT” Boolean logic gates. We summarize the current limitations of CAR-T cells as well as the efficacy and safety of logic-gated CAR-T cells in antitumor therapy. This review will help to explore more optimized strategies to expand the CAR-T cell therapeutic window.

scholarly journals Donor-derived CD19 CAR-T cell therapy of relapse of CD19-positive B-ALL post allotransplant

Leukemia ◽  
2020 ◽  
Author(s):  
Cheng Zhang ◽  
Xiao-Qi Wang ◽  
Rong-Li Zhang ◽  
Fang Liu ◽  
Yi Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Lymphoblastic Leukemia ◽  
Multiorgan Failure ◽  
High Rate ◽  
T Cell Therapy ◽  
Immune Effector ◽  
Car T Cells ◽  
Car T ◽  
Grade 3 ◽  
Histological Remission

Abstract Safety and efficacy of allogeneic anti-CD19 chimeric antigen receptor T cells (CAR-T cells) in persons with CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) relapsing after an allotransplant remain unclear. Forty-three subjects with B-ALL relapsing post allotransplant received CAR-T cells were analyzed. 34 (79%; 95% confidence interval [CI]: 66, 92%) achieved complete histological remission (CR). Cytokine release syndrome (CRS) occurred in 38 (88%; 78, 98%) and was ≥grade-3 in 7. Two subjects died from multiorgan failure and CRS. Nine subjects (21%; 8, 34%) developed ≤grade-2 immune effector cell-associated neurotoxicity syndrome (ICANS). Two subjects developed ≤grade-2 acute graft-versus-host disease (GvHD). 1-year event-free survival (EFS) and survival was 43% (25, 62%). In 32 subjects with a complete histological remission without a second transplant, 1-year cumulative incidence of relapse was 41% (25, 62%) and 1-year EFS and survival, 59% (37, 81%). Therapy of B-ALL subjects relapsing post transplant with donor-derived CAR-T cells is safe and effective but associated with a high rate of CRS. Outcomes seem comparable to those achieved with alternative therapies but data from a randomized trial are lacking.

scholarly journals Practical aspects of building a new immunotherapy program: the future of cell therapy

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 579-584
Author(s):  
Jesús G. Berdeja
Keyword(s):  
T Cells ◽  
Effector Cell ◽  
Hematologic Malignancies ◽  
Immune Effector Cell ◽  
Optimal Care ◽  
Immune Effector ◽  
Car T Cells ◽  
Car T ◽  
Challenges And Opportunities ◽  
Disease Specialist

Abstract Cellular-redirecting therapies, including bispecific T-cell engagers and chimeric antigen receptor (CAR) T cells, are rapidly changing the treatment landscape of hematologic malignancies and solid tumor malignancies. I will discuss the unique safety profile and logistical aspects that pose challenges and opportunities for the safe and successful delivery of these therapies. Close interaction, communication, and established partnerships between the primary oncologist, the disease specialist, and the immune effector cell provider will be needed to provide optimal care longitudinally for any patient. I will discuss practical ways for any program to deliver these therapies and how future advances may widen availability beyond just a few centers.

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.

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