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myeloid cells. Advanced age of the patients, comorbidities, immunosuppressive bone marrow microenvironment, and cytokine release syndrome are some other challenges that are not unique to myeloid malignancies but pose significant challenge for the successful adaptation of this approach for treatment. In this review, we highlight the challenges and solutions to adopt chimeric antigen receptor T-cell therapies to treat myeloid malignancies.

Immune checkpoint inhibition has vastly improved the treatment of solid tumors, but most patients do not experience durable clinical benefit, so novel immunotherapeutic approaches are needed. Autologous T cells genetically engineered to express chimeric antigen receptors (CARs) have led to unprecedented clinical success in hematologic malignancies, and increasing efforts are actively being pursued to translate these benefits to the solid tumor arena. However, solid tumors present unique challenges for CAR T-cell development. In this review, we examine the potential barriers to progress and present emerging approaches to overcome these challenges with CAR therapy in solid tumors.

Immune checkpoint inhibition has vastly improved the treatment of solid tumors, but most patients do not experience durable clinical benefit, so novel immunotherapeutic approaches are needed. Autologous T cells genetically engineered to express chimeric antigen receptors (CARs) have led to unprecedented clinical success in hematologic malignancies, and increasing efforts are actively being pursued to translate these benefits to the solid tumor arena. However, solid tumors present unique challenges for CAR T-cell development. In this review, we examine the potential barriers to progress and present emerging approaches to overcome these challenges with CAR therapy in solid tumors.

Chimeric antigen receptor (CAR) T-cell therapy is a highly effective new treatment for relapsed and refractory hematological cancers but is associated with the novel treatment-limiting toxicities of cytokine release syndrome and neurotoxicity. Neurotoxicity, now more commonly referred to as immune effector cell-associated neurotoxicity syndrome (ICANS), is a clinical and neuropsychiatric syndrome that can occur in the days to weeks following CAR T-cell and other T-cell-engaging therapies. While the clinical characteristics of ICANS have been well described, its pathophysiology is poorly understood, and best treatment and preventive strategies remain elusive. Clinical trial experience and animal models suggest a central role for endothelial cell dysfunction, myeloid cells, blood-brain barrier disruption, and elevated central nervous system cytokine levels in the development of ICANS. Here we discuss ICANS incidence, clinical features, risk factors, biomarkers, pathophysiology, and grading and management.

Chimeric antigen receptor (CAR) T-cell therapy is a highly effective new treatment for relapsed and refractory hematological cancers but is associated with the novel treatment-limiting toxicities of cytokine release syndrome and neurotoxicity. Neurotoxicity, now more commonly referred to as immune effector cell-associated neurotoxicity syndrome (ICANS), is a clinical and neuropsychiatric syndrome that can occur in the days to weeks following CAR T-cell and other T-cell-engaging therapies. While the clinical characteristics of ICANS have been well described, its pathophysiology is poorly understood, and best treatment and preventive strategies remain elusive. Clinical trial experience and animal models suggest a central role for endothelial cell dysfunction, myeloid cells, blood-brain barrier disruption, and elevated central nervous system cytokine levels in the development of ICANS. GSK805 compound library inhibitor Here we discuss ICANS incidence, clinical features, risk factors, biomarkers, pathophysiology, and grading and management.

The successful application of chimeric antigen receptor (CAR) T cells for the treatment of relapsed and refractory B-cell malignancies has ushered in a new frontier for the immunotherapy of cancer. Despite its successes, CAR T-cell therapy presents several challenges. Cytokine release syndrome (CRS) triggered by robust and exponential CAR T-cell expansion is the most common adverse effect and may be severe or life-threatening. Although modulation of the interleukin 6 axis was appreciated early on as a means to manage CRS, the exact underlying mechanisms leading to severe CRS remain to be elucidated. What is clear is that severe CRS involves recruitment of the broader immune system into a hyperinflammatory and unregulated state. Myeloid-derived cells appear to play a critical role in this regard and are at the center of active investigation. In this article, we will focus on important elements of CRS, the clinical manifestations, underlying biology, and management strategies including grading, supportive cargies including grading, supportive care, and treatment via immunosuppression.

Despite improvements in effective therapy, multiple myeloma remains incurable, and virtually all patients will face relapsed disease at some point after diagnosis. The prognosis for relapsed myeloma after developing resistance to anti-CD38 monoclonal antibodies, proteasome inhibitors, immunomodulatory agents, and autologous stem cell transplantation has been poor; however, the development of immune effector cell therapy with chimeric antigen receptor (CAR) T cells may dramatically improve the outlook for patients, although none of these therapies are approved for MM to date. Herein, we review the development and history of CAR T-cell therapy for multiple myeloma, mechanisms of resistance, and strategies to improve outcomes with CAR T therapy.

Despite improvements in effective therapy, multiple myeloma remains incurable, and virtually all patients will face relapsed disease at some point after diagnosis. The prognosis for relapsed myeloma after developing resistance to anti-CD38 monoclonal antibodies, proteasome inhibitors, immunomodulatory agents, and autologous stem cell transplantation has been poor; however, the development of immune effector cell therapy with chimeric antigen receptor (CAR) T cells may dramatically improve the outlook for patients, although none of these therapies are approved for MM to date. Herein, we review the development and history of CAR T-cell therapy for multiple myeloma, mechanisms of resistance, and strategies to improve outcomes with CAR T therapy.