Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy

A paradigm shift has recently occurred in the field of cancer therapeutics. Traditional anticancer agents, such as chemotherapy, radiotherapy and small-molecule drugs targeting specific signalling pathways, have been joined by cellular immunotherapies based on T cell engineering. The rapid adoption of novel, patient-specific cellular therapies builds on scientific developments in tumour immunology, genetic engineering and cell manufacturing, best illustrated by the curative potential of chimeric antigen receptor (CAR) T cell therapy targeting CD19-expressing malignancies. However, the clinical benefit observed in many patients may come at a cost. In up to one-third of patients, significant toxicities occur that are directly associated with the induction of powerful immune effector responses. The most frequently observed immune-mediated toxicities are cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. This Review discusses our current understanding of their pathophysiology and clinical features, as well as the development of novel therapeutics for their prevention and/or management

Monoclonal antibodies in neuro-oncology: Getting past the blood-brain barrier

Monoclonal antibodies (mAbs) are used with increasing success against many tumors, but for brain tumors the blood-brain barrier (BBB) is a special concern. The BBB prevents antibody entry to the normal brain; however, its role in brain tumor therapy is more complex. The BBB is closest to normal at micro-tumor sites; its properties and importance change as the tumor grows. In this review, evolving insight into the role of the BBB is balanced against other factors that affect efficacy or interpretation when mAbs are used against brain tumor targets. As specific examples, glioblastoma multiforme (GBM), primary central nervous system lymphoma (PCNSL) and blood-borne metastases from breast cancer are discussed in the context of treatment, respectively, with the mAbs bevacizumab, rituximab and trastuzumab, each of which is already widely used against tumors outside the brain. It is suggested that success against brain tumors will require getting past the BBB in two senses: physically, to better attack brain tumor targets, and conceptually, to give equal attention to problems that are shared with other tumor sites

ASBMT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells

Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment of patients up to age 25 years with relapsed or refractory B cell acute lymphoblastic leukemia years "?>and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Blood and Marrow Transplantation (ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting

Clinical trials of CAR-T cells in China

Abstract Novel immunotherapeutic agents targeting tumor-site microenvironment are revolutionizing cancer therapy. Chimeric antigen receptor (CAR)-engineered T cells are widely studied for cancer immunotherapy. CD19-specific CAR-T cells, tisagenlecleucel, have been recently approved for clinical application. Ongoing clinical trials are testing CAR designs directed at novel targets involved in hematological and solid malignancies. In addition to trials of single-target CAR-T cells, simultaneous and sequential CAR-T cells are being studied for clinical applications. Multi-target CAR-engineered T cells are also entering clinical trials. T cell receptor-engineered CAR-T and universal CAR-T cells represent new frontiers in CAR-T cell development. In this study, we analyzed the characteristics of CAR constructs and registered clinical trials of CAR-T cells in China and provided a quick glimpse of the landscape of CAR-T studies in China