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An excessive immune response known as cytokine storm is the hallmark of severe COVID-19. The cause of this cytokine rampage is yet not known. Based on recent epidemiological evidence, we hypothesized that CD80/86 signaling is essential for this hyperinflammation, and that blocking this proinflammatory axis could be an effective therapeutic approach to protect against severe COVID-19. Here we provide exploratory evidence that abatacept, a drug that blocks CD80/86 co-stimulation, produces changes at the systemic level that are highly antagonistic of the proinflammatory processes elicited by COVID-19. Using RNA-seq from blood samples from a longitudinal cohort of n = 38 rheumatic patients treated with abatacept, we determined the immunological processes that are significantly regulated by this treatment. We then analyzed available blood RNA-seq from two COVID19 patient cohorts, a very early cohort from the epicenter of the pandemic in China (n = 3 COVID-19 cases and n = 3 controls), and a recent and larger cohort from the USA (n = 49 severe and n = 51 mild COVD-19 patients). We found a highly significant antagonism between SARS-CoV-2 infection and COVID-19 severity with the systemic response to abatacept. Analysis of previous single-cell RNA-seq data from bronchoalveolar lavage fluid from mild and severe COVID-19 patients and controls, reinforce the implication of the CD80/86 proinflammatory axis. Our functional results further support abatacept as a candidate therapeutic approach to prevent severe COVID-19.

Currently, there is a multitude of CD3 bispecifics with different molecular designs and binding properties in preclinical and clinical development for the treatment of liquid or solid tumors. The key safety concerns with CD3 bispecifics are excessive release of cytokines, which may translate to potentially life-threating cytokine release syndrome (CRS), target organ toxicity due to redirection of T-cells to normal tissues expressing the tumor-associated antigen (TAA) (off-tumor/on-target cytotoxicity), and, in some instances, neurotoxicity. Another key challenge is to arrive at a safe clinical starting dose and an efficient escalating strategy that allows patients in early dose cohorts the potential for clinical benefit in Phase 1 trials. To expand the therapeutic index and bring more treatment options to patients, there are intense efforts to overcome these challenges through improvements in molecular design, preclinical safety assessment strategies, and clinical management practices. A recent workshop at the U.S. Food and Drug Administration (FDA) with industry, academic, and regulatory agency representation was held to discuss the challenges and explore where such improvements to the development of CD3 bispecifics can be implemented. Here, the content of the presentations and the discussion that occurred during this workshop are summarized.

Purpose: A task force of experts from 11 United States (US) centers, sought to describe practices for managing chimeric antigen receptor (CAR) T-cell toxicity in the intensive care unit (ICU)., Materials and Methods: Between June-July 2019, a survey was electronically distributed to 11 centers. The survey addressed: CAR products, toxicities, targeted treatments, management practices and interventions in the ICU., Results: Most centers (82%) had experience with commercial and non-FDA approved CAR products. Criteria for ICU admission varied between centers for patients with Cytokine Release Syndrome (CRS) but were similar for Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS). Practices for vasopressor support, neurotoxicity and electroencephalogram monitoring, use of prophylactic anti-epileptic drugs and tocilizumab were comparable. In contrast, fluid resuscitation, respiratory support, methods of surveillance and management of cerebral edema, use of corticosteroid and other anti-cytokine therapies varied between centers., Conclusions: This survey identified areas of investigation that could improve outcomes in CAR T-cell recipients such as fluid and vasopressor selection in CRS, management of respiratory failure, and less common complications such as hemophagocytic lymphohistiocytosis, infections and stroke. The variability in specific treatments for CAR T-cell toxicities, needs to be considered when designing future outcome studies of critically ill CAR T-cell patients., Competing Interests: Declaration of Competing Interest CG, ARBT, CM, MMH, PR, AD, AD, EM, JA, JNB, MVM, NNS, JLN, KP, RSS, SSK, SMP, HPM, AGM, ASA have no conflict of interest to declare. BH: has received research funding from Kite Pharmaceuticals. Have also served as a consultant to Juno, Novartis and Kite Pharmaceuticals. CJT: receives research funding from Juno Therapeutics and Nektar Therapeutics; is a Scientific Advisory Board member for Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Myeloid Therapeutics, T-CURX, and Arsenal Bio; has served on ad hoc advisory boards for Nektar Therapeutics, Allogene, Kite/Gilead, Novartis, Humanigen, PACT Pharma, and Astra Zeneca; has options with Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Myeloid Therapeutics, and Arsenal Bio; and has a patent licensed to Juno Therapeutics. MJF: Does consulting for Novartis, Celgene, Kite and Arcellx. JNK is the principal investigator of Cooperative Research and Development Agreements with Kite, a Gilead Company and Celgene. AB: Ad Board for Kite pharmaceuticals on August 2018. SSN: has received research support from Kite/Gilead, Merck, BMS, Cellectis, Poseida, Karus, Acerta, Allogene, and Unum Therapeutics; and served as advisory Board Member / Consultant for Kite/Gilead, Merck, Celgene, Novartis, Unum Therapeutics, Pfizer, Precision Biosciences, Cell Medica, Allogene, Calibr, Incyte, and Legend Biotech. YL: as Principal Investigator Mayo Clinic receives compensation for research activities and clinical trials with Kite/Gilead, Janssen, Celgene, BlueBird Bio, Merck and Takeda; advisory board with Kite/Gilead, Novartis, Janssen, Legend BioTech, JUNO, Celgene, BlueBird Bio, Ethos; DSMB: Sorrento; steering committee: Celgene, Janssen, Legend BioTech., (Copyright © 2020 Elsevier Inc. All rights reserved.)