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Drug Repurposing and Novel Antiviral Drugs for COVID-19 Management
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Shailendra Dwivedi, Aakanksha Rawat, Amit Ranjan, Ruchika Agrawal, Radhieka Misra, Sunil Kumar Gupta, Surekha Kishore, Sanjeev Misra
Tocilizumab (TCZ) is another humanized mono- clonal antibody that inhibits the IL-6 receptor. TCZ has been used successfully for the treatment of rheumatoid arthritis and other auto-inflammatory processes. It has also been useful for the treatment of severe cytokine release syndrome (CRS) induced by the chimeric antigen receptor. Consequently, TCZ, an IL-6 receptor blocker, may be suitable for treating patients with severe pneumonia. A recent retrospective, observational study demonstrated that TCZ significantly reduced mortality among 630 COVID-19 patients admitted to an ICU [19]. Another study demonstrated that TCZ decreased mortality and duration of hospital stay in critically ill patients but seemed to have a high risk of serious infections [20]. Similar outcomes were reported in another related study involving 158 severe COVID-19 patients claiming significantly decreased mortality with TCZ [21]. Furthermore, in research carried out by Yale University School of Medicine, reduced need for mechanical ventilation and improved inflammatory biomarkers were noted in patients on TCZ [22]. A study in China revealed that TCZ significantly improved clinical outcomes and reduced mortality among patients with severe COVID-19 [23]. It also reduced the risk of cytokine storms among COVID-19 patients in another study. The abilities of the TCZ to relieve inflammation and cytokine storms among COVID-19 patients were further justified in many meta-analyses [24–26].
Immunomodulatory Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Natural Killer (NK) cells have several potential advantages over T cells for use in CAR-type anticancer therapies. They are easier to isolate than T lymphocytes, reducing the risk of contamination, thus minimizing the potential for Graft-versus-Host Disease (GVHD). They also have a shorter life span, decreasing the risk of over-expansion. In addition, cytokines released by NK cells appear to be safer than those released by CAR-T cells in that they are less likely to cause cytokine release syndrome (CRS). Finally, in contrast to T lymphocytes, NK cells trigger the lysis of target cells in an MHC-independent manner, meaning that down-regulation of the CAR target antigen is less likely to occur with NK cells.
Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Over the past year, several new drugs, including blinatumomab, a bispecific T-cell engaging (BiTE) antibody, which binds simultaneously to CD3-positive cytotoxic T-cells and to CD19-positive B-cells, enabling the patient’s T-cells to recognize and eliminate CD19-positive lymphoblasts, have been licensed in an effort to induce sustainable second and subsequent remissions for patients with relapsed/refractory ALL.54 Inotuzumab ozagamicin, an anti-CD22 antibody conjugated to calicheamicin, was approved after it was found to accord MRD negativity with improved OS, which was improved further by allo-SCT.55 Tisagenlecleucel, an adoptive immunotherapy using autologous T-cells genetically engineered to express a CAR, was approved in 2017 for younger patients with relapsed/refractory ALL after it was noted to confer 70–90% response rates.56,57 As with all CAR T-cell therapy, rapid and durable responses occur but are often associated with significant acute toxicities, which can be severe and even fatal. Cytokine release syndrome is the most common side effect, affecting over 50% of patients, and ranges from low-grade constitutional symptoms to life-threatening, multi-organ failure. The second most common acute toxicity is neurotoxicity, comprising confusion, delirium, seizures, and encephalopathy (termed CAR T-cell related encephalopathy syndrome).58
Factors Affecting the Cancer Immunotherapeutic Efficacy of T Cell Bispecific Antibodies and Strategies for Improvement
Published in Immunological Investigations, 2022
Meixiao Long, Alice S. Mims, Zihai Li
Under conditions that eventually lead to T-cell tolerance/anergy, the functional impairment of CD8 T-cells occurs in a hierarchical pattern. In particular, the cytolytic function of effector T cells is retained or less affected than other functions, such as proliferation and cytokine production (Hombach et al. 2001; Mittrücker et al. 2001; Suresh et al. 2001b). This type of “split dysfunctional status” has also been reported with activation-induced nonresponsiveness (AINR), where CD8 T-cells are stimulated with some costimulatory signals and acquire effector functions. However, for a period of time, the T-cells show signs of split anergy, with compromised capability for proliferation and producing IL-2, while cytolytic function remains intact (Deeths et al. 1999; Mescher et al. 2007; Tham et al. 2002). In the case of T-BsAb therapy, with all T-cells of broad antigen specificity being redirected toward target cells, maintaining T-cell cytolytic function is likely crucial for efficacy, whereas proliferation might be less important. Further, diminished cytokine production might actually be desirable to avoid cytokine release syndrome.
The immunologic aspects of cytokine release syndrome and graft versus host disease following CAR T cell therapy
Published in International Reviews of Immunology, 2022
Vahid Mansouri, Niloufar Yazdanpanah, Nima Rezaei
Cytokine release syndrome is the most common and most important life-threatening adverse effect of treatment with CAR T cells. The term CRS was first used in the early 90 s for a monoclonal antibody (muromonab-CD3) [56] and it is affiliated to a systemic inflammation through surge of cytokines and it can be stimulated by different factors. CRS is not a specific toxicity for CAR T cells and could be occurred following using monoclonal antibodies, chemotherapy agents, haploidentical donor stem cell transplantation, and GvHD [57–68]. Furthermore, severe CRS can be a major consequence of high-burden infectious diseases such as COVID-19 and Influenza [69, 70]. Although CRS follows a common pathway in all of these conditions, due to the emergence of CAR T cell products, characterization and identification of CRS following CAR T cell treatment is crucial.
Clinical development of an anti-GPC-1 antibody for the treatment of cancer
Published in Expert Opinion on Biological Therapy, 2022
Saikat Ghosh, Pie Huda, Nicholas Fletcher, Douglas Campbell, Kristofer J. Thurecht, Bradley Walsh
A bispecific approach was investigated using anti-GPC-1 and anti-CD3 in a tandem Fv (variable fragment) format [57]. This mAb format showed good cell killing activity against DU-145 GPC-1 positive cells with minimal activity against GPC-1-negative cell line. Expected T cell activation profiles were observed, together with cytokine release and upregulation of PD-1 on T cells, suggesting a potential ability to synergize with checkpoint inhibitor molecules such as pembrolizumab. Despite successful pre-clinical studies, bi-specifics have not proven as successful in treating solid tumors as they have in treating blood cancers. Furthermore cytokine release syndrome can prove challenging to manage for patients with significant possibility of harm. The bi-specific approach therefore was less favorable for clinical development.