The PI3K δ inhibitor idelalisib impairs the function of human dendritic cells

AbstractThe PI3K δ-inhibitor Idelalisib is approved for the treatment of Non-Hodgkin lymphoma. However, its use has been decreased within the last years due to deleterious infections such as cytomegalovirus and pneumocystis jirovecii. Here, we have investigated the effect of Idelalisib on human monocyte-derived den dritic cells (DCs) as important players in the induction of immune responses. We found that Idelalisib-treated DCs displayed impaired T cell stimulatory function. PI3Kδ inhibition during differentiation resulted in decreased Interleukin-12, Interleukin-13 and TNFα production by DCs after lipopolys accharide stimulation. Moreover, DCs showed decreased expression of the activation marker CD83 after Idelalisib treatment. Further, in line with this was the failure of Idelalisib-treated DCs to properly induce allogeneic T cells in a dose-dependent manner. Finally, activation of the NFκB pathway w as also ablated in Idelalisib-treated DCs. Our results implicate that severe infectious complications may not only result from direct PI3Kδ-inhibition in T cells, but also from impaired DC function in Idelalisib-treated patients. Here, we provide new insight into the pathogenesis of Idelalisib-asso ciated infectious complications. Our study may further provide a rationale for the use of Idelalisib as a novel therapeutic option in inflammatory diseases.
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research

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CONCLUSIONS: We demonstrated the feasibility of our large-scale platform for generating CMV-CD19CAR T cells for clinical application. We plan to initiate a clinical trial at City of Hope using CMV-CD19CAR T cells for patients with intermediate/high-grade B cell non-Hodgkin's lymphoma immediately after autologous hematopoietic cell transplantation followed by vaccination with a novel CMV vaccine based on Modified Vaccinia Ankara (Triplex) 28 days and 56 days post-T cell infusion.PMID:35027426 | DOI:10.1136/jitc-2021-003461
Source: Cancer Control - Category: Cancer & Oncology Authors: Source Type: research
Biochem Pharmacol. 2021 Feb 19:114485. doi: 10.1016/j.bcp.2021.114485. Online ahead of print.ABSTRACTSince the 1950s, great efforts have been made to develop antiviral agents against many infectious diseases such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), human cytomegalovirus (HCMV), herpes simplex virus (HSV), and varicella-zoster virus (VZV). Among the list of nearly 106 antiviral agents approved in the past five decades, Prof. Erik De Clercq has contributed to the development of 7 antiviral drugs: tenofovir disoproxil fumarate (Viread®) for HIV and HBV treatment, tenofo...
Source: Biochemical Pharmacology - Category: Drugs & Pharmacology Authors: Source Type: research
Infectious diseases are still a significant cause of morbidity and mortality worldwide. Despite the progress in drug development, the occurrence of microbial resistance is still a significant concern. Alternative therapeutic strategies are required for non-responding or relapsing patients. Chimeric antigen receptor (CAR) T cells has revolutionized cancer immunotherapy, providing a potential therapeutic option for patients who are unresponsive to standard treatments. Recently two CAR T cell therapies, Yescarta® (Kite Pharma/Gilead) and Kymriah® (Novartis) were approved by the FDA for the treatments of certain types ...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Reena Goswami1, Gayatri Subramanian2, Liliya Silayeva1, Isabelle Newkirk1, Deborah Doctor1, Karan Chawla2, Saurabh Chattopadhyay2, Dhyan Chandra3, Nageswararao Chilukuri1 and Venkaiah Betapudi1,4* 1Neuroscience Branch, Research Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen, MD, United States 2Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States 3Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States 4Department of Physiology and Biophysics, Case Western Reserve University, Clev...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
BackgroundHigh dose chemotherapy and autologous stem cell transplant (ASCT) results in cure for up to 50% of patients with Hodgkin (HL) and aggressive non-Hodgkin lymphoma (NHL) that relapse after initial treatment with chemo-immunotherapy. Despite improvements in supportive care and patient selection, death after ASCT remains a concern due to progressive disease, infection, and other treatment- and non-treatment-related causes. We evaluated causes and predictors of death in patients undergoing ASCT for HL and NHL.MethodsWe conducted a single-institution, retrospective study of all patients with HL and NHL including diffus...
Source: Blood - Category: Hematology Authors: Tags: 731. Clinical Autologous Transplantation: Results: Poster I Source Type: research
Conclusion: Response to acalabrutinib remained consistent during long-term (>24-month) follow-up, including high response rates, median PFS of 19.5 months, and a median OS that has not yet been reached, confirming efficacy in patients with relapsed/refractory MCL. The AE profile was largely similar to earlier reporting, with limited additional safety events observed with an additional year of follow-up.DisclosuresWang: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Honoraria, R...
Source: Blood - Category: Hematology Authors: Tags: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma-Clinical Studies: Poster II Source Type: research
In conclusion, mutations responsible for GCV resistance was detected in 6.6% (2/30) of immunocompromised patients receiving GCV, indicating that the determination of CMV antiviral drug resistance may help clinicians for planning the antiviral therapy. PMID: 26313280 [PubMed - in process]
Source: Mikrobiyoloji Bulteni - Category: Microbiology Tags: Mikrobiyol Bul Source Type: research
Primary disorders of the immune system can be divided into four categories, (1) disorders of the humoral immunity, (2) disorders of cellular immunity, (3) disorders of phagocytes, and (4) disorders of complement. In addition, there are many causes of secondary immunodeficiency such as treatment with immunosuppressive or chemotherapeutic agents, protein-losing enteropathy, and infection with a human immunodeficiency virus (HIV). Generally, immunocompromised patients are unable to mount an immune response to a vaccine or an infection in the same manner as non-immunocompromised individuals. Opportunistic infections to which i...
Source: NIH OTT Licensing Opportunities - Category: Research Authors: Source Type: research
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