acp-196 and Neoplasms

The outbreak of the novel coronavirus disease 2019 (COVID-19) has emerged as one of the biggest global health threats worldwide. As of October 2020, more than 44 million confirmed cases and more than 1,160,000 deaths have been reported globally, and the toll is likely to be much higher before the pandemic is over. There are currently little therapeutic options available and new potential targets are intensively investigated. Recently, Bruton tyrosine kinase (BTK) has emerged as an interesting candidate. Elevated levels of BTK activity have been reported in blood monocytes from patients with severe COVID-19, compared with those from healthy volunteers. Importantly, various studies confirmed empirically that administration of BTK inhibitors (acalabrutinib and ibrutinib) decreased the duration of mechanical ventilation and mortality rate for hospitalized patients with severe COVID-19. Herein, we review the current information regarding the role of BTK in severe acute respiratory syndrome coronavirus 2 infections and the suitability of its inhibitors as drugs to treat COVID-19. The use of BTK inhibitors in the management of COVID-19 shows promise in reducing the severity of the immune response to the infection and thus mortality. However, BTK inhibition may be contributing in other ways to inhibit the effects of the virus and this will need to be carefully studied.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antiviral Agents; Benzamides; COVID-19; COVID-19 Drug Treatment; Humans; Lung; Molecular Targeted Therapy; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrazines; Thrombosis

This analysis aimed to describe the pharmacokinetics (PK) of acalabrutinib and its active metabolite, ACP-5862. A total of 8935 acalabrutinib samples from 712 subjects and 2394 ACP-5862 samples from 304 subjects from 12 clinical studies in patients with B-cell malignancies and healthy subjects were analysed by nonlinear mixed-effects modelling. Acalabrutinib PK was characterized by a 2-compartment model with first-order elimination. The large variability in absorption was adequately described by transit compartment chain and first-order absorption, with between-occasion variability on the mean transit time and relative bioavailability. The PK of ACP-5862 was characterized by a 2-compartment model with first-order elimination, and the formation rate was defined as the acalabrutinib clearance multiplied by the fraction metabolized. Health status, Eastern Cooperative Oncology Group performance status, and coadministration of proton-pump inhibitors were significant covariates. However, none of the investigated covariates led to clinically meaningful changes in exposure, supporting a flat dosing of acalabrutinib.

Topics: Benzamides; Healthy Volunteers; Humans; Models, Biological; Neoplasms; Pyrazines

Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment for patients with CD19 B-cell malignancies. Combination strategies that improve CAR T-cell potency, limit tumor environment-mediated immune dysfunction, and directly reduce tumor burden may increase the potential for durable clinical benefit of CAR T-cell therapy. Lisocabtagene maraleucel (liso-cel) is a product therapy candidate being tested in patients with relapsed/refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia. This study assessed the in vitro and in vivo functionality of CAR T cells transduced to express the anti-CD19 CAR of liso-cel in combination with ibrutinib or acalabrutinib. In prolonged stimulation assays, the presence of ibrutinib or acalabrutinib improved the CAR T-cell effector function. RNA-Seq analysis and surface marker profiling of these CAR T cells treated with ibrutinib but not acalabrutinib revealed gene expression changes consistent with skewing toward a memory-like, type 1 T-helper, Bruton tyrosine kinase phenotype. Ibrutinib or acalabrutinib improved CD19 tumor clearance and prolonged survival of tumor-bearing mice when used in combination with CAR T cells. A combination of the defined cell product therapy candidate, liso-cel, with ibrutinib or acalabrutinib is an attractive approach that may potentiate the promising clinical responses already achieved in CD19 B-cell malignancies with each of these single agents.

Topics: Adenine; Animals; Antigens, CD19; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Biomarkers; Combined Modality Therapy; Cytokines; Cytotoxicity, Immunologic; Disease Models, Animal; Humans; Immunotherapy, Adoptive; Lymphocyte Activation; Mice; Neoplasms; Piperidines; Pyrazines; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes; Treatment Outcome; Xenograft Model Antitumor Assays