Anti-BTK monoclonal antibody, clone 15G8

X-linked agammaglobulinemia (XLA) is a primary humoral immunodeficiency characterized by severe hypogammaglobulinemia and increased risk of infection. The genetic condition results from a mutation in the Bruton tyrosine kinase (BTK) gene located on the X chromosome leading to a near absence of B cells. Patients affected by XLA arc most commonly predisposed to frequent and severe bacterial infections. However, here we report the case of a 20-year-old male with XLA who presented with viral pneumonia with multiple pathogens. This coexistence has been rarely reported. The patient received intravenous immunoglobulin therapy with noted significant improvement in the two weeks of follow-up. His clinical history supports the hypothesis of increased susceptibility to viral pathogens in the absence of immunoglobulin therapy. The humoral defect is the cornerstone of this phenomenon. This case presents the importance of multiviral causes for patients with recurrent episodes of pneumonia in an immunocompromised state.

Chimeric antigen receptor T (CART) cells targeting CD19 have shown promising results in the treatment of chronic lymphocytic leukemia (CLL). However, efficacy seems to be inferior compared to diffuse large B-cell lymphoma or acute lymphoblastic leukemia. Impaired T-cell fitness of CLL patients may be involved in treatment failure. Less-differentiated naive-like T cells play an important role in CART expansion and long-term persistence in vivo. These cells are sparse in CLL patients. Therefore, optimization of CART cell production protocols enriching less differentiated T cell subsets may overcome treatment resistance. The B-cell receptor inhibitor ibrutinib targeting Bruton's tyrosine kinase (BTK) is approved for the treatment of CLL. Besides BTK, ibrutinib additionally inhibits interleukin-2-inducible T-cell kinase (ITK) which is involved in T-cell differentiation. To evaluate the effect of ibrutinib on CART cell production, peripheral blood mononuclear cells from nine healthy donors and eight CLL patients were used to generate CART cells. T-cell expansion and phenotype, expression of homing and exhaustion makers as well as functionality of CART cells were evaluated. CART cell generation in the presence of ibrutinib resulted in increased cell viability and expansion of CLL patient-derived CART cells. Furthermore, ibrutinib enriched CART cells with less-differentiated naive-like phenotype and decreased expression of exhaustion markers including PD-1, TIM-3 and LAG-3. In addition, ibrutinib increased the cytokine release capacity of CLL patient-derived CART cells. In summary, BTK/ITK inhibition with ibrutinib during CART cell culture can improve yield and function of CLL patient-derived CART cell products.