Bridging Radiation Therapy Before Commercial Chimeric Antigen Receptor T-Cell Therapy for Relapsed or Refractory Aggressive B-Cell Lymphoma.

PURPOSE: CD19-targeting chimeric antigen receptor T-cell (CART) therapy has emerged as a promising treatment for relapsed/refractory aggressive B-cell lymphoma (r/rABL), culminating in 2 US Food and Drug Administration-approved therapies: tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel). Following leukapheresis and in preparation for CART infusion, contemporary bridging and lymphodepletion regimens rely mostly on cytotoxic chemotherapy. Here, in a cohort of patients treated with commercial tisa-cel and axi-cel, we show that bridging-RT may offer a supplemental approach. METHODS AND MATERIALS: Thirty-one patients receiving commercial tisa-cel (n = 13) or axi-cel (n = 18) between August 2018 and February 2019 for r/rABL were retrospectively reviewed. Patients were categorized into 2 groups: (1) bridging-RT within 30 days of CART infusion or (2) nonbridging-RT (NBRT), in which patients received either remote RT greater than 30 days before CART infusion or no prior RT. RESULTS: Five patients received bridging-RT within 30 days of CART infusion. Median bridging-RT dose was 37.5 Gy and was completed a median of 13 days before infusion. No grade 3 (G3) or higher RT-toxicities occurred. No patients in the bridging-RT group experienced G3 or higher CART-related toxicities (CRS or neurotoxicity), and 23% (n = 6) and 15% (n = 4) experienced G3-5 CRS and G3-5 neurotoxicity in the NBRT group, respectively. Overall treatment response in the bridging-RT and NBRT groups was 80% and 64%, respectively. The axi-cel CART product was associated with CRS (odds ratio [OR] = 26.67, P = .001) and CRS correlated with neurotoxicity (OR = 12.22, P = .028). There was a trend toward an association for CRS with metabolic tumor volume (OR = 1.06/mL, P = .141) and TLG (OR = 1.01/mL x standard uptake value, P = .099). CONCLUSIONS: Bridging-RT before commercial CART does not appear to increase the risk for CART-related toxicities or negatively affect outcomes in r/rABL patients. No G3 or higher RT-toxicities occurred in this series. Pretreatment metabolic tumor burden may be associated with CART-associated CRS; however, larger patient numbers are required to elucidate significant associations. Future work to prospectively assess the value of bridging-RT is warranted.

Macrophage Migration Inhibitory Factor Is Detrimental in Pneumococcal Pneumonia and a Target for Therapeutic Immunomodulation.

Mortality from pneumococcal pneumonia remains high despite antibiotic therapy, highlighting the pathogenic potential for host inflammation. We demonstrate that macrophage migration inhibitory factor (MIF), an innate immune mediator, is detrimental for survival and associated with lung pathology, inflammatory cellular infiltration, and bacterial replication in a mouse model of pneumococcal pneumonia, despite being necessary for clearance from the nasopharynx. Treatment of animals with a small-molecule inhibitor of MIF improves survival by reducing inflammation and improving bacterial control. Our work demonstrates that MIF modulates beneficial versus detrimental inflammatory responses in the host-pneumococcal interaction and is a potential target for therapeutic modulation.

Macrophage migration inhibitory factor promotes clearance of pneumococcal colonization.

Human genetic polymorphisms associated with decreased expression of macrophage migration inhibitory factor (MIF) have been linked to the risk of community-acquired pneumonia. Because Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and nasal carriage is a precursor to invasive disease, we explored the role of MIF in the clearance of pneumococcal colonization in a mouse model. MIF-deficient mice (Mif(-/-)) showed prolonged colonization with both avirulent (23F) and virulent (6A) pneumococcal serotypes compared with wild-type animals. Pneumococcal carriage led to both local upregulation of MIF expression and systemic increase of the cytokine. Delayed clearance in the Mif(-/-) mice was correlated with reduced numbers of macrophages in upper respiratory tract lavages as well as impaired upregulation of MCP-1/CCL2. We found that primary human monocyte-derived macrophages as well as THP-1 macrophages produced MIF upon pneumococcal infection in a pneumolysin-dependent manner. Pneumolysin-induced MIF production required its pore-forming activity and phosphorylation of p38-MAPK in macrophages, with sustained p38-MAPK phosphorylation abrogated in the setting of MIF deficiency. Challenge with pneumolysin-deficient bacteria demonstrated reduced MIF upregulation, decreased numbers of macrophages in the nasopharynx, and less effective clearance. Mif(-/-) mice also showed reduced Ab response to pneumococcal colonization and impaired ability to clear secondary carriage. Finally, local administration of MIF was able to restore bacterial clearance and macrophage accumulation in Mif(-/-) mice. Our work suggests that MIF is important for innate and adaptive immunity to pneumococcal colonization and could be a contributing factor in genetic differences in pneumococcal disease susceptibility.