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Despite the remarkable success of chimeric antigen receptor (CAR)-T cells against hematologic malignancies, severe off-tumor effects have constrained their use against solid tumors. Recently, CAR-engineered natural killer (NK) cells have emerged as an effective and safe alternative. Here, we demonstrate that HER2 CAR-expression in NK cells from healthy donors and patients with breast cancer potently enhances their anti-tumor functions against various HER2-expressing cancer cells, regardless of MHC class I expression. Moreover, HER2 CAR-NK cells exert higher cytotoxicity than donor-matched HER2 CAR-T cells against tumor targets. Importantly, unlike CAR-T cells, HER2 CAR-NK cells do not elicit enhanced cytotoxicity or inflammatory cytokine production against non-malignant human lung epithelial cells with basal HER2 expression. Further, HER2 CAR-NK cells maintain high cytotoxic function in the presence of immunosuppressive factors enriched in solid tumors. These results show that CAR-NK cells may be a highly potent and safe source of immunotherapy in the context of solid tumors.

Lung cancer remains the leading cause of cancer death worldwide despite the significant progress made by immune checkpoint inhibitors, including programmed death receptor-1 (PD1)/PD ligand 1 (PDL1)-blockade therapy. PD1/PDL1−blockade has achieved unprecedented tumor regression in some patients with advanced lung cancer. However, the majority of patients fail to respond to PD1/PDL1 inhibitors. The high rate of therapy non-response results from insufficient PDL1 expression on most patients’ tumors and the presence of further immunosuppressive mechanisms in the tumor microenvironment. Here, we sensitize non-responding tumors from patients with lung cancer to PD1-blockade therapy using highly cytotoxic expanded natural killer (NK) cells. We uncover that NK cells expanded from patients with lung cancer dismantle the immunosuppressive tumor microenvironment by maintaining strong antitumor activity against both PDL1+ and PDL1− patient tumors. In the process, through a contact-independent mechanism involving interferon γ, expanded NK cells rescued tumor killing by exhausted endogenous TILs and upregulated the tumor proportion score of PDL1 across patient tumors. In contrast, unexpanded NK cells, which are susceptible to tumor-induced immunosuppression, had no effect on tumor PDL1. As a result, combined treatment of expanded NK cells and PD1-blockade resulted in robust synergistic tumor destruction of initially non-responding patient tumors. Thus, expanded NK cells may overcome the critical roadblocks to extending the prodigious benefits of PD1-blockade therapy to more patients with lung cancer and other tumor types.

Triple negative breast cancer holds a dismal clinical outcome and as such, patients routinely undergo aggressive, highly toxic treatment regimens. Clinical trials for TNBC employing immune checkpoint blockade in combination with chemotherapy show modest prognostic benefit, but the percentage of patients that respond to treatment is low, and patients often succumb to relapsed disease. Here, we show that a combination immunotherapy platform utilizing low dose chemotherapy (FEC) combined with oncolytic virotherapy (oHSV-1) increases tumor-infiltrating lymphocytes, in otherwise immune-bare tumors, allowing 60% of mice to achieve durable tumor regression when treated with immune checkpoint blockade. Whole-tumor RNA sequencing of mice treated with FEC + oHSV-1 shows an upregulation of B cell receptor signaling pathways and depletion of B cells prior to the start of treatment in mice results in complete loss of therapeutic efficacy and expansion of myeloid-derived suppressor cells. Additionally, RNA sequencing data shows that FEC + oHSV-1 suppresses genes associated with myeloid-derived suppressor cells, a key population of cells that drive immune escape and mediate therapeutic resistance. These findings highlight the importance of tumor-infiltrating B cells as drivers of antitumor immunity and their potential role in the regulation of myeloid-derived suppressor cells.

Purpose of Review In the midst of the COVID-19 pandemic, several academic studies have emerged that explore the importance of vitamin D in the development of the SARS-CoV2 infection. The basis of this interest comes from the established effect vitamin D status has on other acute respiratory infections, such as influenza. This article aims to determine the role and effect of vitamin D serum concentration in the prevalence and severity of COVID-19. Recent Findings Several observational studies have demonstrated that suboptimal levels of vitamin D serum concentrations can significantly increase the risk of developing COVID-19 and lead to a more severe symptomatology. One study suggests, however, that supplementation of vitamin D could potentially increase the incidence of mortality in COVID-19 patients. Summary Vitamin D status could have an influential role in the development and progression of SARS-CoV2 infection. Further studies are warranted to understand fully the veracity and the extent of this association.

We read with interest the report by DAGHER et al.[1] of a novel anti-eosinophil action of benralizumab. Benralizumab was shown to induce eosinophil apoptosis by a macrophage-derived tumour necrosis factor (TNF)-induced caspase 3/7 activation, and this was amplified by interferon-γ (IFN-γ) secreted from natural killer (NK) cells. Indeed, in patients with severe asthma, including those who are dependent on daily systemic glucocorticosteroids for asthma control, benralizumab effectively depletes sputum eosinophils [2]. Although no direct head-to-head comparisons have been made, eosinophil suppression is likely to be greater than with the currently approved dose of mepolizumab [3], leading to greater clinical efficacy [4]. However, there may be instances when the anti-eosinophil activity of benralizumab may be impaired due to decreased NK cell numbers or activity that are described in patients with severe asthma on high doses of glucocorticosteroids [5].A 34-year-old female with severe airway hyperresponsiveness and mild sinus and asthma symptoms was seen in 2012, shortly after she had a baby, with dyspnoea, diffuse alveolar haemorrhage, left ventricular ejection fraction of 25%, skin vasculitis and peak blood eosinophils of 13.9 cells•µL −1 . Antineutrophil cytoplasmic antibodies (ANCA) were not detected in serum. However, it was detected in sputum in low titres, along with other autoantibodies such as anti-MARCO. She was treated with high doses of systemic corticosteroids and intravenous cyclophosphamide (10 doses), and later switched to oral prednisone and azathioprine. She participated in a clinical trial of subcutaneous mepolizumab 300 mg monthly for eosinophilic granulomatosis with polyangiitis (EGPA) [6], received the active drug, and successfully tapered her daily prednisone from 35 mg to 5 mg, and her asthma remained well controlled on additional high doses of inhaled corticosteroids and long-acting beta-agonists. Her sputum and blood eosinophil levels were 0 after 4 years of follow-up. Mepolizumab had to be discontinued in 2018 when she finished participating in the open-label extension of the clinical trial, and the drug was not re-imbursed by the provincial insurance plan. Her vasculitis did not flare but her asthma exacerbated, with a 1-L decrease in forced expiratory volume in 1 s (FEV 1 ), and her blood eosinophils rose to 0.5 cells•µL −1 . Prednisone dose had to be increased to 15 mg daily, which suppressed eosinophils to 0.1 cells•µL −1 . Given her significant adverse reactions to prednisone, including suicidal psychosis, she was then switched to benralizumab to attempt steroid weaning. She received 30 mg subcutaneously monthly for 3 months, and her prednisone was reduced by 2.5 mg daily after each injection. She noticed increasing shortness of breath with prednisone reduction and, at 7.5 mg daily prednisone, had an exacerbation with a reduction in FEV 1 to 2.24 L (77% predicted) and increase in sputum eosinophils to 78% and blood eosinophils to 0.4 cells•µL −1 . She did not have a relapse of any oth...

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Regulation of immune responses during viral infection is critical to preventing the development immunopathology that impairs host survival. NK cells are well-known for their antiviral functions that promote viral clearance, however their roles in limiting immune-mediated pathology are still unclear. Using a mouse model for genital herpes simplex virus type 2 infection, we find that NK cell derived-IFN-γ directly counteracts IL-6 mediated matrix metalloproteases (MMP) activity in macrophages to limit MMP-mediated tissue damage. Our findings uncover a key immunoregulatory function of NK cells during host-pathogen interactions that highlight the potential of NK cell therapy for treatment of severe viral infections.