Elliott J. Brea

T cells. The regulation of MHC-I by kinases is largely unstudied, even though many patients with cancer are receiving therapeutic kinase inhibitors. Regulators of cell-surface HLA amounts were discovered using a pooled human kinome shRNA interference-based approach. Hits scoring highly were subsequently validated by additional RNAi and pharmacologic inhibitors. MAP2K1 (MEK), EGFR, and RET were validated as negative regulators of MHC-I expression and antigen presentation machinery in multiple cancer types, acting through an ERK output-dependent mechanism; the pathways responsible for increased MHC-I upon kinase inhibition were mapped. Activated MAPK signaling in mouse tumors in vivo suppressed components of MHC-I and the antigen presentation machinery. Pharmacologic inhibition of MAPK signaling also led to improved peptide/MHC target recognition and killing by T cells and TCR-mimic antibodies. Druggable kinases may thus serve as immediately applicable targets for modulating immunotherapy for many diseases. Cancer Immunol Res; 4(11); 936-47. ©2016 AACR.

Abstract Chimeric antigen receptor (CAR) T-cells have emerged as an efficacious modality in patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). Clonal hematopoiesis of indeterminate potential (CHIP), a state in which mutations in hematopoietic cells give rise to a clonal population of cells, is more common in patients exposed to cytotoxic therapies, has been shown to influence inflammatory immune programs, and is associated with an adverse prognosis in patients with NHL and MM receiving autologous transplantation. We therefore hypothesized that CHIP could influence clinical outcomes in patients receiving CAR T-cell therapy. In a cohort of 154 patients with NHL or MM receiving CAR T-cells, we found that CHIP was present in 48% of patients and associated with increased rates of complete response and cytokine release syndrome severity, but only in patients younger than age 60 years. Despite these differences, CHIP was not associated with a difference in progression-free or overall survival, regardless of age. Our data suggest that CHIP can influence CAR T-cell biology and clinical outcomes, but, in contrast to autologous transplantation, CHIP was not associated with worse survival and should not be a reason to exclude individuals from receiving this potentially life-prolonging treatment.

A Case of COVID-19 and Pneumocystis jirovecii CoinfectionTo the Editor:Lymphocytopenia has been identified as a common laboratory finding in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, particularly among those with more severe presentations (1); however, there are limited data on which specific lymphocyte populations may be affected or the clinical sequelae.In this report, we describe the case of a woman with hypoxemic respiratory failure found to have coinfection with SARS-CoV-2 and Pneumocystis jirovecii, a pathogen commonly seen in patients with defects in T-cell immunity.An 83-year-old female nonsmoker presented to our hospital on March 12, 2020, with fevers, malaise, headache, dry cough, and dyspnea.She had a history of mild intermittent asthma, managed with an albuterol inhaler as needed, mitral valve prolapse with moderate to severe mitral regurgitation, and mild to moderate ulcerative colitis, which was well controlled on oral budesonide (3 mg daily and being tapered) as well as maintenance-dose sulfasalazine (1,500 mg twice daily).Her symptoms had started approximately 2 weeks prior to presentation, shortly after travel from Florida to Massachusetts, and had failed to improve with courses of azithromycin and amoxicillin-clavulanate.In the emergency department, she had a fever of 39.3 8 C and oxygen saturation of 86% on room air, which improved to 95% on 5 L/min of supplemental oxygen by nasal cannula.Initial laboratory evaluation revealed leukocytosis and relative lymphocytopenia (absolute lymphocyte count, 1,090 cells/ml) (Table 1).Chest computed tomography was notable for diffuse bilateral ground-glass opacities with patchy bands of atelectasis and small nodular foci of consolidation with a distribution suggestive of a viral pneumonia.Subtle cystic changes were also seen in the affected regions (Figure 1).She was admitted to the medical intensive care unit and placed on strict isolation precautions given concern for community-acquired SARS-CoV-2.She developed worsening tachypnea with a respiratory rate of 40 breaths/min and hypoxia with an oxygen saturation of 80% requiring supplemental oxygen through a nonrebreather mask at a rate of 15 L/min.An arterial blood gas measurement showed a Pa O 2 of 63 mm Hg on 15 L/min of supplemental oxygen.She was intubated for hypoxemic respiratory failure and supported on low VT ventilation according to the Acute Respiratory Distress Syndrome Network

KRAS is one of the driver oncogenes in non-small-cell lung cancer (NSCLC) but remains refractory to current modalities of targeted pathway inhibition, which include inhibiting downstream kinase MEK to circumvent KRAS activation. Here, we show that pulsatile, rather than continuous, treatment with MEK inhibitors (MEKis) maintains T cell activation and enables their proliferation. Two MEKis, selumetinib and trametinib, induce T cell activation with increased CTLA-4 expression and, to a lesser extent, PD-1 expression on T cells in vivo after cyclical pulsatile MEKi treatment. In addition, the pulsatile dosing schedule alone shows superior anti-tumor effects and delays the emergence of drug resistance. Furthermore, pulsatile MEKi treatment combined with CTLA-4 blockade prolongs survival in mice bearing tumors with mutant Kras. Our results set the foundation and show the importance of a combinatorial therapeutic strategy using pulsatile targeted therapy together with immunotherapy to optimally enhance tumor delay and promote long-term anti-tumor immunity.