A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade.

Evidence from mouse chronic viral infection models suggests that CD8+ T cell subsets characterized by distinct expression levels of the receptor PD-1 diverge in their state of exhaustion and potential for reinvigoration by PD-1 blockade. However, it remains unknown whether T cells in human cancer adopt a similar spectrum of exhausted states based on PD-1 expression levels. We compared transcriptional, metabolic and functional signatures of intratumoral CD8+ T lymphocyte populations with high (PD-1T), intermediate (PD-1N) and no PD-1 expression (PD-1-) from non-small-cell lung cancer patients. PD-1T T cells showed a markedly different transcriptional and metabolic profile from PD-1N and PD-1- lymphocytes, as well as an intrinsically high capacity for tumor recognition. Furthermore, while PD-1T lymphocytes were impaired in classical effector cytokine production, they produced CXCL13, which mediates immune cell recruitment to tertiary lymphoid structures. Strikingly, the presence of PD-1T cells was strongly predictive for both response and survival in a small cohort of non-small-cell lung cancer patients treated with PD-1 blockade. The characterization of a distinct state of tumor-reactive, PD-1-bright lymphocytes in human cancer, which only partially resembles that seen in chronic infection, provides potential avenues for therapeutic intervention.

Local Tumor Treatment in Combination with Systemic Ipilimumab Immunotherapy Prolongs Overall Survival in Patients with Advanced Malignant Melanoma.

Immune checkpoint inhibition with ipilimumab has revolutionized cancer immunotherapy and significantly improved outcomes of patients with advanced malignant melanoma. Local peripheral treatments (LPT), such as radiotherapy or electrochemotherapy, have been shown to modulate systemic immune responses, and preliminary data have raised the hypothesis that the combination of LPT with systemic immune checkpoint blockade might be beneficial. Clinical data from 127 consecutively treated melanoma patients at four cancer centers in Germany and Switzerland were analyzed. Patients received either ipilimumab (n = 82) or ipilimumab and additional LPT (n = 45) if indicated for local tumor control. The addition of LPT to ipilimumab significantly prolonged overall survival (OS; median OS 93 vs. 42 weeks, unadjusted HR, 0.46; P = 0.0028). Adverse immune-related events were not increased by the combination treatment, and LPT-induced local toxicities were in most cases mild. In a multivariable Cox regression analysis, we show that the effect of added LPT on OS remained statistically significant after adjusting for BRAF status, tumor stage, tumor burden, and central nervous system metastases (adjusted HR, 0.56; 95% confidence interval, 0.31-1.01, P = 0.05). Our data suggest that the addition of LPT to ipilimumab is safe and effective in patients with metastatic melanoma irrespective of clinical disease characteristics and known risk factors. Induction of antitumor immune responses is most likely the underlying mechanism and warrants prospective validation. Cancer Immunol Res; 4(9); 744-54. ©2016 AACR.

Trends in imported malaria to Basel, Switzerland.

BACKGROUND: Due to persistent international travel and immigration trends, imported malaria remains to be of clinical and public health importance in nonendemic countries. The aim of this study was to investigate trends in imported malaria over a period of more than three decades. METHODS: We assessed travel history, demographic characteristics, and clinical course with special regard to malaria diagnosis and intensive care unit (ICU) admission of patients diagnosed with malaria. The sample comprised 109 patients with the diagnosis of malaria according to the International Statistical Classification of Diseases and Related Health Problems (ICD)-coding system (versions 9 and 10) at the University Hospital and at a teaching hospital in Basel between January 1994 and June 2004. Changes in clinical management and outcomes were compared with previous studies at the same institutions dating back to the 1970s. RESULTS: The most common reason for travel was to visit friends and relatives in the country of origin (37%), and most infections were acquired in Africa (82%), with Plasmodium falciparum malaria the most frequently found parasite (84%). The mean time between first symptoms and the diagnosis of malaria was 4 days (range 0.5-31 d). Delay in diagnosis occurred in 14% of cases, and 37% of hospitalized patients were referred to the ICU. In 22% of referred cases, high parasitemia (>2%) according to internal criteria was a reason for referral. The course of disease remained mild in the great majority (90%) of patients, and none of the patients died. CONCLUSIONS: Prompt and specific diagnosis of malaria could be improved. Malaria-associated mortality was reduced over time. As ICU referral showed to be inappropriately high in relation to a moderate clinical course of several admitted patients, criteria for ICU admission should be reevaluated. The trend toward malaria in patients originating from endemic areas suggests that preventive travel advice should specifically address these patients.