Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma.

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action

Patients with genetically heterogeneous synchronous colorectal cancer carry rare damaging germline mutations in immune-related genes

Synchronous colorectal cancers (syCRCs) are physically separated tumours that develop simultaneously. To understand how the genetic and environmental background influences the development of multiple tumours, here we conduct a comparative analysis of 20 syCRCs from 10 patients. We show that syCRCs have independent genetic origins, acquire dissimilar somatic alterations, and have different clone composition. This inter- and intratumour heterogeneity must be considered in the selection of therapy and in the monitoring of resistance. SyCRC patients show a higher occurrence of inherited damaging mutations in immune-related genes compared to patients with solitary colorectal cancer and to healthy individuals from the 1,000 Genomes Project. Moreover, they have a different composition of immune cell populations in tumour and normal mucosa, and transcriptional differences in immune-related biological processes. This suggests an environmental field effect that promotes multiple tumours likely in the background of inflammation

Activated stromal cells transfer mitochondria to rescue acute lymphoblastic leukaemia cells from oxidative stress

We investigated and modelled the mesenchymal stromal cell (MSC) niche in adult acute lymphoblastic leukaemia (ALL). We used gene expression profiling, cytokine/chemokine quantification, flow cytometry and a variety of imaging techniques to show that MSC directly isolated from the primary bone marrow specimens of patients with ALL frequently adopted an activated, cancer-associated fibroblast phenotype. Normal, primary human MSC and the MSC cell line HS27a both became activated when exposed to the reactive oxygen species (ROS)-inducing chemotherapy agents cytarabine (AraC) and daunorubicin (DNR), a phenomenon blocked by the anti-oxidant N-acetyl cysteine. Chemotherapy-activated HS27a cells were functionally evaluated in a co-culture model with ALL targets. Activated MSC prevented therapy-induced apoptosis and death in ALL targets, via mitochondrial transfer through tunnelling nanotubes (TNT). Reduction of mitochondrial transfer by selective mitochondrial depletion or interference with TNT formation by microtubule inhibitors such as vincristine (VCR) - prevented the 'rescue' function of the activated MSC. Corticosteroids - also a mainstay of ALL therapy - prevented the activation of MSC. We also demonstrated that AraC (but not VCR) - induced activation of MSC, mitochondrial transfer and mitochondrial mass increase in a murine NSG model of disseminated SEM-derived ALL wherein CD19+ cells closely associated with nestin+ MSC after AraC but not the other conditions. Our data propose a readily clinically-exploitable mechanism for improving treatment ALL in which traditional, ROS-inducing chemotherapies are often ineffective at eradicating residual ALL, despite efficiently killing the bulk population

Observation of the rare decay B+ -> K+ pi(0)pi(0) and measurement of the quasi-two-body contributions B+ -> K* (892)(+) pi(0), B+ -> f(0)(980)K+, and B+ -> chi K-c0(+)

We report an analysis of charmless hadronic decays of charged B mesons to the final state K+ pi(0)pi(0), using a data sample of (470.9 +/- 2.8) x 10(6) B (B) over bar events collected with the BABAR detector at the Y(4S) resonance. We observe an excess of signal events, with a significance above 10 standard deviations including systematic uncertainties, and measure the branching fraction and CP asymmetry to be B(B+ -> K+ pi(0)pi(0)) = (16.2 +/- 1.2 +/- 1.5) x 10(-6) and A(CP)(B+ -> K+ pi(0)pi(0)) = -0.06 +/- 0.06 +/- 0.04, where the uncertainties are statistical and systematic, respectively. Additionally, we study the contributions of the B+ -> K*(892)(+) pi(0), B+ -> f(0)(980)K+, and B+ -> chi K-c0(+) quasi-two-body decays. We report the world's best measurements of the branching fraction and CP asymmetry of the B+ -> K+ pi(0)pi(0) and B+ -> K+(892)(+) pi(0) channels

Measurement of D0-D0 mixing parameters using D0 K(S)(0)pi+ pi- and D0 K(S)(0)K+ K- decays.

We report a direct measurement of D0-D0 mixing parameters through a time-dependent amplitude analysis of the Dalitz plots of D(0) K(S)(0) pi+ pi- and, for the first time, D0 K(S)(0)K+ K- decays. The low-momentum pion pi(s)(+) in the decay D*+ D0 pi(s)(+) identifies the flavor of the neutral D meson at its production. Using 468.5 fb(-1) of e+ e- colliding-beam data recorded near square root(s)=10.6 GeV by the BABAR detector at the PEP-II asymmetric-energy collider at SLAC, we measure the mixing parameters x = [1.6 2.3(stat) 1.2(syst) 0.8(model)] * 10(-3), and y = [5.7 2.0(stat) 1.3(syst) 0.7(model)] * 10(-3). These results provide the best measurement to date of x and y. The knowledge of the value of x, in particular, is crucial for understanding the origin of mixing

Search for charged lepton flavor violation in narrow upsilon decays.

Charged-lepton flavor-violating processes are unobservable in the standard model, but they are predicted to be enhanced in several extensions to the standard model, including supersymmetry and models with leptoquarks or compositeness. We present a search for such processes in a sample of 99x10(6)Upsilon(2S) decays and 117x10(6)Upsilon(3S) decays collected with the BABAR detector. We place upper limits on the branching fractions B(Upsilon(nS)-->e(+/-)tau(-/+)) and B(Upsilon(nS)-->mu(+/-)tau(-/+)) (n=2,3) at the 10(-6) level and use these results to place lower limits of order 1 TeV on the mass scale of charged-lepton flavor-violating effective operators