Ipilimumab is a first-in-class immunological checkpoint blockade agent and monoclonal antibody against Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) that has demonstrated survival benefit and durable responses in patients with metastatic melanoma. To date, solid organ transplant recipients have been excluded from clinical trials with cancer immunotherapies on the basis of their concurrent treatment with immunosuppressive agents. We present the first case to our knowledge of a patient with advanced cutaneous melanoma receiving ipilimumab status post orthotopic liver transplantation with a partial response. Transaminitis was observed 4 months after administration of ipilimumab that resolved with close observation. No evidence of graft rejection has been observed to date. This case advocates for further investigation of the safety and efficacy of cancer immunotherapies in solid organ transplant recipients.

Many microbial communities contain organized patterns of cell types, yet relatively little is known about the mechanism or function of this organization. In colonies of the budding yeast Saccharomyces cerevisiae, sporulation occurs in a highly organized pattern, with a top layer of sporulating cells sharply separated from an underlying layer of nonsporulating cells. A mutant screen identified the Mpk1 and Bck1 kinases of the cell-wall integrity (CWI) pathway as specifically required for sporulation in colonies. The CWI pathway was induced as colonies matured, and a target of this pathway, the Rlm1 transcription factor, was activated specifically in the nonsporulating cell layer, here termed feeder cells. Rlm1 stimulates permeabilization of feeder cells and promotes sporulation in an overlying cell layer through a cell-nonautonomous mechanism. The relative fraction of the colony apportioned to feeder cells depends on nutrient environment, potentially buffering sexual reproduction against suboptimal environments.KEYWORDS cell-wall integrity; cell permeability; cell-cell signaling; Saccharomyces cerevisiae; sporulation A S embryos develop, cells of different fates organize into patterns [reviewed in Kicheva et al. (2012) and Perrimon et al. (2012)] . Intriguingly, even unicellular microbial species form communities in which different cell types are organized into patterns [reviewed in Kaiser et al. (2010), Honigberg (2011, and Loomis (2014)]. For example, colonies of the budding yeast Saccharomyces cerevisiae form an upper layer of larger cells (U cells) overlying a layer of smaller cells (L cells). U and L cells differ in their metabolism, gene expression, and resistance to stress, and U and L layers are separated by a strikingly sharp boundary Vachova et al. 2013). Patterns are also observed in yeast biofilms, where cells closest to the plastic surface grow as ovoid cells, whereas cells further from the surface differentiate into hyphae for Candida species [reviewed in Finkel and Mitchell (2011)] or pseudohyphae and eventually asci for S. cerevisiae (White et al. 2011).Sporulation also occurs in patterns within yeast colonies. Specifically, a narrow horizontal layer of sporulated cells forms through the center of the colony early during colony development. As colonies continue to mature, this layer progressively expands upward to include the top of the colony; this wave is driven by progressive alkalization and activation of the Rim101 signaling pathway . In contrast, cells at the bottom of the colony, i.e., directly contacting the agar substrate, also sporulate at early stages of colony development, but this narrow cell layer does not expand as the colony matures . The same colony sporulation pattern is observed in a range of laboratory yeasts as well as in S. cerevisiae and S. paradoxus isolated from the wild. Indeed, in these wild yeasts, the same colony sporulation pattern forms on a range of fermentable and nonfermentable carbon sources .The mechanism of sporulation patterning and its function remai...

10004 Background: Aberrant Hedgehog and Notch signaling is seen in sarcoma and anti-tumor activity is enhanced by inhibiting both pathways. This first in man Phase Ib study evaluated safety and efficacy of the combination of GDC-0449 (G), a smoothened inhibitor with RO4929097 (R), a gamma-secretase/notch inhibitor. Methods: The study evaluated fixed dose G (150 mg qd) for 21 days followed by G + R at either 10 mg (level 1) or 15 mg (level 2) QD. At MTD pts were evaluated with G + R (without “lead in” G) or single agent R. Pre and post treatment tumor biopsies were obtained to assess notch and hedgehog inhibition. PK was assessed for each drug. Key eligibility: advanced sarcoma, ECOG ≤ 2, age ≥ 18 and prior therapies ≤ 4. RECIST response was assessed Q6 wks. Results: 34 pts had a median age of 53 yrs (23-78), median priors 3 and various histologies [liposarcoma (7), chondrosarcoma (7), leiomyosarcoma (4), osteosarcoma (2), GIST (2) and other (12)]. No DLT was seen. Common (≥10 %) grade ≤3 toxicity was hypophosphatemia (18%). Systemic exposure (AUC0-24 and Cmax) of G was similar to established studies (not shown). AUC0-24 and Cmax of R was significantly lower (~70%) when administered with G (Table). However, measurement of unbound, free drug (Cfree) of R showed comparable levels between single agent R and G + R, but not when G was a “lead in” (Table). Target inhibition of the notch pathway (cleaved notch) and pAkt was observed in matched tumor biopsies with both arms. Durable SD was seen in both arms: myxoid chondrosarcoma (56 wks), liposarcoma (24+ wks), clear cell (21+ wks), desmoid (17+ wks), spindle cell (15+ wks) and chondrosarcoma (13+ wks). Conclusions: The combination of G+R is well tolerated and the RP2D is G 150 mg qd and R 15 mg qd without a “lead in” G. Despite reduction in total levels of R in the combination, free drug was similar and inhibits target. Disease stability was seen with R and R + G. Further clinical development of notch and hedgehog inhibitors in sarcomas is warranted. [Table: see text]

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