The aberrant activity of Ras homologous (Rho) family small GTPases (20 human members) has been implicated in cancer and other human diseases. However, in contrast to the direct mutational activation of Ras found in cancer and developmental disorders, Rho GTPases are activated most commonly by indirect mechanisms in disease. One prevalent mechanism involves aberrant Rho activation via the deregulated expression and/or activity of Rho family guanine nucleotide exchange factors (RhoGEFs). RhoGEFs promote formation of the active GTP-bound state of Rho GTPases. The largest family of RhoGEFs is comprised of the Dbl family RhoGEFs with 70 human members. The multitude of RhoGEFs that activate a single Rho GTPase reflect the very specific role of each RhoGEF in controlling distinct signaling mechanisms involved in Rho activation. In this review, we summarize the role of Dbl RhoGEFs in development and disease, with a focus on Ect2, Tiam1, Vav and P-Rex1/2.

Key Points Ibrutinib treatment of CLL enhances the generation of CAR T cells for adoptive immunotherapy. Concurrent ibrutinib therapy improves the engraftment and therapeutic efficacy of anti-CD19 CAR T cells in mouse models.

The SHGH conjecture proposes a solution to the question of how many conditions a general union of fat points imposes on the complete linear system of curves in P 2 of fixed degree d, and it is known to be true in many cases. We propose a new problem, namely to understand the number of conditions imposed by a general union of fat points on the incomplete linear system defined by the condition of passing through a given finite set of points Z (not general). Motivated by work of Di Gennaro-Ilardi-Vallès and Faenzi-Vallès, we give a careful analysis for the case where there is a single general fat point, which has multiplicity d − 1. There is an expected number of conditions imposed by this fat point, and we study those Z for which this expected value is not achieved. We show, for instance, that if Z is in linear general position then such unexpected curves do not exist. We give criteria for the occurrence of such unexpected curves and describe the range of values of d for which they occur. Unexpected curves have a very particular structure, which we describe, and they are often unique for a given set of points. In particular, we give a criterion for when they are irreducible, and we exhibit examples both where they are reducible and where they are irreducible. Furthermore, we relate properties of Z to properties of the arrangement of lines dual to the points of Z. In particular, we obtain a new interpretation of the splitting type of a line arrangement. Finally, we use our results to establish a Lefschetz-like criterion for Terao's conjecture on the freeness of line arrangements. 2

We generated two humanized interleukin-13 receptor α2 (IL-13Rα2) chimeric antigen receptors (CARs), Hu07BBz and Hu08BBz, that recognized human IL-13Rα2, but not IL-13Rα1. Hu08BBz also recognized canine IL-13Rα2. Both of these CAR T cell constructs demonstrated superior tumor inhibitory effects in a subcutaneous xenograft model of human glioma compared with a humanized EGFRvIII CAR T construct used in a recent phase 1 clinical trial (ClinicalTrials.gov: NCT02209376). The Hu08BBz demonstrated a 75% reduction in orthotopic tumor growth using low-dose CAR T cell infusion. Using combination therapy with immune checkpoint blockade, humanized IL-13Rα2 CAR T cells performed significantly better when combined with CTLA-4 blockade, and humanized EGFRvIII CAR T cells’ efficacy was improved by PD-1 and TIM-3 blockade in the same mouse model, which was correlated with the levels of checkpoint molecule expression in co-cultures with the same tumor in vitro. Humanized IL-13Rα2 CAR T cells also demonstrated benefit from a self-secreted anti-CTLA-4 minibody in the same mouse model. In addition to a canine glioma cell line (J3T), canine osteosarcoma lung cancer and leukemia cell lines also express IL-13Rα2 and were recognized by Hu08BBz. Canine IL-13Rα2 CAR T cell was also generated and tested in vitro by co-culture with canine tumor cells and in vivo in an orthotopic model of canine glioma. Based on these results, we are designing a pre-clinical trial to evaluate the safety of canine IL-13Rα2 CAR T cells in dog with spontaneous IL-13Rα2-positive glioma, which will help to inform a human clinical trial design for glioblastoma using humanized scFv-based IL-13Rα2 targeting CAR T cells.

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