A whole genome association study was performed in a phase 3 clinical trial conducted to evaluate a novel antipsychotic, iloperidone, administered to treat patients with schizophrenia. Genotypes of 407 patients were analyzed for 334,563 single nucleotide polymorphisms (SNPs). SNPs associated with iloperidone efficacy were identified within the neuronal PAS domain protein 3 gene (NPAS3), close to a translocation breakpoint site previously observed in a family with schizophrenia. Five other loci were identified that include the XK, Kell blood group complex subunit-related family, member 4 gene (XKR4), the tenascin-R gene (TNR), the glutamate receptor, inotropic, AMPA 4 gene (GRIA4), the glial cell line-derived neurotrophic factor receptor-alpha2 gene (GFRA2), and the NUDT9P1 pseudogene located in the chromosomal region of the serotonin receptor 7 gene (HTR7). The study of these polymorphisms and genes may lead to a better understanding of the etiology of schizophrenia and of its treatment. These results provide new insight into response to iloperidone, developed with the ultimate goal of directing therapy to patients with the highest benefit-to-risk ratio.
Introduction: RX-3117 is an oral, small molecule cytidine analog anticancer agent with an improved pharmacological profile relative to gemcitabine and other nucleoside analogs. The agent has excellent activity against various cancer cell lines and xenografts including gemcitabine-resistant variants and it has excellent oral bioavailability; it is not a substrate for the degradation enzyme cytidine deaminase. RX-3117 is being evaluated at a daily oral schedule of 700 mg (5 days/week for 3 weeks) which results in plasma levels in the micromolar range that have been shown to be cytotoxic to cancer cells. It has shown clinical activity in refractory bladder cancer and pancreatic cancer. Areas covered: The review provides an overview of the relevant market and describes the mechanism of action, main pharmacokinetic/pharmacodynamic features and clinical development of this investigational small molecule. Expert opinion: RX-3117 is selectively activated by uridine-cytidine kinase 2 (UCK2), which is expressed only in tumors and has a dual mechanism of action: DNA damage and inhibition of DNA methyltransferase 1 (DNMT1). Because of its tumor selective activation, novel mechanism of action, excellent oral bioavailability and candidate biomarkers for patient selection, RX-3117 has the potential to replace gemcitabine in the treatment of a spectrum of cancer types.
829 Adoptive transfer of donor-derived cytotoxic T lymphocytes (CTLs) can reconstitute antiviral immunity to Epstein-Barr virus (EBV), cytomegalovirus (CMV) and adenovirus in recipients of allogeneic hemopoietic stem cell transplantation (HSCT). However, the time taken to prepare patient-specific products and the lack of virus-specific memory T cells in cord blood and seronegative donors restricts application. One means of avoiding growing CTLs for individual patients is to bank lines that are then available as an “off the shelf” product of most closely HLA-matched allogeneic cytotoxic T lymphocyte lines (CHM-CTLs). We are evaluating this strategy in a multicenter study through the NHLBI Specialized Centers for Cell-Based Therapy (SCCT) program. Our goal is to determine the feasibility, safety and antiviral activity of 3rd party CHM-CTLs in HSCT recipients who have viral reactivation or infection refractory to standard therapy. Using the NHLBI Production Assistance for Cellular Therapies (PACT) program, we manufactured and safety tested more than 30 multivirus CTL lines from normal donors by stimulating peripheral blood mononuclear cells with autologous monocytes and EBV-transformed LCLs, both transduced with an Ad5f35 vector encoding the CMV-derived pp65 antigen. All the lines are polyclonal comprising CD4+ (median 10%, range 1.5–99%) and CD8+ (median 83%, range 0–96%) T cells. These CTL lines were specific for CMV, EBV and adenovirus (mean 1463, 101, and 227 SFC/1×105 cells, respectively), with recognition of both CD8+ and CD4+ epitopes as determined using individual epitope peptides and overlapping Hexon and pp65 peptide pools (median 1.5; range 0–5 and median 3; range 0–10 pools/peptides recognized, respectively) in ELISPOT assays. These CHM-CTLs were available for administration to subjects who had persistent viral infection and matched at least one HLA antigen with a dose of up to 2.0 x107CHM-CTL/m2. We selected the CTL line for administration based on their specificity for the target virus through a shared allele, and on the overall level of HLA match. Patients were eligible for a subsequent infusion in the event of a partial response. To date 47 patients have been screened after marrow (n=9) blood (n=18) or cord (10 single, 10 double) transplantation and a potential line identified on 43. Of 4 patients with no line available 3 died of progressive adenovirus infection and one with CMV infection is alive. Of 43 patients with an identified line, 25 received lines that matched at 1 to 3 HLA antigens as either one (n=19), two (n=4) or 3 (n=2) CTL infusions. Five patients received CHM-CTLs for refractory EBV PTLD (Post Transplant Lymphoproliferative Disease), 11 patients for persistent CMV infection, 8 patients for persistent adenovirus infection and one for both CMV and adenovirus. There were no immediate adverse effects related to infusion, and the incidence of GVHD was low, with two patient having reactivation of previous acute skin or chronic GVHD, and two having transient skin rashes. Two patients developed transplant-associated microangiopathy but had other risk factors including Rapamycin use. Preliminary responses for the overall cumulative incidence of first CR/PR in the first 22 patients based on viral load by day 42 post-infusion is 77.3% (90% for CMV, 80% for EBV and 71% for adenovirus). Two patients with widespread EBV-PTLD (one CD20-negative and one refractory to Rituximab) achieved sustained complete responses by RECIST criteria. Of note complete antiviral responses occurred even in recipients of lines matching at only a single HLA antigen. For example, one patient with both CMV and adenovirus infections received a CTL line that only matched at HLA B53 and cleared both viruses and we were able to show specificity against both viruses through this one allele. Despite objective antiviral activity, immune monitoring studies using IFN-g ELISPOT assays showed little or no rise in peripheral blood virus-reactive T cells post-infusion, a result that contrasts with the large rise seen in recipients of donor-derived T cell lines. Nevertheless these preliminary results show the feasibility of adoptive immunotherapy for CMV, EBV, and adenovirus using banked allogeneic multivirus-CTLs, and that the approach may be applicable to a majority of recipients in need. The antiviral responses we observe are encouraging and suggest than an “off-the-shelf” CTL cell line may be a practical strategy. Disclosures: Off Label Use: T cell products manufactured under INDs.
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