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Showing papers by "David Altshuler published in 2019"


Journal ArticleDOI
05 Feb 2019-ACS Nano
TL;DR: Data indicate that sHDL nanodiscs constitute an effective drug delivery platform for the treatment of GBM, resulting in tumor regression, long-term survival, and immunological memory when used in combination with IR.
Abstract: Glioblastoma multiforme (GBM) is an aggressive primary brain tumor, for which there is no cure. Treatment effectiveness for GBM has been limited due to tumor heterogeneity, an immunosuppressive tumor microenvironment (TME), and the presence of the blood-brain barrier, which hampers the transport of chemotherapeutic compounds to the central nervous system (CNS). High-density lipoprotein (HDL)-mimicking nanodiscs hold considerable promise to achieve delivery of bioactive compounds into tumors. Herein, we tested the ability of synthetic HDL nanodiscs to deliver chemotherapeutic agents to the GBM microenvironment and elicit tumor regression. To this end, we developed chemo-immunotherapy delivery vehicles based on sHDL nanodiscs loaded with CpG, a Toll-like receptor 9 (TLR9) agonist, together with docetaxel (DTX), a chemotherapeutic agent, for targeting GBM. Our data show that delivery of DTX-sHDL-CpG nanodiscs into the tumor mass elicited tumor regression and antitumor CD8+ T cell responses in the brain TME. We did not observe any overt off-target side effects. Furthermore, the combination of DTX-sHDL-CpG treatment with radiation (IR), which is the standard of care for GBM, resulted in tumor regression and long-term survival in 80% of GBM-bearing animals. Mice remained tumor-free upon tumor cell rechallenge in the contralateral hemisphere, indicating the development of anti-GBM immunological memory. Collectively, these data indicate that sHDL nanodiscs constitute an effective drug delivery platform for the treatment of GBM, resulting in tumor regression, long-term survival, and immunological memory when used in combination with IR. The proposed delivery platform has significant potential for clinical translation.

141 citations


01 Jan 2019
TL;DR: The authors used exome-sequencing analyses of a large cohort of patients with Type 2 diabetes and control individuals without diabetes from five ancestries to identify gene-level associations of rare variants that are associated with type 2 diabetes.
Abstract: Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10−3) and candidate genes from knockout mice (P = 5.2 × 10−3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000–185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.Exome-sequencing analyses of a large cohort of patients with type 2 diabetes and control individuals without diabetes from five ancestries are used to identify gene-level associations of rare variants that are associated with type 2 diabetes.

107 citations


Journal ArticleDOI
TL;DR: This is the initial report on a first in human Phase I dose escalation trial of the combination of two adenoviral vectors expressing HSV1-TK or Flt3L for the treatment of newly diagnosed patients with central giant cell granuloma.
Abstract: 2019Background: This is the initial report on a first in human Phase I dose escalation trial of the combination of two adenoviral vectors expressing HSV1-TK or Flt3L for the treatment of newly diag...

21 citations


Journal ArticleDOI
TL;DR: Results show for the first time that reprogramming of the host’s brain immune system to recognize gliomas reveals a new approach for the treatment of highly malignant brain tumors.
Abstract: This is an interim report on a first in human Phase I dose escalation trial of the combination of two adenoviral vectors expressing HSV1-TK or Flt3L for the treatment of newly diagnosed, resectable malignant gliomas. Lack of dendritic cells from the brain precludes anti-glioma immune responses. We combined tumor cytotoxicity (Ad-HSV1TK) with recruitment of dendritic cells to gliomas (Ad-Flt3L) to induce anti-glioma immunity. In experimental models this treatment induces powerful cytotoxic CD8 and CD4 T-dependent anti-glioma immunity, immunological memory, and the capacity to recognize neo-antigens. The trial was approved through a FDA-IND, and all institutional cttees. Treatment was administered intraoperatively following complete glioma resection in newly diagnosed tumors. The trial consisted of vector dose escalation, starting at 1x10^9 v.p., and increasing to 1x10^11 v.p. of each vector, through 6 cohorts of 3 patients each. Two cycles of 14 days of valacyclovir were administered to activate HSV1-TK cytotoxicity. Cycle 1 starts on Day 1–3 post surgery for 14 days, and Cycle 2 on Week 8–12. Standard radiation, i.e., 60 Gy in 2 Gy fractions over 6 weeks, with concurrent temozolomide, was followed by cyclic temozolomide. Examination of tumor samples at primary resection and first recurrence show an increase in the infiltration of inflammatory cells. The experimental treatment was well tolerated. An MTD was not reached. There were approx. 248 AEs, and 26 SAEs; these were not linked to treatment. As secondary outcome, median survival of contemporary controls was 604 days, and median survival of trial patients was 742 days. Our results show for the first time that reprogramming of the host’s brain immune system to recognize gliomas reveals a new approach for the treatment of highly malignant brain tumors. Clinical trial information: NCT01811992.

4 citations


Journal ArticleDOI
TL;DR: The findings provide reference for distribution and types of DNA variation underlying inherited predisposition to some common cancer types and aid the future searches for new cancer susceptibility genes.
Abstract: Along with traditional effects of aging and carcinogen exposure-inherited DNA variation has substantial contribution to cancer risk. Extraordinary progress made in analysis of common variation with GWAS methodology does not provide sufficient resolution to understand rare variation. To fulfill missing classification for rare germline variation we assembled dataset of whole exome sequences from>2000 patients (selected cases tested negative for candidate genes and unselected cases) with different types of cancers (breast cancer, colon cancer, and cutaneous and ocular melanomas) matched to more than 7000 non-cancer controls and analyzed germline variation in known cancer predisposing genes to identify common properties of disease-associated DNA variation and aid the future searches for new cancer susceptibility genes. Cancer predisposing genes were divided into non-overlapping classes according to the mode of inheritance of the related cancer syndrome or known tumor suppressor activity. Out of all classes only genes linked to dominant syndromes presented significant rare germline variants enrichment in cases. Separate analysis of protein-truncating and missense variation in this list of genes confirmed significant prevalence of protein-truncating variants in cases only in loss-of-function tolerant genes (pLI 0.9). In addition to findings in genetically enriched cases, we observed significant burden of rare variation in unselected cases, suggesting substantial role of inherited variation even in relatively late cancer manifestation. Taken together, our findings provide reference for distribution and types of DNA variation underlying inherited predisposition to some common cancer types.

3 citations