ORCID Profile
0000-0002-8772-8680
Current Organisation
University of California, San Diego
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Publisher: Springer Science and Business Media LLC
Date: 25-04-2019
DOI: 10.1038/S41598-019-42459-5
Abstract: A correction has been published and is appended to both the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Publisher: American Association for Cancer Research (AACR)
Date: 05-2020
DOI: 10.1158/1535-7163.MCT-19-0959
Abstract: Gastrointestinal stromal tumor (GIST), the most common sarcoma, is characterized by KIT protein overexpression, and tumors are frequently driven by oncogenic KIT mutations. Targeted inhibition of KIT revolutionized GIST therapy and ushered in the era of precision medicine for the treatment of solid malignancies. Here, we present the first use of a KIT-specific DNA aptamer for targeted labeling of GIST. We found that an anti-KIT DNA aptamer bound cells in a KIT-dependent manner and was highly specific for GIST cell labeling in vitro. Functionally, the KIT aptamer bound extracellular KIT in a manner similar to KIT mAb staining, and was trafficked intracellularly in vitro. The KIT aptamer bound dissociated primary human GIST cells in a mutation agnostic manner such that tumors with KIT and PDGFRA mutations were labeled. In addition, the KIT aptamer specifically labeled intact human GIST tissue ex vivo, as well as peritoneal xenografts in mice with high sensitivity. These results represent the first use of an aptamer-based method for targeted detection of GIST in vitro and in vivo.
Publisher: American Association for Cancer Research (AACR)
Date: 10-2019
DOI: 10.1158/2326-6066.CIR-19-0101
Abstract: Irreversible electroporation (IRE) is a nonthermal ablation technique that is used clinically in selected patients with locally advanced pancreatic cancer, but most patients develop recurrent distant metastatic disease. We hypothesize that IRE can induce an in situ vaccination effect by releasing tumor neoantigens in an inflammatory context. Using an immunocompetent mouse model, we demonstrated that IRE alone produced complete regression of subcutaneous tumors in approximately 20% to 30% of mice. IRE was not effective in immunodeficient mice. Mice with complete response to IRE demonstrated prophylactic immunity and remained tumor free when rechallenged with secondary tumors on the contralateral flank. CD8+ T cells from IRE-responsive mice were reactive against peptides representing model-inherent alloantigens and conferred protection against tumor challenge when adoptively transferred into immunocompromised, tumor-naïve mice. Combining IRE with intratumoral Toll-like receptor-7 (TLR7) agonist (1V270) and systemic anti-programmed death-1 receptor (PD)-1 checkpoint blockade resulted in improved treatment responses. This combination also resulted in elimination of untreated concomitant distant tumors (abscopal effects), an effect not seen with IRE alone. These results suggest that the systemic antitumor immune response triggered by IRE can be enhanced by stimulating the innate immune system with a TLR7 agonist and the adaptive immune system with anti–PD-1 checkpoint blockade simultaneously. Combinatorial approaches such as this may help overcome the immunosuppressive pancreatic cancer microenvironment.
Publisher: Proceedings of the National Academy of Sciences
Date: 25-04-2022
Abstract: High-grade serous ovarian carcinoma (HGSOC) is an immunotherapy-resistant lethal cancer. An HGSOC hallmark is elevated checkpoint pathway ligand expression that limits antitumor immune responses. Computational, preclinical, and patient tumor multiplexed analyses revealed that tumor-associated focal adhesion kinase (FAK) activation regulates CD155 expression, a checkpoint ligand for TIGIT (T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains). Using an aggressive mouse ovarian tumor model, we find that combined oral FAK inhibitor plus function-blocking TIGIT antibody immunotherapy reduced tumor burden, prolonged mouse survival, and led to immune cell activation and tertiary lymphoid structure formation, hallmarks of an antitumor immune response. As FAK is commonly overexpressed in HGSOC tumors, targeting FAK and TIGIT may limit tumor immune evasion.
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1016/J.DRUDIS.2014.02.009
Abstract: Aptamers have emerged as a novel and powerful class of biomolecules with an immense untapped potential. The ability to synthesise highly specific aptamers against any molecular target make them a vital cog in the design of effective therapeutics for the future. However, only a minutia of the enormous potential of this dynamic class of molecule has been exploited. Several aptamers have been studied for the treatment of eye-related disorders, and one such strategy has been successful in therapy. This review gives an account of several eye diseases and their regulatory biomolecules where other nucleic acid therapeutics have been attempted with limited success and how aptamers, with their exceptional flexibility to chemical modifications, can overcome those inherent shortcomings.
Publisher: Elsevier BV
Date: 09-2020
Publisher: MyJove Corporation
Date: 08-06-2018
DOI: 10.3791/57265
Publisher: American Association for Cancer Research (AACR)
Date: 04-2020
DOI: 10.1158/2326-6074.TUMIMM18-A14
Abstract: The pancreatic cancer (PC) microenvironment is notoriously immunosuppressive and responds poorly to conventional checkpoint blockade immunotherapy, necessitating a need to overcome this challenge. Irreversible electroporation (IRE) is a nonthermal method of inducing cell death that is currently being used clinically for selected patients with locally advanced PC. Using a robust syngeneic mouse model of PC using cells established from a tumor arising in an LSL-KrasG12D/+ LSL-Trp53R172H/+ PDX1Cre/+ LSL-ROSA26 Luc/+ mouse (KPC), we have demonstrated that IRE alone can serve as an “in situ vaccine” and induce systemic immune responses that prevent secondary tumor growth (prophylactic immunity). We have furthermore demonstrated that these effects are augmented by combination with innate immune activators and PD-1 checkpoint blockade. We observed a significant decrease in immunosuppressive myeloid-derived suppressor cells (MDSCs) (CD11b+, CD11c-, GR1+) at one week in the IRE and drug alone groups with an additive effect in the combination groups. We also saw a profound shift in the ratio of immunostimulatory M1 (MHC II+, CD206 lo): immunosuppressive M2 (MHC II -, CD206 hi) macrophages in the combination groups and a modest increase in CD8+ T cells with IRE alone that was almost doubled in the combination groups with a concomitant decrease in T regulatory cells. Using exome and RNA sequencing of the KPC tumors expressed, nonsynonymous mutations in these tumors were identified and 101 long peptides (20 mer) were generated harboring these mutations at positions 9 and 15. When the CD8+ T-cells post-IRE were incubated along with these mutant peptides and bone marrow-derived dendritic cells, we were able to observe that these T cells were reactive (Interferon gamma secretion) to these neoantigenic peptide pools. Further, we were able to identify specific mutant peptides against which T-cell response was stimulated post IRE that were similar or even better than vaccinating the mice with irradiated KPC cells, suggesting that IRE induced tumor neoantigen-specific prophylactic immune response. Specifically, local delivery of toll-like receptor 7 (TLR7) agonist (1V270) and agonistic CD40 antibody resulted in complete regression of treated primary tumors in 7/10 mice in the experimental group. Increased presence of CD8+ dendritic cells (CD45+ CD11C+) in the draining lymph node suggested that the agonistic CD40 antibody could have triggered increased dendritic cell maturation and cross-presentation. Moreover, it resulted in the complete elimination of the untreated secondary tumors in the group, which IRE as a monotherapy failed to achieve, showing that with appropriate combination strategies, successful therapeutic systemic antitumor immunity can also be achieved with IRE to be used for the management of metastatic PC in the near future. Citation Format: Jayanth S. Shankara Narayanan, Aaron Miller, Tomoko Hayashi, Partha Ray, Stephen Schoenberger, Dennis Carson, Rebekah White. Irreversible electroporation is an “in situ vaccine” and induces antitumor immune responses in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy 2018 Nov 27-30 Miami Beach, FL. Philadelphia (PA): AACR Cancer Immunol Res 2020 (4 Suppl):Abstract nr A14.
Publisher: Public Library of Science (PLoS)
Date: 15-09-2014
Publisher: Springer Science and Business Media LLC
Date: 31-08-2016
DOI: 10.1038/SREP32062
Abstract: Advanced, metastatic, castration resistant and chemo-resistant prostate cancer has triggered change in the drug development landscape against prostate cancer. Bovine lactoferrin (bLf) is currently attracting attention in clinics for its anti-cancer properties and proven safety profile. bLf internalises into cancer cells via receptor mediated endocytosis, boosts immunity and complements chemotherapy. We employed bLf as an excellent functional carrier protein for delivering doxorubicin (Dox) into DU145 cells, CD44+/EpCAM+ double positive enriched DU145 3D prostaspheres and drug resistant ADR1000-DU145 cells, thus circumventing Dox efflux, to overcome chemo-resistance. Successful bLf-Dox conjugation with iron free or iron saturated bLf forms did not affect the integrity and functionality of bLf and Dox. bLf-Dox internalised into DU145 cells within 6 h, enhanced nuclear Dox retention up to 24 h and proved significantly effective (p 0.001) in reducing LC 50 value of Dox from 5.3 μM to 1.3 μM (4 fold). Orally fed iron saturated bLf-Dox inhibited tumour development, prolonged survival, reduced Dox induced general toxicity, cardiotoxicity, neurotoxicity in TRAMP mice and upregulated serum levels of anti-cancer molecules TNF-α, IFN-γ, CCL4 and CCL17. The study identifies promising potential of a novel and safer bLf-Dox conjugate containing a conventional cytotoxic drug along with bLf protein to target drug resistance.
Publisher: American Chemical Society (ACS)
Date: 25-08-2014
DOI: 10.1021/LA502960H
Abstract: Plasma, generated in liquid at atmospheric pressure by a nanosecond pulsed voltage, was used to fabricate hybrid structures from boron nitride nanotubes and gold nanoparticles in deionized water. The pH was greatly reduced, conductivity was significantly increased, and concentrations of reactive oxygen and nitrogen species in the water were increased by the plasma treatment. The treatment reduced the length of the nanotubes, giving more in idual cuplike structures, and introduced functional groups onto the surface. Gold nanoparticles were successively assembled onto the functionalized surfaces. The reactive species from the liquid plasma along with the nanosecond pulsed electric field seem to play a role in the shortening and functionalization of the nanotubes and the assembly of gold nanoparticles. The potential for targeted drug delivery was tested in a preliminary investigation using doxorubicin-loaded plasma-treated nanotubes which were effective at killing ∼99% of prostate cancer cells.
Publisher: Springer Science and Business Media LLC
Date: 06-04-2022
DOI: 10.1007/S12672-022-00483-4
Abstract: There is a great need to reduce the toxicity of chemotherapy used in the management of pancreatic ductal adenocarcinoma (PDAC). Here we explore if regional pressurized delivery of oxaliplatin can minimize peripheral neuropathy in mice. We used an orthotopic PDAC mouse model and delivered a single dose of oxaliplatin through the portal vein using a pressure-enabled system (pancreatic retrograde venous infusion, PRVI). We analyzed the effects of PRVI on tumor burden and peripheral neuropathy using histopathological and functional assays. Tumor weights in mice treated with 2 mg/kg oxaliplatin using PRVI were significantly lower than in mice treated with the same dose systemically. This resulted in reduced peripheral neuropathy signatures in PRVI mice compared to the 20 mg/kg systemic dose required to achieve similar tumor control. Regional delivery of highly cytotoxic agents using PRVI can reduce the therapeutic dose of these drugs, thereby lowering toxic side effects.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 11-2019
Publisher: Cold Spring Harbor Laboratory
Date: 06-10-2022
DOI: 10.1101/2022.10.04.510847
Abstract: Pancreatic cancer (PC) has a poor prognosis, and most patients present with either locally advanced or distant metastatic disease. Irreversible Electroporation (IRE) is a non-thermal method of ablation used clinically in locally advanced PC, but most patients eventually develop distant recurrence. We have previously shown that IRE alone is capable of generating protective, neoantigen-specific immunity. Here we aim to generate meaningful therapeutic immune effects by combining IRE with local (intratumoral) delivery of a CD40 agonistic antibody (CD40Ab). KPC46 organoids were generated from a tumor-bearing male KrasLSL-G12D-p53LSL-R172H-Pdx-1-Cre (KPC) mouse. Orthotopic tumors were established in the pancreatic tail of B6/129 F1J mice via laparotomy. Mice were randomized to treatment with either sham laparotomy, IRE alone, CD40Ab alone, or IRE followed immediately by CD40Ab injection. Metastatic disease and immune infiltration in the liver were analyzed 14 days post-procedure using flow cytometry and multiplex immunofluorescence imaging with spatial analysis. Candidate neoantigens were identified by mutanome profiling of tumor tissue for ex vivo functional analyses. The combination of IRE+CD40Ab improved median survival to greater than 35 days, significantly longer than IRE (21 days) or CD40Ab (24 days) alone (p .01). CD40Ab decreased metastatic disease burden, with less disease in the combination group than in the sham group or IRE alone. Immunohistochemistry of liver metastases revealed a more than two-fold higher infiltration of CD8+ T-cells in the IRE+CD40Ab group than in any other group (p .01). Multiplex immunofluorescence imaging revealed a 4-6-fold increase in the density of CD80+CD11c+ activated dendritic cells (p .05), which were spatially distributed throughout the tumor unlike the sham group, where they were restricted to the periphery. In contrast, CD4+FoxP3+ T-regulatory cells (p .05) and Ly6G+ MDSCs (P .01) were reduced and restricted to the tumor periphery in the IRE+CD40Ab group. T-cells from the IRE+CD40Ab group recognized significantly more peptides representing candidate neoantigens than did T-cells from the IRE or untreated control groups. IRE can induce local tumor regression and neoantigen-specific immune responses. Addition of CD40Ab to IRE improved dendritic cell activation and neoantigen recognition, while generating a strong systemic anti-tumor T-cell response that inhibited metastatic disease progression.
Publisher: BMJ
Date: 2023
Abstract: Pancreatic cancer (PC) has a poor prognosis, and most patients present with either locally advanced or distant metastatic disease. Irreversible electroporation (IRE) is a non-thermal method of ablation used clinically in locally advanced PC, but most patients eventually develop distant recurrence. We have previously shown that IRE alone is capable of generating protective, neoantigen-specific immunity. Here, we aim to generate meaningful therapeutic immune effects by combining IRE with local (intratumoral) delivery of a CD40 agonistic antibody (CD40Ab). KPC46 organoids were generated from a tumor-bearing male KrasLSL-G12D-p53LSL-R172H-Pdx-1-Cre (KPC) mouse. Orthotopic tumors were established in the pancreatic tail of B6/129 F1J mice via laparotomy. Mice were randomized to treatment with either sham laparotomy, IRE alone, CD40Ab alone, or IRE followed immediately by CD40Ab injection. Metastatic disease and immune infiltration in the liver were analyzed 14 days postprocedure using flow cytometry and multiplex immunofluorescence imaging with spatial analysis. Candidate neoantigens were identified by mutanome profiling of tumor tissue for ex vivo functional analyses. The combination of IRE+CD40 Ab improved median survival to greater than 35 days, significantly longer than IRE (21 days) or CD40Ab (24 days) alone (p .01). CD40Ab decreased metastatic disease burden, with less disease in the combination group than in the sham group or IRE alone. Immunohistochemistry of liver metastases revealed a more than twofold higher infiltration of CD8+T cells in the IRE+CD40 Ab group than in any other group (p .01). Multiplex immunofluorescence imaging revealed a 4–6 fold increase in the density of CD80+CD11c+ activated dendritic cells (p .05), which were spatially distributed throughout the tumor unlike the sham group, where they were restricted to the periphery. In contrast, CD4+FoxP3+ T-regulatory cells (p .05) and Ly6G+myeloid derived cells (p .01) were reduced and restricted to the tumor periphery in the IRE+CD40 Ab group. T-cells from the IRE+CD40 Ab group recognized significantly more peptides representing candidate neoantigens than did T-cells from the IRE or untreated control groups. IRE can induce local tumor regression and neoantigen-specific immune responses. Addition of CD40Ab to IRE improved dendritic cell activation and neoantigen recognition, while generating a strong systemic antitumor T-cell response that inhibited metastatic disease progression.
Location: United States of America
No related grants have been discovered for Jayanth Surya Narayanan Shankara Narayanan.