Atique Ahmed | Northwestern University (original) (raw)

Papers by Atique Ahmed

Stem cells (Dayton, Ohio), Jan 11, 2015

The treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer has... more The treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer has been revolutionized by trastuzumab. However, longer survival of these patients now predisposes them to forming HER2 positive brain metastases, as the therapeutic antibodies cannot cross the blood brain barrier. The current oncologic repertoire does not offer a rational, nontoxic targeted therapy for brain metastases. In this study, we used an established human neural stem cell line, HB1.F3 NSCs and generated a stable pool of cells secreting a high amount of functional full-length anti-HER2 antibody, equivalent to trastuzumab. Anti-HER2Ab secreted by the NSCs (HER2Ab-NSCs) specifically binds to HER2 overexpressing human breast cancer cells and inhibits PI3K-Akt signaling. This translates to HER2Ab-NSC inhibition of breast cancer cell growth in vitro. Preclinical in vivo experiments using HER2Ab overexpressing NSCs in a breast cancer brain metastases (BCBM) mouse model demonstrate that in...

Journal of immunology (Baltimore, Md. : 1950), Jan 29, 2015

Dendritic cells (DCs) are professional APCs that are traditionally divided into two distinct subs... more Dendritic cells (DCs) are professional APCs that are traditionally divided into two distinct subsets, myeloid DC (mDCs) and plasmacytoid DC (pDCs). pDCs are known for their ability to secrete large amounts of IFN-α. Apart from IFN-α production, pDCs can also process Ag and induce T cell immunity or tolerance. In several solid tumors, pDCs have been shown to play a critical role in promoting tumor immunosuppression. We investigated the role of pDCs in the process of glioma progression in the syngeneic murine model of glioma. We show that glioma-infiltrating pDCs are the major APC in glioma and are deficient in IFN-α secretion (p < 0.05). pDC depletion leads to increased survival of the mice bearing intracranial tumor by decreasing the number of regulatory T cells (Tregs) and by decreasing the suppressive capabilities of Tregs. We subsequently compared the ability of mDCs and pDCs to generate effective antiglioma immunity in a GL261-OVA mouse model of glioma. Our data suggest that ...

Human gene therapy, Jan 25, 2015

The dismal clinical context of advanced-grade glioma demands the development of novel therapeutic... more The dismal clinical context of advanced-grade glioma demands the development of novel therapeutic strategies with direct patient impact. Adenovirus-mediated virotherapy represents a potentially effective approach for glioma therapy. In this research, we generated a novel glioma specific adenovirus by instituting more advanced genetic modifications which can maximize the efficiency and safety of therapeutic adenoviral vectors. In this regard, a glioma-specific targeted fiber was developed through the incorporation of previously published glioma-specific, phage-panned peptides (VWT peptide) on a fiber fibritin-based chimeric fiber, designated as 'GliomaFF.' We showed that the entry of this virus was highly restricted to glioma cells, supporting the specificity imparted by the phage-panned peptide. Additionally, the stability of the targeting moiety presented by fiber fibritin structure permitted greatly enhanced infectivity. Furthermore, the replication of this virus was restr...

Expert Review of Neurotherapeutics, 2015

Glioma stem cells (GSCs) constitute a slow-dividing, small population within a heterogeneous glio... more Glioma stem cells (GSCs) constitute a slow-dividing, small population within a heterogeneous glioblastoma. They are able to self-renew, recapitulate a whole tumor, and differentiate into other specific glioblastoma multiforme (GBM) subpopulations. Therefore, they have been held responsible for malignant relapse after primary standard therapy and the poor prognosis of recurrent GBM. The failure of current therapies to eliminate specific GSC subpopulations has been considered a major factor contributing to the inevitable recurrence in GBM patients after treatment. Here, we discuss the molecular mechanisms of chemoresistance of GSCs and the reasons why complete eradication of GSCs is so difficult to achieve. We will also describe the targeted therapies currently available for GSCs and possible mechanisms to overcome such chemoresistance and avoid therapeutic relapse.

Expert Opinion on Drug Delivery, 2014

A limitation of small molecule inhibitors, nanoparticles (NPs) and therapeutic adenoviruses is th... more A limitation of small molecule inhibitors, nanoparticles (NPs) and therapeutic adenoviruses is their incomplete distribution within the entirety of solid tumors such as malignant gliomas. Currently, cell-based carriers are making their way into the clinical setting as they offer the potential to selectively deliver many types of therapies to cancer cells. Here, we review the properties of stem cells, induced pluripotent stem cells and engineered cells that possess the tumor-tropic behavior necessary to serve as cell carriers. We also report on the different types of therapeutic agents that have been delivered to tumors by these cell carriers, including: i) therapeutic genes; ii) oncolytic viruses; iii) NPs; and iv) antibodies. The current challenges and future promises of cell-based drug delivery are also discussed. While the emergence of stem cell-mediated therapy has resulted in promising preclinical results and a human clinical trial utilizing this approach is currently underway, there is still a need to optimize these delivery platforms. By improving the loading of therapeutic agents into stem cells and enhancing their migratory ability and persistence, significant improvements in targeted cancer therapy may be achieved.

Expert review of neurotherapeutics, 2014

Many different experimental molecular therapeutic approaches have been evaluated in an attempt to... more Many different experimental molecular therapeutic approaches have been evaluated in an attempt to treat brain cancer. However, despite the success of these experimental molecular therapies, research has shown that the specific and efficient delivery of therapeutic agents to tumor cells is a limitation. In this regard, cell carrier systems have garnered significant attraction due to their capacity to be loaded with therapeutic agents and carry them specifically to tumor sites. Furthermore, cell carriers can be genetically modified to express therapeutic agents that can directly eradicate cancerous cells or can modulate tumor microenvironments. This review describes the current state of cell carriers, their use as vehicles for the delivery of therapeutic agents to brain tumors, and future directions that will help overcome the present obstacles to cell carrier mediated therapy for brain cancer.

Journal of Neuroimmunology, 2014

Two characteristic features of malignant gliomas (MG) are the presence of hypoxia and accumulatio... more Two characteristic features of malignant gliomas (MG) are the presence of hypoxia and accumulation of regulatory T cells (Tregs). Heme-oxygenase-1 (HO1) is a cytoprotective enzyme expressed in high level by Tregs in glioma. In this study, we show that higher HO1 expression in Tregs is associated with increased survival under hypoxic conditions and that HO1 inhibitor, tin protoporphyrin (SnPP), abrogates the survival benefits. Moreover, SnPP preferentially eliminates Tregs and treatment with SnPP of tumor bearing mice significantly increases survival (23 to 31days (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05)). Thus HO1 inhibition provides another alternative way of therapeutically targeting Tregs in MG.

Cancer Gene Therapy, 2014

Brain, Behavior, and Immunity, 2012

ABSTRACT Glioblastoma multiforme (GBM) is a malignant and aggressive primary brain tumor with an ... more ABSTRACT Glioblastoma multiforme (GBM) is a malignant and aggressive primary brain tumor with an average patient survival of 14.6 months following diagnosis. Our laboratory has previously demonstrated that immunosuppressive regulatory T cells (Tregs; CD4+FoxP3+) infiltrate and accumulate in brain tumors, by utilizing mouse models. Importantly, depleting those Tregs is associated with a significant increase in overall survival. To understand the underlying mechanisms that promote Treg recruitment to brain tumors, our laboratory has investigated the enzyme, indoleamine 2,3-dioxygenase 1 (IDO). We have found that the upregulation of IDO in glioma patients (n = 343) is associated with a significantly decreased probability of overall survival (p < 0.005). Utilizing a mouse model that intracranially-injects GL261 (brain tumor) cells, we have confirmed that IDO knockdown (IDOkd), specifically in brain tumor cells, results in decreased Treg recruitment to the tumor, as well as increased long-term survival (p < 0.001). This was accomplished by comparing WT and IDO−/− mice, intracranially-injected control or IDOkd GL261 cells (p < 0.001). Interestingly, the long-term survival mediated through IDO-deficiency was lost in CD4−/−, CD8−/− and Rag1−/− mice, suggesting a contextual role for T cells in mediating brain tumor rejection vs. promotion. These data confirm the importance of IDO1 in brain tumors and provide further support for understanding the mechanism of immune-mediated IDO1-dependent tumor progression.

Oncolytic virotherapy for cancer is an innovative therapeutic option where the ability of a virus... more Oncolytic virotherapy for cancer is an innovative therapeutic option where the ability of a virus to promote cell lysis is harnessed and reprogrammed to selectively destroy cancer cells. Such treatment modalities exhibited antitumor activity in preclinical and clinical settings and appear to be well tolerated when tested in clinical trials. However, the clinical success of oncolytic virotherapy has been significantly hampered due to the inability to target systematic metastasis. This is partly due to the inability of the therapeutic virus to survive in the patient circulation, in order to target tumors at distant sites. An early study from various laboratories demonstrated that cells infected with oncolytic virus can protect the therapeutic payload form the host immune system as well as function as factories for virus production and enhance the therapeutic efficacy of oncolytic virus. While a variety of cell lineages possessed potential as cell carriers, copious investigation has established stem cells as a very attractive cell carrier system in oncolytic virotherapy. The ideal cell carrier desire to be susceptible to viral infection as well as support viral infection, maintain immunosuppressive properties to shield the loaded viruses from the host immune system, and most importantly possess an intrinsic tumor homing ability to deliver loaded viruses directly to the site of the metastasis-all qualities stem cells exhibit. In this review, we summarize the recent work in the development of stem cell-based carrier for oncolytic virotherapy, discuss the advantages and disadvantages of a variety of cell carriers, especially focusing on why stem cells have emerged as the leading candidate, and finally propose a future direction for stem cell-based targeted oncolytic virotherapy that involves its establishment as a viable treatment option for cancer patients in the clinical setting.