Julius W. Kim
Northwestern University
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Publication
Featured researches published by Julius W. Kim.
Clinical Cancer Research | 2014
Derek A. Wainwright; Alan L. Chang; Mahua Dey; Irina V. Balyasnikova; Chung Kwon Kim; Alex Tobias; Yu Cheng; Julius W. Kim; Jian Qiao; Lingjiao Zhang; Yu Han; Maciej S. Lesniak
Purpose: Glioblastoma (GBM) is the most common form of malignant glioma in adults. Although protected by both the blood–brain and blood–tumor barriers, GBMs are actively infiltrated by T cells. Previous work has shown that IDO, CTLA-4, and PD-L1 are dominant molecular participants in the suppression of GBM immunity. This includes IDO-mediated regulatory T-cell (Treg; CD4+CD25+FoxP3+) accumulation, the interaction of T-cell–expressed, CTLA-4, with dendritic cell-expressed, CD80, as well as the interaction of tumor- and/or macrophage-expressed, PD-L1, with T-cell–expressed, PD-1. The individual inhibition of each pathway has been shown to increase survival in the context of experimental GBM. However, the impact of simultaneously targeting all three pathways in brain tumors has been left unanswered. Experimental Design and Results: In this report, we demonstrate that, when dually challenged, IDO-deficient tumors provide a selectively competitive survival advantage against IDO-competent tumors. Next, we provide novel observations regarding tryptophan catabolic enzyme expression, before showing that the therapeutic inhibition of IDO, CTLA-4, and PD-L1 in a mouse model of well-established glioma maximally decreases tumor-infiltrating Tregs, coincident with a significant increase in T-cell–mediated long-term survival. In fact, 100% of mice bearing intracranial tumors were long-term survivors following triple combination therapy. The expression and/or frequency of T cell expressed CD44, CTLA-4, PD-1, and IFN-γ depended on timing after immunotherapeutic administration. Conclusions: Collectively, these data provide strong preclinical evidence that combinatorially targeting immunosuppression in malignant glioma is a strategy that has high potential value for future clinical trials in patients with GBM. Clin Cancer Res; 20(20); 5290–301. ©2014 AACR.
Expert Review of Neurotherapeutics | 2014
Jacob S. Young; Julius W. Kim; Atique U. Ahmed; Maciej S. Lesniak
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.
Stem Cells | 2015
Deepak Kanojia; Irina V. Balyasnikova; Ramin A. Morshed; Richard T. Frank; Dou Yu; Lingjiao Zhang; Drew A. Spencer; Julius W. Kim; Yu Han; Dihua Yu; Atique U. Ahmed; Karen S. Aboody; Maciej S. Lesniak
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 intracranial injection of HER2Ab‐NSCs significantly improves survival. In effect, these NSCs provide tumor localized production of HER2Ab, minimizing any potential off‐target side effects. Our results establish HER2Ab‐NSCs as a novel, nontoxic, and rational therapeutic approach for the successful treatment of HER2 overexpressing BCBM, which now warrants further preclinical and clinical investigation. Stem Cells 2015;33:2985–2994
Expert Opinion on Drug Delivery | 2014
Jacob S. Young; Ramin A. Morshed; Julius W. Kim; Irina V. Balyasnikova; Atique U. Ahmed; Maciej S. Lesniak
Introduction: 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. Areas covered: 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. Expert opinion: 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.
Molecular Cancer Therapeutics | 2015
Deepak Kanojia; Ramin A. Morshed; Lingjiao Zhang; Jason Miska; Jian Qiao; Julius W. Kim; Peter Pytel; Irina V. Balyasnikova; Maciej S. Lesniak; Atique U. Ahmed
Brain metastases occur in about 10% to 30% of breast cancer patients, which culminates in a poor prognosis. It is, therefore, critical to understand the molecular mechanisms underlying brain metastatic processes to identify relevant targets. We hypothesized that breast cancer cells must express brain-associated markers that would enable their invasion and survival in the brain microenvironment. We assessed a panel of brain-predominant markers and found an elevation of several neuronal markers (βIII-tubulin, Nestin, and AchE) in brain metastatic breast cancer cells. Among these neuronal predominant markers, in silico analysis revealed overexpression of βIII-tubulin (TUBB3) in breast cancer brain metastases (BCBM) and its expression was significantly associated with distant metastases. TUBB3 knockdown studies were conducted in breast cancer models (MDA-Br, GLIM2, and MDA-MB-468), which revealed significant reduction in their invasive capabilities. MDA-Br cells with suppressed TUBB3 also demonstrated loss of key signaling molecules such as β3 integrin, pFAK, and pSrc in vitro. Furthermore, TUBB3 knockdown in a brain metastatic breast cancer cell line compromised its metastatic ability in vivo, and significantly improved survival in a brain metastasis model. These results implicate a critical role of TUBB3 in conferring brain metastatic potential to breast cancer cells. Mol Cancer Ther; 14(5); 1152–61. ©2015 AACR.
Oncotarget | 2017
Wojciech K. Panek; J. Robert Kane; Jacob S. Young; Aida Rashidi; Julius W. Kim; Deepak Kanojia; Maciej S. Lesniak
Glioblastoma is a highly aggressive malignant brain tumor with a poor prognosis and the median survival 14.6 months. Immunomodulatory proteins and oncolytic viruses represent two treatment approaches that have recently been developed for patients with glioblastoma that could extend patient survival and result in better treatment outcomes for patients with this disease. Together, these approaches could potentially augment the treatment efficacy and strength of these anti-tumor therapies. In addition to oncolytic activities, this combinatory approach introduces immunomodulation locally only where cancerous cells are present. This thereby results in the change of the tumor microenvironment from immune-suppressive to immune-vulnerable via activation of cytotoxic T cells or through the removal of glioma cells immune-suppressive capability. This review discusses the strengths and weaknesses of adenoviral oncolytic therapy, and highlights the genetic modifications that result in more effective and targeted viral agents. Additionally, the mechanism of action of immune-activating agents is described and the results of previous clinical trials utilizing these treatments in other solid tumors are reviewed. The feasibility, synergy, and limitations for treatments that combine these two approaches are outlined and areas for which more work is needed are considered.
OncoImmunology | 2015
Jian Qiao; Mahua Dey; Alan L. Chang; Julius W. Kim; Jason Miska; Alexander Ling; Dirk M. Nettlebeck; Yu Han; Lingjiao Zhang; Maciej S. Lesniak
Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor and is associated with poor survival. Virotherapy is a promising candidate for the development of effective, novel treatments for GBM. Recent studies have underscored the potential of virotherapy in enhancing antitumor immunity despite the fact that its mechanisms remain largely unknown. Here, using a syngeneic GBM mouse model, we report that intratumoral virotherapy significantly modulates the tumor microenvironment. We found that intratumoral administration of an oncolytic adenovirus, AdCMVdelta24, decreased tumor-infiltrating CD4+ Foxp3+ regulatory T cells (Tregs) and increased IFNγ-producing CD8+ T cells in treated tumors, even in late stage disease in which a highly immunosuppressive tumor microenvironment is considered to be a significant barrier to immunotherapy. Importantly, intratumoral AdCMVdelta24 treatment augmented systemically transferred tumor-antigen-specific T cell therapy. Furthermore, mechanistic studies showed (1) downregulation of Foxp3 in Tregs that were incubated with media conditioned by virus-infected tumor cells, (2) downregulation of indoleamine 2,3 dioxygenase 1 (IDO) in glioma cells upon infection by AdCMVdelta24, and (3) reprograming of Tregs from an immunosuppressive to a stimulatory state. Taken together, our findings demonstrate the potency of intratumoral oncolytic adenoviral treatment in enhancing antitumor immunity through the regulation of multiple aspects of immune suppression in the context of glioma, supporting further clinical development of oncolytic adenovirus-based immune therapies for malignant brain cancer.
Current protocols in human genetics | 2015
Julius W. Kim; J. Robert Kane; Jacob S. Young; Alan L. Chang; Deepak Kanojia; Shuo Qian; Drew A. Spencer; Atique U. Ahmed; Maciej S. Lesniak
The use of stem cells (SCs) as carriers for therapeutic agents has now progressed to early clinical trials. These clinical trials exploring SC‐mediated delivery of oncolytic adenoviruses will commence in the near future, hopefully yielding meritorious results that can provoke further scientific inquiry. Preclinical animal studies have demonstrated that SCs can be successfully loaded with conditionally‐replicative adenoviruses and delivered to the tumor, whereupon they may evoke pronounced therapeutic efficacy. In this protocol, we describe the maintenance of SCs, provide an analysis of optimal adenoviral titers for SC loading, and evaluate the optimized viral loading on SCs.
Therapeutic Delivery | 2015
Drew A. Spencer; Jacob S. Young; Deepak Kanojia; Julius W. Kim; Sean P. Polster; Jason Murphy; Maciej S. Lesniak
Malignant glioma is a relentless burden to both patients and clinicians, and calls for innovation to overcome the limitations in current management. Glioma therapy using viruses has been investigated to accentuate the nature of a virus, killing a host tumor cell during its replication. As virus mediated approaches progress with promising therapeutic advantages, combination therapy with chemotherapy and oncolytic viruses has emerged as a more synergistic and possibly efficacious therapy. Here, we will review malignant glioma as well as prior experience with oncolytic viruses, chemotherapy and combination of the two, examining how the combination can be optimized in the future.
Scientific Reports | 2016
Julius W. Kim; Jacob S. Young; Elena Solomaha; Deepak Kanojia; Maciej S. Lesniak; Irina V. Balyasnikova
The generation of a targeting agent that strictly binds to IL13Rα2 will significantly expand the therapeutic potential for the treatment of IL13Rα2-expressing cancers. In order to fulfill this goal, we generated a single-chain antibody (scFv47) from our parental IL13Rα2 monoclonal antibody and tested its binding properties. Furthermore, to demonstrate the potential therapeutic applicability of scFv47, we engineered an adenovirus by incorporating scFv47 as the targeting moiety in the viral fiber and characterized its properties in vitro and in vivo. The scFv47 binds to human recombinant IL13Rα2, but not to IL13Rα1 with a high affinity of 0.9 · 10−9 M, similar to that of the parental antibody. Moreover, the scFv47 successfully redirects adenovirus to IL13Rα2 expressing glioma cells both in vitro and in vivo. Our data validate scFv47 as a highly selective IL13Rα2 targeting agent and justify further development of scFv47-modified oncolytic adenovirus and other therapeutics for the treatment of IL13Rα2-expressing glioma and other malignancies.