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Gaithersburg, MD, United States

Dropulic B.,Lentigen Corporation
Human Gene Therapy | Year: 2011

Lentiviral vectors have been successfully used in the clinic and they are increasingly being used for nonclinical applications. They are capable of stably transducing a broad range of mammalian cell types, including nondividing cells, with high efficiency. This review summarizes the evolving molecular design of lentiviral vectors, describing how they have improved since their first description. Lentiviral vector safety and issues surrounding genotoxicity are discussed. Examples of successful application of lentiviral vectors in laboratory and preclinical research are described. These include functional genomics, target validation, protein manufacturing, in vivo imaging, transgenic animals, and stem cell research. © 2011 Mary Ann Liebert, Inc.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 5.12M | Year: 2010

DESCRIPTION (provided by applicant): This Phase II proposal is a continuation of our Phase I award, Lentiviral Vectors for TCR Immunotherapy Targeted to Melanoma. We have successfully achieved the milestones laid out in our initial application. We generated a lentiviral gene vector capable of expressing a T cell receptor (TCR) specific for the tyrosinase:368-376 epitope, and demonstrated the activity of this cloned TCR in in vitro and in vivo models. The targeting of the melanoma-associated differentiation antigen by T cells transduced with this specific TCR will create a new therapeutic option for patients with melanoma. According to the American Cancer Society melanoma is currently the sixth most common cancer in men and the seventh most common cancer in American women. In this proposal we will generate clinical grade TCR vector, transduce patient-derived T cells, and then initiate a phase I clinical trial to evaluate the safety of this procedure. Recent findings from the NCI indicate that a transient lymphopenia induced by chemotherapy is essential for therapeutic effect. The trial we propose will be the first to try this procedure outside of the confines of the NCI, and will establish a new paradigm for the treatment of melanoma in the hospital setting. Secondarily this grant will move product development for the lentiviral vector expressing this TCR another step forward in the critical path of product development, and further key corporate goals of Lentigen to become the leader in clinical application of lentiviral vector technology. It is clear that immunotherapy will be a key feature for effective control of melanoma, a type of tumor for which current therapies do not offer satisfactory results. Lentiviral vectors have been evaluated in Phase I trials in HIV/AIDS. This proposal will be the first to use lentiviral technology in the treatment of melanoma. Our milestones will be 1) To generate GMP grade lentiviral vector, establishing release criteria for clinical use, and 2) to transduce patient T cells with this vector and infuse them according to our phase I FDA clinical trial- designed to evaluate the safety of transduced T cell infusion in lymphodepleted patients. In summary, Lentigen Corp. along with Dr. Michael Nishimura and his clinical team at the Medical University of South Carolina are uniquely positioned to provide a comprehensive evaluation of engineered human T cells in a clinical setting that can be generalized to other centers treating this life-threatening malignancy. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to develop a novel and improved immunotherapy for melanoma, a tumor for which current therapies do not offer satisfactory results. This therapy will feature the activation of immune cells that will be manipulated in the laboratory and infused back into the patient in order to eliminate melanoma tumor cells. Because of its great potential to offer a solution for those patients failing other therapies, this therapy will have significant relevance for cancer patients with melanoma and health care providers in the United States and worldwide.

Agency: Department of Defense | Branch: Army | Program: STTR | Phase: Phase I | Award Amount: 98.51K | Year: 2007

This proposal focuses on developing a protein manufacturing platform based on a novel vector system that can rapidly and efficiently generate cell lines capable of producing proteins at high yield and purity in a short time period. Lentigen is able to perform such a quick protein manufacturing process based on its LentiMaxT lentiviral (LV) gene delivery technology that stably delivers one or more nucleic acid sequence(s) encoding a protein(s) to a mammalian cell with up to 100 % efficiency. Lentigen is able to produce multiple protein producing mammalian cell lines quickly, in as little as four (4) weeks, because its LentiMax system is inherently flexible and modular allowing all nucleic acid sequences under 6 Kb in length to be rapidly cloned. Transduction of cells with lentiviral particles is simple and cell lines theoretically should be able to produce protein indefinitely. Lentigen has monitored one cell line and has demonstrated that is has produced protein for up to three months with less than a 2 % decrease in yield over that time frame. Lentigen is currently working with four clients (the names of these clients can not be disclosed do to confidentiality constraints) to develop a plurality of cell lines able to produce monoclonal antibodies at high yields and purity for research and development purposes. To date, Lentigen has been able to generate in excess of 1 gram per Liter of Erythropoietin from cells that have been bulk transduced with LentiMax. This is a remarkable result given that the cells were not selected for high producers or manipulated in any way to increase protein production from routine cell culture conditions. Lentigen is confident that its LentiMax technology will be able to produce clonal cells that express secreted proteins of interest to an excess of 10 grams per Liter. Such an accomplishment would dramatically reduce the cost to produce valuable proteins such as monoclonal antibodies. Lentigen is applying for this STTR to adapt its protein manufacturing technology to be able to produce proteins in CHO cells, in serum free medium, for large scale clinical and commercial applications.

Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 283.75K | Year: 2007

DESCRIPTION (provided by applicant): Our long term goal is to develop cellular based immunotherapy for the treatment of malignancy. One approach to enhancing the effects of cellular immunotherapy is via gene therapy. We are currently focused on enhancing the antitumor effects of adoptive T cell therapy using lentiviral vector-mediated genetic modification of cells to express a universal T cell receptor (TCR), or chimeric immune receptor (CIR). CIRs are comprised of an extracellular antibody fragment specific to a tumor antigen linked to an intracellular T cell activation domain capable of providing the cell with MHC unrestricted antigen-specific activation. Current treatments for B cell malignancies include chemotherapy, radiation therapy, bone marrow transplantation, and peripheral blood stem cell transplantation. Despite these treatment modalities, most patients will remain incurable. Cell based immunotherapy offers the promise of an alternative treatment option for patients who have tried and failed presently available treatment options. We have developed a CIR targeting the pan-B cell marker CD19. In comparison to the CD3-( alone signaling chain, we will test the multipartite signaling domains 41BB-( and CD28:41BB:( in our aCD19 CIR. Our specific goal in the proposed studies is to establish in preclinical (phase I) and an exploratory clinical study (phase II) the optimal signaling chain for CIR immunotherapy for B cell malignancy, using competitive repopulation experiments to identify the best candidate for commercialization of the therapy. Optimizing safety is a critical step towards a commercially feasible gene-based immunotherapy for cancer. One way to improve the safety of CIR T cells is to include a suicide gene switch that in the case of CIR-mediated toxicity will facilitate specific deletion of gene-modified cells by chemotherapy that is a low enough dose to leave an in tact immune system. A new class of suicide genes isolated from drosophila melanogaster, called dNK (for deoxyribonucleoside kinase) have been developed which offer altered substrate activity that is not influenced by the antivirals commonly used in cancer patients. We hypothesize that expression of the suicide gene will not alter the ability of CIR engineered cells to control tumors and that it will permit selective killing of the engineered cell upon introduction of substrate chemotherapy. In Aim 1, we will build and test the function of single and multipartite signaling chain CIR constructs with the dNK suicide gene in vitro; in Aim 2 we will evaluate the function of these CIRs and dNK suicide gene in a competitive repopulation in vivo in the NOG mouse model.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 289.68K | Year: 2007

DESCRIPTION (provided by applicant): The overall goal of this proposal is to evaluate the novel concept whether using lentiviral-engineered T cells that express T cell receptor (TCR) capable of recognizing hepatitis C (HCV)-induced liver tumor cells will improve efficacy of immunotherapy for this disease. Chronic infection with HCV can lead to several liver diseases including hepatocellular carcinoma and cirrhosis. These liver diseases are the major indication for liver transplantation. IFN-? in combination with ribavirin is used to treat HCV infections with limited success. In order to reduce the worldwide morbidity and mortality from HCV infection and HCV related diseases more effective treatments for HCV infected patients are necessary. In this proposal we will test the fundamental hypothesis that human T cells with redirected specificity for HCV associated liver tumor cells can be created by using lentiviral vector technology and can offer a clinically relevant and successful therapeutic approach. The ultimate goal is the development of a novel and improved therapy for hepatitis HCV related malignancy, a potentially major public health concerns with approximately 3% of the world's population. Lentiviral vectors (LVs) have been successfully evaluated in Phase l clinical trials in patients with HIV/AIDS, offering the possibility to more broadly apply this technology for the treatment of other diseases, including chronic infections and cancer. Lentigen's collaborator Dr. Michael Nishimura has helped pioneer adoptive immunotherapy as a potential therapeutic approach for hepatitis. Therefore, in Aim 1 of this proposal we will develop self inactivating (SIN) LVs expressing a and a chains of the TCR capable of recognizing the HCV and/or liver tumor cells. In Aim 2, together with Dr. Nishimura's team, we will test safety and efficacy of LVTCR transduced T cells in preventing HCV- induced liver tumor growth and treating established tumors in vivo. In summary, Lentigen Corp. and Dr. Nishimura's laboratory are uniquely positioned to provide the first comprehensive evaluation of the redirected T cell approach to generate anti-HCV induced liver tumor effects in patients infected with HCV and to apply this in a future clinical trial for patients with this life threatening disease.

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