SBIR-STTR Award

The overall goal of this proposal is to evaluate the novel concept whether using lentiviral-engineered T cells that express high affinity T cell receptor (TCR) capable of recognizing the tyrosinase:368-376 epitope, a melanoma/melanocytes differentiation tumor associated antigen have improved efficacy for melanoma immunotherapy. According to the American Cancer Society melanoma is currently the sixth most common cancer in American men and the seventh most common in American women. In this proposal we will test the fundamental hypothesis that human T cells with redirected specificity for melanoma 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 melanoma, a type of tumor for which the current therapies do not offer satisfactory results. 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, particularly cancer. Lentigen's collaborator Dr. Michael Nishimura has helped pioneer adoptive immunotherapy as a potential therapeutic approach for melanoma. 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 tyrosinase: 368-376 epitope. In Aim 2, together with Dr. Nishimura's team, we will test safety and efficacy of LV-TCR transduced T cells in preventing melanoma tumor growth and treating established tumors in vivo. We will carry out two general types of experiments in order to test the in vivo efficacy and engraftment potential of our lentiviral vectors expressed in engineered human T cells. 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-tumor effects in melanoma patients and to apply this in a future clinical trial for patients with this life threatening malignancy. The ultimate goal of this proposal is the development of a novel and improved immunotherapy therapy for melanoma, a tumor for which the current therapies do not offer satisfactory results. This therapy is based on activation of immune cells that will be manipulated in the laboratory and put back to patient to fight melanoma tumor cells. Because of its great potential to offer 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.

Thesaurus Terms:
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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.

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