The overall goal of this proposal is to evaluate the novel concept whether using lentiviral-engineered T cells that express chimeric receptors and signaling modules will improve efficacy for cancer immunotherapy directed against mesothelin. Mesothelin is a tumor associated antigen and a promising target in mesothelioma, ovarian, squamous cell cancers of head and neck, cervical, esophageal, pancreatic and many non-small cell lung cancers (NSCLC). In this proposal, we will test the fundamental hypothesis that human T cells with redirected specificity for carcinomas that express mesothelin can be created and can offer a clinically relevant and successful therapeutic approach. The ultimate goal is the development of a novel and improved therapy in those tumors for which the current therapies do not offer satisfactory results. Lentiviral vectors (LVs) have been successfully evaluated in Phase I clinical trials in patients with HIV/AIDS, offering the possibility to apply this technology for the treatment of cancer. Lentigen's collaborator Dr. Carl June has helped pioneer adoptive immunotherapy as a potential therapeutic approach for hematologic malignancies. He has recently found that optimal growth of human CD8 cells required signals from CD137 (4-1BB). Therefore, in Aim 1 of this proposal, we will develop self inactivating (SIN) LVs expressing the chimeric anti-mesothelin single chain antibody, linked to the intracellular domain of the T cell receptor (TCR) zeta chain in tandem with 4-1BB (CD137) or CD28 intracellular co-stimulatory domains using a CD8 alpha hinge and trans-membrane domain.
In Aim 2, we will test the anti-mesothelin LV vectors in T cells for safety and functionality.
In Aim 3 in collaboration with Drs. June and Grupp, we will determine whether vector constructs are optimal to kill tumorigenic cells in vivo and to enable efficient engraftment and proliferation. In summary, Lentigen Corp., and Dr. June's laboratory are uniquely positioned to provide the first comprehensive evaluation of the redirected T cell approach to generate anti-tumor effects in cancer patients and to apply this in a future clinical trial for patients with common and life threatening malignancies. Project Narrative: The ultimate goal of this proposal is the development of a novel and improved therapy for those tumors 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 the patient to fight cancer cells. Because of its great potential to offer a solution for those patients failing other therapies, this therapy will have a significant relevance for cancer patients and health care providers in the United States and worldwide. ? ? ?
