Advanced immune monitoring and TCR cloning in clinical trials of T cell receptor (TCR) engineered adoptive cell transfer therapy

This proposal is aimed at merging two forms of cancer immunotherapy strategies that can synergize to treat metastatic melanoma. It will be carried out by a Team Science that has been working together since 2006 with the overall goal of genetically programming the human immune system to fight melanoma. Our research group merges broad expertise in molecular biology, immunotherapy, vectorology, molecular imaging and translational cancer research to advance the science with patient-focused goals. We have jointly generated and published scientific data, raised funds and gone through the regulatory procedures to open an investigator-initiated clinical trial that involves the genetic modification of white blood cells (called lymphocytes) to create large armies of melanoma killer cells for the treatment of patients with metastatic melanoma. The generation of clinical grade and highly specific melanoma killer cells involves the genetic modification of patient-derived white blood cells to provide them with the fine recognition machinery for melanoma cells. These cells are produced in a facility at UCLA that meets the standards of the US Food and Drug Administration (FDA) for the manufacture of products for human use. The gene modified melanoma killer cells are injected back to patients through a vein. These cells then expand and kill melanoma as evidenced by tumor responses in 7 out of the first 8 patients treated. However, this impressive antitumor activity is hampered by the development of resistance. In parallel, our Team Science group has been working in the clinical development of anti-CTLA4 antibodies for melanoma therapy. This is an approach that releases a major break for the immune system, resulting gin the unleashing of a cancer-fighting immune system. The clinical experience to date demonstrates that a small subset of patients (approximately 10%) have responses to this therapy that are mediated by tumor infiltration by melanoma killer cells. It is remarkable