Grant: Project Grant

Ordinarily, a cancer patient's immune system can recognize cancer cells as being altered, and mount a natural immune response. The immune cells that directly attack the cancer are called T lymphocytes, a type of white blood cell, but sometimes they are ineffective - they may fail to recognize tumour cells, fail to activate, or fail to be maintained long enough to have an impact. Recent clinical research has shown that it is possible for these limitations to be overcome by isolating a sample of a patient's T lymphocytes from their blood, genetically modifying and activating the cells in the lab, and then re-administering them to the same patient. The genetic modification step involves introducing into the T cells an extra gene for a new cell surface molecule called a "Chimeric Antigen Receptor" or "CAR" that confers precise and powerful recognition and killing of tumor cells. These therapies are called CAR-T therapies and currently they are very personalized (they require genetically engineering the patient's own cells) and there is considerable laboratory and hospital infrastructure and expertise required to manufacture and deliver treatment. This adds logistical complexity and cost to an already overburdened health care system. We will test (in mice) the feasibility of a radically different approach that would allow CAR-T therapy to be administered in the same manner as a vaccine. Specifically, the approach involves injecting a gene transfer vector (a type of genetically modified, non-infectious virus) into the bloodstream to deliver the CAR gene to directly to T cells, rather than first extracting T cells, processing them outside of the body in the lab, and re-administering them. Additional testing, genetic engineering and virus development is required to evaluate this direct method, and this work is the basis of the current proposal.