NCE (Year 4)
Gene therapy can be used to alter the genome of cancer cells and induce them to make anti-tumor proteins. We have developed a highly efficient gene delivery vehicle (known as a “vector”) derived from a modified virus, which efficiently spreads though brain tumors and infects and permanently alters the genome of cancer cells, but does not infect normal brain cells. This modified virus, called a “replication-competent retrovirus (RCR) vector”, is currently being evaluated in clinical trials on-going at multiple sites throughout California to treat patients with malignant brain tumors, with highly encouraging results. However, to administer the therapeutic virus into brain tumors, the virus is injected directly into the center of the tumor, or around the margins of the cavity after surgical removal of most of the tumor. Yet, human brain tumors often diffusely spread into the surrounding normal brain tissue, and may be difficult to eliminate with a locally-injected RCR vector by itself. Therefore, in this project, we evaluated the use of a type of adult stem cell, called a “mesenchymal stem cell”, as a delivery system for RCR vectors. Human mesenchymal stem cells (hMSCs) have been shown to have natural tumor-homing abilities, and can migrate to tumor foci and penetrate throughout the interior of tumor masses.
Through this project, we have established and optimized manufacturing methods to engineer hMSCs into “aircraft carriers” that release our tumor-selective RCR vectors, which we then confirmed can efficiently spread both a non-therapeutic “reporter gene”, as well as a therapeutic “suicide gene” to brain tumors. We have further confirmed that the use of hMSCs as a carrier system for delivery of RCR vectors results in more rapid spread of the vectors through the tumor mass, as compared to injecting the virus by itself, in human brain tumor models implanted both under the skin as well as in the brain. We have also confirmed that, when this hMSC -based RCR vector delivery system is employed to deliver an anti-tumor ‘suicide’ gene, the faster spread of the virus delivered by the stem cell carrier translates into more rapid shrinkage of tumors implanted under the skin, and prolongs survival in intracranial brain tumor models. In the final project period, we have also obtained results demonstrating that hMSC delivery of RCR vectors injected into intracranial brain tumors does not result in unwanted spread of virus to normal tissues outside the brain. We have initiated discussions with the UC Davis Stem Cell Institute to develop clinical grade manufacturing processes for hMSC-based RCR vector producer cells, and with a San Diego-based biotech partner, Tocagen Inc., toward the initiation of a clinical trial to test this strategy in brain tumor patients in the near future.