Year 2

The awarded grant supports a patient-oriented research project to genetically engineer the human immune system to become cancer-targeted and provide benefit to patients with metastatic melanoma, a deadly form of skin cancer currently devoid of successful treatment options.

During the second funding period we continued to conduct a clinical trial where patients with metastatic melanoma receive immune cells that have been re-directed by gene engineering techniques to become melanoma-specific. The immune cells are obtained from the patient’s own blood and they are manipulated in an in-house clinical grade facility for one week to insert into the cells two genes (T cell receptor or TCR genes) that turn them specific melanoma killer cells, called the. The genetic reprogramming of the immune system cells to express TCR genes is done using a crippled virus called a gene transfer vector. These cells undergo extensive testing to meet the standards of the Food and Drug Administration (FDA) before they can be given back to patients.

Ten patients have been enrolled onto this study at this time. In nine of them there has been evidence of tumor shrinkage, demonstrating the strong therapeutic activity of TCR redirected lymphocytes. However, these have been transient beneficial effects. Our ongoing studies point to a loss of function of the TCR transgenic cells over time. Therefore, it is of key importance to develop means to optimize the presence of long lasting memory cells. As proposed in the initial grant we are conducting studies to characterize the presence of T memory stem cells, which are cells able to self-replicate and maintain a cancer-fighting immune system for long periods of time. These are ongoing studies that will continue to the next funding period.

In addition, we have put a lot of work to set up a follow up clinical trial where we will genetically modify patient’s blood stem cells, which we hypothesize will allow the continuous generation of TCR re-directed immune cells starting from the stem cells. This would provide means for immune system regeneration that would have applications to other cancers and non-cancer diseases like infectious diseases and autoimmune diseases. To this end, we have generated new gene transfer vectors that are being studied for optimal function in relevant animal models to then allow an informed decision on the vector to take for clinical grade production and use it in the proposed next generation clinical trial.