The awarded grant supports patient-oriented research with the ultimate goal of reconstituting a cancer-fighting immune system. The research is conducted in samples obtained from patients with metastatic melanoma, a deadly form of skin cancer, and using preclinical models.
During the third funding period we have introduced modifications to enhance the ability of immune cell long term persistence within a clinical trial where patients with metastatic melanoma receive immune cells that have been re-directed by gene engineering techniques to become cancer-fighter cells. 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. 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.
When using a higher number of the TCR genetically engineered lymphocytes that are not frozen before their infusion to patients we are now detecting a higher ability of these cancer-fighting immune system cells to persist for long periods of time. This may be because the protocol modifications were guided to foster a higher ability to generate immune system cells that have long term memory and ability to self-renew (termed T memory stem cells). The detection of these cells is one of the research projects in this grant, since there is no defined set of markers for them. We have been testing several strategies to detect these cells and these are ongoing studies that will continue to the next funding period.
In addition, we have continued to move forward 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 tested the performance of two candidate gene transfer vectors for optimal function in humanized animal models. The results of these studies have demonstrated that one of the vectors is better suited for continued testing and it is the one that we plan to take into clinical grade production with the pre-IND activities being completed during the next funding period.