Year 2

A current immunotherapy strategy in the treatment of cancer, called adoptive cell therapy, is to use an individual’s own immune cells (T cells) and genetically modify them to attempt to kill the cancer. The patient’s white blood cells are modified in the laboratory using genetic techniques to express a specific receptor against cancer cells. Gene modification of cells involves the transfer of foreign genetic material (DNA) into a cell, in this case the immune system cells. This process will endow the recipient immune cells with the ability to eliminate cancer cells that express the cancer specific protein, NY-ESO-1. The specific receptor against cancer cells that will be transferred to the immune cells is called NY-ESO-1 T cell receptor (or TCR).

Our emerging clinical data demonstrates that these gene-modified T cells are very active in killing tumor cells initially, but they lose their ability to function within a few weeks. This experience points to the need to have a continuous source of gene-modified cells to maintain the ability to kill cancer cells long term. In this study, we hypothesize that the administration of gene-modified stem cells will allow a sustained production of active T cells with antitumor activity. Since there is a delay before the T cells that develop from stem cells emerge from the bone marrow into the blood, we will give patients both gene-modified T cells for a first wave of antitumor activity and gene-modified stem cells which will provide a bridge of therapy until the stem cells have produced more T cells. The purpose of the current study is to give gene-modified T cells in combination with gene-modified stem cells to reprogram the immune system to recognize and kill cancer cells that have the NY-ESO-1 protein with sustained killing activity. This will be the first time that gene-modified immune cells will be given in combination with gene-modified stem cells.

We have manufactured a batch of the lentiviral vector necessary to transfer the NY-ESO-1 TCR into stem cells and have demonstrated that this vector can effectively gene-modify human stem cells. Preclinical safety studies are currently ongoing. To date, we have demonstrated that when mouse stem cells are gene-modified with this lentiviral vector, the stem cells take up residence in the bone marrow and produce appropriate blood cells. There is no detrimental effect of the genes used to modify the cells on the blood cells that are derived from the stem cells. Cell assays have also been performed to assess whether the lentiviral vector could potentially cause cancer. The data indicate that the lentiviral vector has no cancerous potential. A preclinical study is also ongoing in mice to assess the safety of combining the gene-modified T cells and stem cells in mice. In addition, because stem cells have the potential to multiply indefinitely, the vector includes a suicide gene which we have shown can be used to kill cells if necessary. A preclinical study was performed to demonstrate that the stem cells can be eliminated in vivo using the drug ganciclovir.

Preparations are ongoing towards opening a clinical trial. The clinical grade lentiviral vector has been generated and is currently being evaluated to determine whether it is acceptable for use in patients. The cell manufacturing process is being optimized to determine optimal delivery of the gene-modified T cells and stem cells. The clinical documents have been submitted to internal regulatory committees for review, and documents are being prepared for submission to the Food and Drug Administration as part of an Investigational New Drug (IND) Application.