Victor Peperzak and his team (Center for Translational Immunology, UMC Utrecht) have received a grant of € 581.000 from KWF (2020 call) to further develop new immune therapies based on engineered immune cells for the treatment of both solid tumors and blood cancers.
Tumor cell killing by T cells is nature’s answer to prevent development of cancer. In fact, mice that lack the pore-forming protein perforin, used by T cells to allow entry of granzyme B into tumor cells, were shown to be more than 1,000-fold more susceptible to lymphoma development compared with immunocompetent mice, in which tumor rejection was controlled by CD8+ T cells. Unfortunately, the fact that tumors do develop is a sign that in some cases this T cell-mediated tumor immunosurveillance is not effective enough.
Currently, different strategies are being deployed using gene engineered T or NK cells to eradicate cancer. These strategies include chimeric antigen receptor (CAR) T or NK cells, αβ T cell receptor (TCR)-modified T cells and T cells engineered to express a defined γδ TCR (TEGs). All these gene-modified cells use granzyme B to kill tumor cells. Although these approaches are promising and tumor cell killing can be observed, relapse after therapy remains a problem. To improve gene-engineered T cells, multiple strategies have been considered. However, no one attempted to directly improve their killing capacity. This is especially remarkable given the fact that T cell-mediated killing is often hampered by tumor cell-specific overexpression of natural granzyme B-inhibitors, including serpin B9 (PI-9). In fact, serpin B9 was recently identified as the main resistance regulator for cancer treatment by immune checkpoint blockade. So far, gene engineered T cells were shown to be successful in the treatment of hematologic malignancies, but much less so in solid tumors. High expression of serpin B9 has been observed in melanoma, liver cancer, breast cancer, colorectal cancer, lung cancer and prostate cancer, which may contribute to resistance against gene engineered T of NK cells.
For this project we developed a technology to boost tumor cell killing of engineered T or NK cells, thereby bypassing the action of granzyme B-inhibitors. In order to do so, we introduce a lentiviral vector containing a modified version of a known pro-apoptotic protein that will be targeted directly to cytotoxic granules of these engineered cells. After tumor cell recognition perforin, granzyme B and the introduced pro-apoptotic protein will be secreted into the synapse between the T cell and tumor cell. Due to the directed secretion into the closed environment of the synapse, toxicity to neighboring cells will be minimal. The modified pro-apoptotic protein will enter tumor cells through perforin pores and induce apoptosis of the tumor cell. The effectiveness of our approach will be tested in in vitro culture experiments, as well as in mouse models. In summary, by using our optimized killing technology we aim to overcome tumor resistance to T and NK cell-induced elimination and improve treatment of cancer.
Principal investigator Victor Peperzak explains: “Immune therapy using modified immune cells is promising. Unfortunately, metastases after treatment remain a recurring problem. By making better use of the toxicity of these immune cells, we want to enhance their capacity to prevent cancer recurrence. With this research we build on our earlier research. If our strategy proves to work, it will increase the effectiveness of immunotherapy and the chance of recovery.”
