Immunotherapy of Cancer using Engineered Hematopoietic Cells
Yan Cui PhD, Associate Professor
The major focus and long-term goal of our research is to develop innovative approaches for cancer treatment through active immunotherapy. This relies on enhancing and sustaining the activity of tumor-recognizing immune effector cells. The lack of such cells underlies the failure of current immunotherapy regimens.
Enhancing tumor antigen-specific immune activation with engineered hematopoietic stem cells
Dendritic cells (DCs) are the most potent immune regulators in mediating antigen specific T lymphocyte activation and have been widely used in cancer immunotherapy. To further enhance their ability in augmenting anti-tumor immunity, we recently developed a novel stem cell-based strategy with engineered blood stem cells modified to carry a tumor antigen gene. This is based on the superior ability of activated tumor antigen-presenting dendritic cells (DC) from engineered stem cells to sustain immune activation. Using this approach, we have demonstrated significant improvement in the survival of mice bearing established hematological malignancies, as well as pulmonary metastases of renal cell carcinoma. This is mediated by augmented activation of effector T cells and enhanced recruitment of these functional effectors to tumor sites (see Figure).
Prolonged anti-tumor immunity through engineering antigen-specific effector cells
It has recently been demonstrated that the interleukin (IL)-7 signaling pathway is critical for immune T and B cell development, as well as the survival and proliferation of memory T cells. More importantly, long-term naïve and memory T cells all express high levels of IL-7 receptor. However, upon activation, IL-7 receptor numbers on the T cell surface are greatly down-regulated, which might contribute to the observed activation-induced T cell death that results in the loss of over 90% activated effector T cells. We hypothesize, therefore, that engineering of effector T cells to provide constitutive expression of IL-7 receptors on their surface may prevent activation-induced cell death and thus prolong cell survival and activity, thereby augmenting anti-tumor immunity. We are currently evaluating whether this approach will further enhance therapeutic efficacy for tumor treatment in combination with our engineered hematopoietic stem cell strategy.