Targeting breast cancer via combined natural killer T cell immunotherapy and oncolytic virotherapy

Breast cancer is the most common type of cancer in Canadian women and the second leading cause of cancer deaths. Despite advances in screening and treatments, a significant number of patients experience local recurrence or spread of their cancer to other organs. This highlights the continued need for new therapeutic strategies to combat this disease. One approach is to enhance tumor control by manipulating the function of the immune system in order to recognize and target cancer cells better. Dr. Johnston's laboratory has been examining the anti-tumor properties of a population of white blood cells called natural killer T (NKT) cells. Activation of NKT cells can induce potent anti-tumor responses that control tumor growth and prevent metastasis (the spread of cancer cells). Dr. Johnston's group has found that NKT cell activation following surgical removal of established breast tumors can enhance the control of tumor cell metastasis and increase survival in experimental models. When NKT cell therapy was combined with chemotherapeutic drugs, survival could be increased further. However, these drugs have many unpleasant side effects and could impact long term health. In this project, Dr. Johnston and his team will examine the benefits derived from combining NKT cell therapies with engineered viruses that selectively infect cancer cells and increase recognition of tumor cells by the immune system. Preliminary data show that combined therapy significantly increases survival in a breast cancer model compared to individual treatments. This project will determine that immune mechanisms that underlie this benefit and perform experiments to optimize the response to combined therapy. This work will increase our understanding of the immune system and establish whether combined therapies can work together to target tumor cells more effectively. The findings will help to validate this novel treatment approach, laying the groundwork for the use of these new therapies to target metastatic breast cancer in patients. Aim 1: Immune impact of oncolytic virus and NKT cell activation therapies in breast cancer. We will use transplantable and spontaneous tumor models to examine the impact of combined oncolytic virotherapy and NKT cell immunotherapy on survival, immune cell infiltration, and functional immune responses. We will examine the ability of oncolytic vesiculoviruses (VSV and Maraba) to induce immunogenic cell death, and use NKT cell reconstituted mice to determine the mechanisms by which they contribute to tumor control, alone and in combination with oncolytic viruses.Aim 2: Regulation of immunosuppressive cells by NKT cells.We have shown that activated NKT cells can inhibit the immunosuppressive activity of MDSCs. We will use antibodies and knockout cells to examine the mechanisms (ie. cytokine release, cytotoxic targeting) by which NKT cells inhibit MDSC suppression, and examine whether and how NKT cells can overcome the suppressive effects of Tregs.Aim 3: Impact of engineered VSV/Msaraba constructs expressing CXCL10 or IL-15 in combined therapy.The chemokine CXCL10 and cytokine IL-15 enhance NKT cell recruitment and activity. We will examine the impact of oncolytic viruses engineered to deliver CXCL10 and/or IL-15 on immune cell infiltration, activation, and survival in breast cancer models. NKT cell-deficient mice will be used to determine NKT cell-independent effects of oncolytic virus treatments.