Antibody therapy of cancer: Novel therapeutic strategies for prevention and treatment of metastases

Cancer is one of the main global health problems. Most cancer patients die from metastases rather than from the primary tumor. Therefore, it is of utmost importance to develop novel treatment options to prevent and treat metastases. A promising treatment option for cancer is immunotherapy. Immunotherapy aims to stimulate the patient’s own immune system to destroy the tumors. There are several types of immunotherapy, including antibody therapy. Antibodies have both direct effects and indirect effects. Antibodies bind tumor cells to reduce their growth (direct effect). Simultaneously, antibodies can bind immune cells, including macrophages, natural killer (NK) cells and neutrophils, creating a bridge between these cells and tumor cells. In this way, the immune cells are stimulated to eliminate the tumor cells (indirect effect). In my thesis I investigated multiple strategies to enhance the efficacy of antibody therapy. In Part I of my thesis I focused on the prevention of metastases. In Chapter 2 we discuss the process through which tumor cells detach from the primary tumor in the intestine and grow out as metastasis in the liver. As tumor cells detach from the tumor and enter the blood circulation, they are referred to as circulating tumor cells. It has been described that surgical removal of tumors in the intestine results in an increased number of circulating tumor cells. This increases the chance to develop metastases. Therefore, elimination of circulating tumor cells represents a promising treatment option to prevent development of metastases. In Chapter 3 we investigated if, for this purpose, we could use antibodies against the molecule EGFR that is highly expressed on tumor cells compared to healthy cells. We demonstrated that treatment with anti-EGFR antibodies stimulates macrophages to eat tumor cells. Therefore, we advise to treat patients with anti-EGFR antibodies prior to surgical removal of tumors in the intestine. In this way, macrophages can eat circulating tumor cells, potentially limiting development of metastases. In Chapter 4 we describe a novel method to detect circulating tumor cells in blood of cancer patients. Unfortunately, many cancer patients already present with metastases at the time of diagnosis, or develop resistance against current treatment options. Therefore, I investigated novel treatment options based on antibody therapy in Part II of my thesis. In Chapter 5, we combined antibody therapy with another type of immunotherapy: TLR stimulation. TLR are molecules expressed on immune cells that can strongly activate these cells. We demonstrated that the combination treatment enhanced the capacity of NK cells to kill tumor cells. Additionally, NK cells released certain factors that stimulate other components of the immune system, improving tumor destruction. Treatment of mice with the combination treatment resulted in reduced tumor growth and prolonged survival. In Chapter 6 we discuss the role of neutrophils in cancer, as well as potential therapeutic strategies to stimulate tumor cell killing by neutrophils. In Chapter 7 we developed a novel antibody, referred to as TrisomAb. TrisomAb simultaneously stimulates macrophages, NK cells and neutrophils, enhancing tumor cell killing. Treatment of mice with TrisomAb resulted in reduced tumor growth and prolonged survival. In Chapter 8 we investigated if TrisomAb is able to stimulate other components of the immune system. We demonstrated that treatment with TrisomAb resulted in release of certain factors that cause recruitment of other immune cells, in particular neutrophils, to the tumor. In this way, the reaction of the immune system to the tumor is strengthened, enhancing destruction of tumors.