Antibody therapy of cancer
Authors:   , Gruijs Mandy 
Published: August 2023

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.