Cervical cancer is caused by infection with high-risk types of Human Papillomavirus (HPV). In the Netherlands, the highest number of new cases of cervical cancer occurs in women between the ages of 35 and 45 years. New treatment strategies are needed to improve the prognosis in these relatively young patients.
Immunotherapy
Dr. Stijn Mom, a gynecological oncologist at Cancer Center Amsterdam and the research institute Amsterdam Reproduction & Development, plans to investigate if a combination of immunotherapy drugs administered locally can improve the response of the immune system against cervical cancer cells. Immunotherapy aims to stimulate and enlist the body’s own immune system to actively fight cancer cells, a defense that is often short-circuited by tumor trickery.
One-way tumors suppress the natural immune system is by increased production of “immune checkpoint” proteins. One of these proteins called “Programmed cell death ligand 1” (PD-L1) binds to and delivers a “stand down” message to cytotoxic T-cells, a type of immune cell that could otherwise have recognized and killed cancer cells. From earlier research with an antibody against this checkpoint protein, Dr. Mom knew that local administration by injection around the tumor had advantages. “By administering the drug locally, we were able to give a lower dose, with fewer serious side effects, and it ended up exactly where it should do its job, namely in the lymph nodes,” explains Dr. Mom.
“Unfortunately, on closer examination of the lymph nodes and blood, we found that the immune-stimulating effect of the drug was canceled out by increased presence of regulatory T-cells. These cells suppress the immune response,” says Dr. Mom.
New strategy
Together with her research team, which includes co-investigators Prof. Tanja de Gruijl and Dr. Katja Jordanova, a new strategy was formulated. “In this project, we will combine two antibodies: one that targets PD-1 and one that targets CTLA-4.” CTLA-4 is another immune checkpoint that is highly expressed on tumor-induced regulatory T cells. Binding of an antagonistic antibody to CTLA-4 can shift the balance between regulatory T cells and anti-tumor killer T cells in favor of the latter.
These combined anti-PD-1 and anti-CTLA-4 antibodies have been studied before in relapsed and metastatic cervical cancer patients, and it was found that the combination had a better anti-tumor effect than anti-PD-1 alone. However, the medication, administered intravenously, had serious immune-related side effects.
Dr. Mom: “In our study, therefore, we want to administer a PD-1 inhibitor, and a CTLA-4 inhibitor, locally, so that we can avoid unwanted side effects. By local application, the antibodies will be delivered exactly where they need to work, namely in the lymph nodes, so that they can activate cytotoxic T-cells and thus protect against metastases.”
Research design
In this open-label, non-randomized phase I study, patients with early-stage cervical cancer will receive a varying dosage of PD-1 and CTLA-4 targeting antibodies injected around the tumor, two weeks prior to radical hysterectomy and pelvic lymphadenectomy. Tumor, lymph nodes, and blood samples will be collected for immune profile analysis.
“The primary research question is how safe a single low-dose peritumoral injection of these combined immune checkpoint inhibitors is in patients with early-stage cervical cancer,” says Dr. Mom. “We also want to know the immunological effects of this local administration on the primary tumor and draining lymph nodes, in addition to the systemic anti-tumor immune response.”
With the knowledge gained from this study, Dr. Mom and her team aim to find an improved treatment with fewer side effects that will allow a better prognosis and quality of life for cervical cancer patients.
Dr. Stijn Mom.
For more information contact Dr. Stijn Mom.
Researchers involved at Cancer Center Amsterdam:
Dr. Stijn Mom
Prof. Tanja de Gruijl
Dr. Katja Jordanova
Dr. Jacqueline Tromp
Text by Laura Roy.