T cell therapy: a personal approach


Internist-oncologist John Haanen, researcher Wouter Scheper and pharmacist Joost van den Berg of the Netherlands Cancer Institute are going to set up a new T cell therapy in which T cells from the patient are given a helping hand in recognizing the tumor.

Every tumor is unique. Tumor cells have unique DNA mutations that make them express different proteins on the outside than normal cells. T cells - white blood cells from the immune system - can specifically recognize these tumor proteins and then get rid of the tumor cells. But in reality, it appears that in some tumors more than 90% of the T cells present within the tumor environment do not recognize the tumor, which also means they won't get rid of it. This is one of the main obstacles in the development of immunotherapy.


Internist-oncologist John Haanen, researcher Wouter Scheper and pharmacist Joost van den Berg of the Netherlands Cancer Institute are setting up a new T cell therapy in which the patient's own T cells are given a helping hand in recognizing the tumor. For this, they have received a 1.5 million euro subsidy from ZonMw as part of the " Translational research 2" program. In this exploratory clinical study, 5 patients with metastatic melanoma each receive a customized set of T cells that specifically recognize their tumor. They do this by tracing the unique tumor proteins for each patient and then finding the matching T cell receptor - important for tumor recognition - and transferring it to 'fresh' T cells from the patient's blood, using the genetic CRISPR/Cas9 technology. These modified T cells are then returned to the patient intravenously, after which the cells can detect the tumor and eliminate it. This study investigates whether and how well this new T cell therapy works for this group of patients and whether this treatment is safe.  


Immunotherapies for skin cancer patients

Every year there are approximately 800-900 new cases of patients with metastatic melanoma in the Netherlands. Immunotherapy with checkpoint inhibitors has revolutionized the treatment of this group in recent years: about half of the patients respond well to this.  But this also means that the treatment does not work for the other half of the patients.


TIL therapy

An alternative treatment - now only in the context of research - is the so-called "Tumor Infiltrating Lymphocytes" (TIL) therapy. In this treatment, the T cells are removed from the tumor and brought to the lab, where they are grown into billions of T cells. They are then returned to the patient via an infusion. John Haanen: "In this study, we see in 10-20% of patients that the tumor disappears completely and stays away for a long time."

Whether or not immunotherapy with TIL works depends on the number of T cells that can recognize the tumor. Joost van den Berg: "You really only want to return the T cells that you know are certain to recognize the tumor. In addition, it is important that those T cells that recognize the tumor are also fit enough to perform their most important task, getting rid of the tumor."

That is why the Netherlands Cancer Institute started a new T cell study a few years ago. In this treatment, "fresh" T cells from the blood of the patient are provided with a T cell receptor that recognizes the "MART-1" protein present on melanoma cells. Just like in the TIL study, patients get their own T cells back, but in an adapted form. These cells can attack the tumor, but there is also a chance of side effects because the T cells can also attack a number of healthy tissues that express this protein. It is, therefore, not yet the perfect solution.


T-cell therapy 2.0: a personal approach

Wouter Scheper and others in the research group of immunologist Ton Schumacher have therefore searched for proteins that can only be seen on tumor cells and not on healthy cells. Wouter Scheper: "These so-called neo-antigens arise as a result of DNA mutations in the tumor. We have set up a method to identify these neo-antigens on a large scale and to find the associated T-cell receptors. In cooperation with experts in the CRISPR/Cas9 technology in Germany, we can place the selected receptors in fresh T cells from the blood of the patient relatively quickly and let them grow in our pharmacy to the correct numbers and return them to the patient. Because every tumor is different, each patient needs a different set of T cells to get rid of the tumor."


From research to clinic

John Haanen: "Through our  joint experience in the pharmacy with the production of a T cell medicine, and in the clinic with giving immunotherapy, we can apply the latest knowledge from the lab directly in the clinic."

"The grant from ZonMw allows us to test our new form of treatment in practice. We start with a small group of patients and hope to expand this to larger groups if the result is positive. The great thing about this approach is that it can be applied to various types of cancer and can be a solution for patients with tumors that respond poorly to existing immunotherapies, such as patients with breast, colon, pancreas and ovarian cancer."

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