Give way to the immune system: immunotherapy prior to surgery instead of after

In In The News by Barbara Jacoby

Source: Netherlands Cancer Institute

Physicians can possibly use immunotherapy in cancer patients more effectively. More and more voices are in favor of giving this new treatment before the surgeon removes a tumor instead of afterwards. This could have huge benefits, like a better immune response against the tumor. On 22 October,  researcher Christian Blank and his colleagues at the Netherlands Cancer Institute presented the results of a new study among melanoma patients at the ESMO conference.

With cancer immunotherapy oncologists have added a powerful new weapon to their arsenal of therapeutic strategies. Cancer immunotherapies aim to unleash the patient’s immune system against the tumor cells. This strategy works particularly well in some patients, but unfortunately not yet for a larger group. Predicting who will respond to which immunotherapy is a puzzle many people are trying to solve.

Oncologist and researcher Christian Blank and immunologist Ton Schumacher of the Netherlands Cancer Institute focus on a new approach: immunotherapy prior to surgery instead of after, as is currently the case. Such a neoadjuvant treatment could potentially have many advantages. “You can determine whether a patient responds to a certain drug, because you can see in the tumor material that is obtained during surgery whether the cancer cells are still alive or not”, says Blank. “Also, the immune response induced by the immunotherapy is expected to be broader and therefore better. If the tumor is still present in the body, the immune system can learn to recognize the entire tumor with all its variations and thereby build up a more extensive immunological memory. Finally, the tumor may also be smaller and easier to remove after immunotherapy.”

On 8 October 2018, the research teams of Christian Blank and Ton Schumacher of the Netherlands Cancer Institute published the OpACIN study (phase 1) among 20 high-risk stage III melanoma patients with palpable lymph node metastases in Nature Medicine. Patients at this stage of the disease face a poor prognosis: more than half of them die within 5 years after removal of all lymph node metastases because they often already have small invisible metastases elsewhere in the body. The OpACIN study shows that it is feasible to treat melanoma patients with immunotherapy before surgery, in this case a combination of two drugs called ipilimumab and nivolumab.

One of the reasons why melanoma patients had thus far only received immunotherapy after surgery was the fear of not being able to perform the planned surgery, because of side effects or worsening of the disease. However, all patients in the OpACIN study who had first been treated with immunotherapy could undergo the planned surgery. The researchers also showed that immunotherapy before surgery induced a more profound immune response. Moreover, after 2 years of follow-up, none of the patients who dad eben responding to the neo-adjuvant therapy experienced recurrence of the disease. However, the side effects of the combination therapy were such that only 2 patients could complete the immunotherapy.

For this reason, the team at The Netherlands Cancer Institute together with colleagues in Sydney (Georgina Long) and Stockholm (Johan Hansson) designed a subsequent study that aimed to preserve the anti-cancer effects of the neoadjuvant immunotherapy, while reducing its side effects. Today Christian Blank presents the results of this OpACIN-neo study (phase 2) which included 86 melanoma patients with palpable lymph node metastases, at the European ESMO conference in Munich.

The treatment schedule that came out best clearly has less side effects compared to the schedule used in the OpACIN study. Tumor reduction was seen in 23 out of 30 patients in this group (77%), and in 17 of them all cancer cells in the tumor were destroyed (57%). After a follow-up of on average 8 months none of the patients who responded to either one of the three tested treatment schedules have relapsed (0 of 65). In 9 out of the 21 non-responders the disease did recur. Blank: “This study confirms that neoadjuvant therapy is effective for many people, and we now also have a schedule with acceptable side effects.”

A recently started extension study called PRADO (phase 2) has been set up to confirm the efficacy of the optimal treatment schedule of the OpACIN-neo study in 100 additional melanoma patients with palpable lymph node metastases.

Blank: “The elegant aspect of the neoadjuvant treatment is that none of the patients who responded well have relapsed to date. So in the future you may be able to inform patients about their prospects after only 6 weeks of treatment. Our studies also indicate that we might be able predict whether a patient will respond to this drug combination based on a small number of biomarkers. We’ll have to investigate this in a larger group though.”

Together with two other large melanoma centers in Australia and the US, Blank has now set up an international consortium to streamline the clinical development of neoadjuvant cancer immunotherapy. “If all future studies share the same study design and analysis of biomarkers, identification of biomarkers that predict which combination treatment a patient is likely to respond to will become much more efficient. And in that way personalized cancer immunotherapy may soon be within reach.”

About immunotherapy

Immunotherapy is already standard of care for patients with a number of cancer types and clinical trials are ongoing for many others, in particular for patients in a late stage of the disease. A widely used form of immunotherapy is treatment with checkpoint inhibitors (see video), which were also tested in the OpACIN studies. Checkpoint inhibitors prevent cancer cells from deactivating immune cells, thereby allowing these immune cells to attack and kill the cancer cells. Physicians at the Netherlands Cancer Institute have also started studies that evaluate neoadjuvant immunotherapy for patients with colon, breast, stomach, bladder, lung, renal cell, and head and neck cancer.

PRADO study

Treatment:  Immunotherapy prior to surgery (neoadjuvant)

For whom:  Melanoma patients with palpable lymph node metastases (stage III)

When:   This phase 2 study opened in October 2018

About the Netherlands Cancer Institute
The Netherlands Cancer Institute has been at the international forefront of cancer care and research for more than a century. The unique combination of health care and scientific research within the same institute offers great benefit for cancer patients. The research institute employs more than 650 scientists investigating many aspects of cancer development, diagnosis, treatment and epidemiology. The Netherlands Cancer Institute is the only OECI designated Comprehensive Cancer Center in the Netherlands. For more information please visit our websites and