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."