Despite considerable recent success in developing personalized and targeted cancer treatments, head and neck tumors have proven stubbornly resistant to treatment. Can the addition of immunotherapy before surgery make a difference? Researchers at Cancer Center Amsterdam report on promising results from a small clinical trial combining immunotherapy with established treatments to improve outcome for patients with head and neck cancer.
For over 40 years, the Department of Otolaryngology and Head and Neck Surgery at Cancer Center Amsterdam has provided patients with head and neck cancer the most up-to-date care in addition to research to find better treatments. Despite significant advances in the treatment of other tumor types, head and neck cancers have remained very resistant to new therapies. Treatment mainly relies on surgery or radiotherapy for early-stage disease, and combinations of surgery and/or radiotherapy with concomitant chemotherapy for patients presenting more advanced tumors. Despite these invasive treatment protocols, only modest gains in life expectancy have been obtained.
In light of the recent successes with immunotherapy in cancer treatment in general, Prof. René Leemans and Associate Prof. Willemien Menke initiated an Investigator Sponsored Trial called ‘the NeoNivo study’ to investigate whether neoadjuvant administration of a new immune checkpoint inhibiting medicine (nivolumab) could induce responses of tumors in the oral cavity.
Center of Expertise for Head and Neck Tumors Amsterdam UMC - Cancer Center Amsterdam
Amsterdam UMC Center of Expertise for Tumors of the Head and Neck, chaired by Prof. René Leemans, head of the Dept. Otolaryngology/head and neck surgery, has been recognized as a leading multidisciplinary tumor working group not only in the Netherlands, but also in Europe and worldwide. The center specializes in the clinical management of tumors arising in the mouth, throat, and larynx. These tumors account for around 5% of the total number of cancer incidences - about 3,000 new patients annually in the Netherlands, of which around 500 visit the expertise center at Amsterdam UMC
The expertise center's strong regional network and partnerships with other hospitals ensure that patients receive the appropriate treatment based on their individual circumstances. The multidisciplinary team includes medical professionals from pathology, radiology, nuclear medicine, medical oncology, and radiotherapy. The center also benefits from strong ties with the Dutch Head and Neck Cancer Patient Association, a patient advocate group.
NeoNivo Trial Methods
In this clinical trial at Cancer Center Amsterdam, 16 patients with primary oral cancers were treated with a single course of neoadjuvant nivolumab to test whether immunotherapy before surgical resection could improve treatment outcome. In collaboration with the Imaging Centre, patients also underwent PET imaging and tissue & liquid biopsies.
PhD students Iris Miedema and Niels Wondergem coordinated the clinical trial and worked out all the scheduling, medical imaging, sample collections, lab work, and data analyses. Iris explains: “This type of therapy before surgery is called ‘neoadjuvant’ treatment and aims to shrink the tumor before surgery.” It is also the origin of the study title NeoNivo: short for Neoadjuvant Nivolumab.
“To investigate if nivolumab would have an effect, all participants first got tattooed inside their mouth to indicate the boundaries of tumors before treatment,” says Niels. “Marking the tumor outline was also important in guiding the surgeon to make sure all of the original tumor area was removed.”
NeoNivo shines
In this patient group, tumors are notoriously unresponsive to therapies. That makes the outcome of the NeoNivo trial quite spectacular: 6 out of 16 patients showed a response to nivolumab, with 3 patients achieving a near complete response.
After surgery, histopathology data from three patients indicated a near complete response to nivolumab. We were thrilled with this spectacular result.” Dr. Willemien Menke, Associate Professor.
New insights, new questions
“This is a spectacular step forward in the treatment of primary oral cancer,” says Professor Ruud Brakenhoff, head of the Head and Neck Cancer Biology & Immunology Research Group. “But it also raises questions. Why didn’t nivolumab work for all treated patients?”
The researchers are looking for answers in the patient data and samples that were collected during the trial. Using medical imaging to scan for potential diagnostic clues, they examined the distribution of the immune-suppressing PD-1 ligand in the patient’s tumors. In addition, comprehensive genome (DNA) and transcriptome (RNA) data were obtained to investigate if the different tumor responses could be correlated with molecular profiles.
“It is unique that patient samples are available before and after nivolumab treatment. Professor Tanja de Gruijl and Assistant Professor Rieneke van de Ven aim to fully utilize this tissue collection for immunological studies to find biomarkers of response, and potential leads to further improve immunotherapy.”
The long road ahead
Before nivolumab can become a first line treatment for this patient group, a long road lies ahead. Follow up and more clinical research with larger patient numbers is needed. In addition, many regulatory and financial hurdles remain to be cleared before checkpoint blockers become available to more patients with early head and neck cancer.
Professor René Leemans: “Compared to more frequent types of cancer - like breast, lung, melanoma or prostate tumors - head and neck cancers are found in only a minority of patients with cancer. This makes it more difficult to attract funding or support from the pharmaceutical industry for larger clinical studies to move this research forward. Obviously, we are very eager to continue with this immunotherapy and want to see if we can achieve even better response rates by combining PD-1 blockers with other immune-active drugs.
We can now look down the long road ahead and see a glimmer of hope that one day we may have effective head and neck cancer treatments without the invasive treatments of today.” Professor René Leemans, principal investigator and head of the Department of Otolaryngology and Head and Neck Surgery at Cancer Center Amsterdam.
For more information, contact Prof. René Leemans or Associate Prof. Willemien Menke.
Funding: The NeoNivo trial was sponsored by Bristol Myers Squibb.
This article was previously published in the Annual Review 2022 of Cancer Center Amsterdam.
Text by New Haven Biosciences Consulting – All rights reserved © 2023.