Ravi Uppaluri

While any form of cancer can profoundly impact a person’s life, head and neck cancers can be particularly pernicious. Because of their location, head and neck cancers and their treatment can affect a person’s ability to speak, breathe, and eat, making daily activities particularly challenging. Given the interconnected effects of cancer and treatment, Ravi Uppaluri, MD, chief of the Division of Otolaryngology in the Department of Surgery at the Brigham and chief of Head and Neck Surgical Oncology at Dana-Farber Brigham Cancer Center, and his colleagues take a multi-disciplinary approach to helping patients.

“We want patients to have a one-stop shop, team-based approach, where they can come in and see specialists from multiple disciplines on the same day and where we can have a discussion as a team, so that the patient immediately knows the plan for their care,” said Uppaluri.

Uppaluri highlighted the dramatic changes over the last two to three decades in the understanding and treatment of head and neck cancers.

“Since I first entered the field 25 years ago, the change has been dramatic,” said Uppaluri. “A deeper understanding of the difference between HPV-associated and non-associated cancers and innovations in minimally invasive and reconstruction have been practice changing. And we are committed to continue to develop novel ways to help patients who don’t respond to existing therapies. Dana-Farber Brigham has a rich history of moving the needle in terms of patient care and are actively working to improve the future treatment of patients.”

HPV Points to New Opportunities to De-Intensify Treatment

In recent years, mounting evidence has indicated that human papillomavirus (HPV) infection may not only be a risk factor for head and neck cancer but also a predictor of a patient’s response to treatment.

“Patients with HPV-associated head and neck cancer have better outcomes than HPV-negative disease and we and others are considering ways to safely de-intensify treatment,” said Uppaluri. Dana-Farber Brigham surgeons, including Donald Annino, MD, DMD, Rosh Sethi, MD, and Eleni Rettig, MD use minimally invasive robotic surgery to remove the tumor, and Dana-Farber Brigham has the only ongoing clinical trial in New England to evaluate strategies that de-intensify treatment after surgery. Patients with HPV-associated head and neck cancers who enroll undergo surgery, and depending on the patient’s pathology, are offered radiation therapy at a lower dose without any chemotherapy.

“This represents a huge change from what we’ve done in the past, where patients would get surgery, chemotherapy and full course radiation,” said Uppaluri. “We’re now studying ways to safely avoid intensive tri-modality therapy for patients with HPV-associated cancer.”

Investigators including Rettig from Otolaryngology and Glenn Hanna, MD, from Medical Oncology are also studying biomarkers of HPV, which could allow them to monitor blood samples from patients to detect tumor recurrences. They are also looking to monitor blood-based biomarkers in the context of clinical trials to help monitor patients’ responses to treatment and tailor treatment plans accordingly.

Head and neck surgeon Eleni Rettig, MD, is leveraging data from the hospital-based research biobank to detect liquid biomarkers of HPV-associated cancers in blood samples collected from years before a patient’s diagnosis. Rettig and colleagues recently published evidence from such studies in the International Journal of Cancer.

Innovations in Reconstruction

Patients with non-HPV associated head and neck cancers generally have poorer outcomes than those with HPV-associated disease, but innovations in reconstruction are also transforming their care. Dana-Farber Brigham reconstructive surgeons, including Annino, Laura Goguen, MD, Rettig and Rosh Sethi, MD, from the Otolaryngology-Head and Neck Surgery Team use 3D modeling to preplan bone reconstructions after cancer or other ablative surgeries and are actively studying how this impacts functional outcomes. At the Dana-Farber Brigham, surgeons perform major, complex surgeries known as free flaps, in which a patient’s tissue is removed from one part of the body and transferred and reconnected to another keeping the blood supply intact. Surgeons at the Dana-Farber Brigham have removed a patient’s jaw cancer and reconstructed the jaw with a fibula free flap based on a pre-operative 3D printed modeling approach that allows precise design to makes the surgeries efficient and ultimately impact patient outcomes.

Moonshot: Overcoming Resistance

Uppaluri and colleagues have conducted first-in-class clinical trials of neoadjuvant immunotherapy for patients with higher risk head and neck cancers.

“Immunotherapies have transformed how we manage cancer patients across many disease types,” said Uppaluri. “So when a high-risk head and neck cancer patient comes in for surgery, we now start thinking, ‘Should we integrate immunotherapy as a neoadjuvant approach into this patient’s care before surgery?’”

Uppaluri and co-authors from the Dana-Farber Brigham have published results from three clinical trials of neoadjuvant immunotherapy for head and neck cancer and are now working to identify responders and non-responders — patients who are likely to respond favorably to neoadjuvant immunotherapy and patients whose cancer may be resistant to treatment to immunotherapy.

Since 2019, a collaborative research team from Dana-Farber Brigham, supported by a multi-year cancer immunotherapy research grant from the National Institutes of Health (NIH) as part of the Cancer Moonshot program, has been studying immunotherapy resistance in head and neck cancer. As part of this grant, Uppaluri and colleagues are working with medical oncologists  Robert Haddad, MD, and David Barbie, MD, to look at innate signaling in tumors. They are also working with Robert Manguso, PhD, of the Broad Institute, to use a CRISPR screening method in a preclinical model of head and neck cancer to identify new methods to improve response to therapy. Additional investigators include Ann Marie Egloff, PhD and James Lederer, PhD from BWH.

Another project currently underway is a collaboration with medical oncologist Catherine Wu, MD. The team is using single-cell RNA sequencing technologies to look at patient samples from clinical trials collected before and after the patient received therapy. The project may yield insights into which subsets of cells are targeted by therapy, what changes over time and what mechanisms may lead to non-responsiveness to therapy.

The Cancer Moonshot aims to accelerate cancer research, making more therapies available to more patients while also improving the ability to prevent cancer and detect it at an early stage. Dana-Farber Brigham’s five-year, $4.2 million grant was issued by the Immuno-Oncology Translational Network (IOTN), which was formed by the NIH/National Cancer Institute Blue Ribbon Panel to help meet the Cancer Moonshot’s goal of making a decade’s worth of progress in cancer research in five years.

Uppaluri, who joined the Brigham in 2016, draws his motivation and inspiration from the patients he treats.

“Our approach is that for every patient we see, we are thinking about what we can learn from them to improve cancer care,” he said. “To me, the patient impact is the biggest driver for our work as we aim to improve on current standards of care in our team based approach.”