Impact of lymph node sparing on the anti-tumor response for head and neck cancer treated with radiation and immunotherapy

Abstract
As a board-certified veterinary radiation oncologist and radiobiologist, I am committed to, and excited for, a
career in translational cancer research as a physician scientist. My long-term career goal is to develop into an
independent veterinary clinician scientist, proficient in designing and performing innovative radiation research,
with a focused interest in tumor microenvironmental effects of radiation therapy and immunotherapy to improve
treatment outcomes for patients with head and neck cancer.
Head and neck cancer (HNC) is common in the United States and Europe and the prognosis is poor for patients
with advanced disease. Stereotactic body radiation therapy (SBRT), which allows delivery of high dose, high
precision radiation in a few fractions, is a novel therapy that can be used to treat HNC patients. Evidence exists
that SBRT is a more potent activator of anti-tumor immune responses compared to conventional radiotherapy.
Emerging preclinical and clinical data suggest SBRT combined with immunotherapy has the potential to convert
immunologically “cold” (immunosuppressed) tumors into “hot” (inflamed) tumors. SBRT and IO combinations can
stimulate effector T cell responses to each patient’s tumor. HNC patients with high risks for lymph node
metastasis typically receive RT targeted to their primary tumor and regional lymph nodes (RLN) in order to
eradicate latent metastatic tumor cells; however, RLNs are critical sites for generating immune responses, and
RLN irradiation is likely to destroy the immune cells responsible for anti-tumor responses.
Based on my preliminary data that SBRT caused depletion of T cell density and expansion of
immunosuppressive immune cell populations in RLNs compared to RLNs spared from RT, we propose to study
how RLN irradiation affects local and systemic anti-tumor immunity when combined with RT and IO. We will test
our hypotheses with orthotopic murine head and neck cancer models and in canine cancer patients who have
developed oral carcinoma. For the study, we will use the local tumor immunotherapy combination of agonistic
OX-40 monoclonal antibody + TLR9 ligand, which has demonstrated positive tumor microenvironmental immune
effects in mice and dogs.
If we demonstrate RT+IO and RLN sparing improves outcomes in translational preclinical models of advanced
HNC, the results of this project would challenge the current standard of care and clinical paradigm surrounding
radiation, immunotherapy, and elective RLN irradiation for patients with advanced HNC. Through the K01 career
development program, I will have the opportunity to delve deeper into radiation and immunology research and
grow as an independent translational scientist through the direct influence, support, and guidance of my strong
mentorship team, Dr. Steven Dow, Dr. Xiao-Jing Wang, and Dr. Sana Karam.

Grant Number: 5K01OD031809-05
NIH Institute/Center: NIH
Principal Investigator: Mary-Keara Boss