Genetic Changes in Head and Neck Cancer, Immunotherapy Resistance Identified

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A multi-institutional team of researchers has identified both the genetic abnormalities that drive pre-cancer cells into becoming an invasive type of head and neck cancer and patients who are least likely to respond to immunotherapy.

“Through a series of surprises, we followed clues that focused more and more tightly on specific genetic imbalances and their role in the effects of specific immune components in tumor development,” said co-principal investigator Webster Cavenee, PhD, Distinguished Professor Emeritus at University of California San Diego School of Medicine.

“The genetic abnormalities we identified drive changes in the immune cell composition of the tumors that, in turn, dictates responsiveness to standard of care immune checkpoint inhibitors.”

Reporting in the April 26, 2021 online issue of the Proceedings of the National Academy of Sciences, researchers describe the role of somatic copy-number alterations — abnormalities that result in the loss or gain in a copy of a gene — and the loss of chromosome 9p in the development of human papillomavirus (HPV)-negative head and neck cancer.

The loss of chromosome 9p and the deletion of JAK2 and PD-LI, two neighboring genes found on chromosome 9p, was associated with resistance to immune checkpoint inhibitors, a type of cancer immunotherapy that uses antibodies to make tumor cells visible to a patient’s immune system.

“Although programmed death-1 (PD-1) immune checkpoint inhibitors represent a major breakthrough in cancer treatment, only 15 percent of patients with HPV-negative head and neck cancer respond to treatment,” said co-principal investigator Scott M. Lippman, MD, senior associate dean, associate vice chancellor for cancer research and care and Chugai Pharmaceutical Chair in Cancer at UC San Diego School of Medicine.

“The ability to predict a patient’s response or resistance to this class of therapies, a major unmet clinical need, is a unique and novel discovery. Knowing who will not respond avoids losing several months to ineffective therapy with huge financial costs and impacts to quality of life,” said Lippman, director of UC San Diego Moores Cancer Center and medical oncologist who specializes in the treatment of patients with head and neck cancer at UC San Diego Health, San Diego’s only National Cancer Institute-designated comprehensive cancer center.

For this study, co-led by New York University Langone Health’s Teresa Davoli, PhD, and The University of Texas MD Anderson Cancer Center’s William N. William, MD, with co-investigator Steve Dubinett, MD, of UCLA Jonsson Comprehensive Cancer Center, researchers prospectively followed 188 patients at MD Anderson Cancer Center to study genomic and immune drivers of the transition to invasive HPV-negative head and neck cancer. They reviewed comprehensive genomic and transcriptomic data of 343 HPV-negative head and neck cancer patients from The Cancer Genome Atlas and 32 HPV-negative head and neck cancer cell lines from the Cancer Cell Line Encyclopedia project, and analyzed patient survival after immunotherapy in real-world evidence cohort data from Caris Life Sciences.

In 2021, the National Cancer Institute estimates approximately 54,000 new cases of head and neck cancers will be diagnosed in the United States, with 10,850 deaths. HPV-negative head squamous cell carcinomas are the most common, increasing and lethal subtype of this malignancy worldwide, said Lippman.

“The data serves as a powerful predictive marker, transforming standard of care for precision immunotherapy for patients with advanced, recurrent head and neck cancer,” said Lippman. “And, while we focused in an unprecedented extensive interrogation of the most globally lethal form of head and neck squamous cancer, accounting for more than 300,000 deaths annually, the application may be useful in a wide variety of solid tumors for which immune checkpoint inhibitors comprises standard of care.”

Co-authors include: Xin Zhao, Joy J. Bianchi and Pan Cheng, all of New York University Langone Health; Heather Y. Lin and J. Jack Lee of MD Anderson Cancer Center; Hannah Carter and Ludmil B. Alexandrov, UC San Diego; Jim P. Abraham and David B. Spetzler of Caris Life Sciences; and Don W. Cleveland, UC San Diego and Ludwig Institute for Cancer Research.

This research was funded, in part, by the National Institutes of Health (5U01CA196408, UL1TR001881, P01 CA106451, P50 CA097007, R01DE026644, P30-CA023100), Cancer Prevention and Research Institute of Texas Grant (RP140464), Conquer Cancer Foundation Career Development Award, Barbanti Funds for Cancer Research, Cancer Research UK Grand Challenge, Mark Foundation for Cancer Research (C5470/A27144, R00 CA212621), MRA Young Investigator Award, V Foundation Fellowship, Instituto Cura, a postdoctoral fellowship from the National Cancer Center, support for Precancer Genome Atlas work by the Packard Fellowship for Science and Engineering, Stand Up To Cancer LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Cancer Research Grant (SU2C-AACR-DT-23-17), and Stand Up To Cancer–Lustgarten Foundation Pancreatic Cancer Interception Dream Team Translational Cancer Research Grant (SU2C-AACR-DT-25-17).

Disclosures: William has received honoraria, speaker’s fees, and/or participated in advisory boards from Roche/Genentech, BMS, Eli Lilly, Merck, AstraZeneca, Bayer, Boeringher Ingelheim, and Pfizer. Abraham and Spetzler are employees of Caris Life Sciences. Dubinett is on the scientific advisory boards of Early Diagnostics, Johnson & Johnson Lung Cancer Initiative, Lung Life AI, Inc., and T-Cure Bioscience, Inc. He has research funding from Johnson & Johnson Lung Cancer Initiative and Novartis. Cavenee is on the board of directors of Genetron Health LLC and is a founder of Interleukin Combinatorial Therapies, Inc. and InVaMet, Inc. Lippman is on the scientific advisory boards of Human Longevity, Inc. (uncompensated) and Biological Dynamics, Inc.


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