Article Topic: Sidharth V. Puram, MD, PhD

Puram Elected to American Society for Clinical Investigation

Sidharth (Sid) V. Puram, MD, PhD, co-director of The Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, has been elected to the American Society for Clinical Investigation (ASCI), one of the nation’s oldest and most respected medical honor societies. Siteman is based at Barnes-Jewish Hospital and WashU Medicine, where Puram also is the Lindburg Professor and chair of the Department of Otolaryngology – Head and Neck Surgery.

The ASCI focuses on the special role of physician-scientists in research, clinical care and medical education, as well as their leadership in academic medicine and industry.

Founded in 1908, the ASCI recognizes early- to mid-career physician scientists who have made significant contributions to translational or clinical research. Election is a recognition of outstanding scholarly achievement and impactful, sustained work that advances the understanding, diagnosis or treatment of human disease.

Puram has advanced scientists’ understanding of tumor growth, treatment resistance and metastasis in head and neck cancers — discoveries that have opened new options for treating these challenging tumors. His research explores the complex ecosystem of diverse cells within a tumor and how they communicate with one another, using single-cell and spatial analyses to understand tumors in exquisite detail. His work has helped define the cellular and molecular diversity within head and neck cancers, informed several innovative clinical trials and identified potential therapeutic targets to improve patient outcomes.

He was one of three WashU Medicine physicians elected to the society this year. The others are Suzanne E. Schindler, MD, PhD, an associate professor of neurology, and Christopher D. Smyser, MD, the A. Ernest & Jane G. Stein Professor of Developmental Neurology and chief of the Division of Pediatric & Developmental Neurology.

Their election to ASCI highlights WashU Medicine’s strength in supporting physician-scientists who bridge laboratory research and clinical care. Puram, Schindler and Smyser were formally inducted at the 2026 annual joint meeting of the ASCI, the Association of American Physicians and the American Physician Scientists Association in Chicago.

They are among seven WashU Medicine physicians who have been elected to the ASCI since 2012. Of the seven, four are affiliated with Siteman Cancer Center or Siteman Kids at St. Louis Children’s Hospital: Puram, Jorge A. Di Paola, MD, Patricia Dickson, MD, and Angela Hirbe, MD, PhD.

Tumor Markers May Help Doctors Decide Which Head and Neck Cancer Patients Need Immunotherapy Before Surgery

WashU Medicine physician-scientists at Siteman Cancer Center identify a promising way to help guide immunotherapy treatment decisions and enhance patient care

Building upon more than a decade of investigator-initiated clinical trials at Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine, researchers have identified a malignant cell biomarker that may predict which patients will respond to the immunotherapy drug pembrolizumab, known commercially as Keytruda, for the treatment of resectable locally advanced head and neck squamous cell carcinoma (LA-HNSCC).

The research, published March 31 in Cell Reports Medicine, is the latest discovery from one of the nation’s leading head and neck tumor centers, the Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center. The findings point to a cell surface protein, major histocompatibility complex class II (MHC-II), as the tumor marker that may help guide treatment decisions. It is typically expressed on immune cells and is important for activating immune responses in the body.

In the study, the researchers found that malignant cells expressing MHC-II and interferon response genes respond better to pembrolizumab administered before surgery, suggesting that a malignant-interferon (IFN)/MHC-II program could be developed into a genomic test to stratify patients into those who should proceed with immunotherapy before surgery and those who should proceed directly to surgery and not be given immunotherapy beforehand.

“Patients with advanced head and neck cancer often undergo immunotherapy prior to and after surgery,” said Sidharth V. Puram, MD, PhD, the Lindburg Professor of Otolaryngology and chair of the Department of Otolaryngology — Head & Neck Surgery at WashU Medicine and co-director of the Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center. “The use of immunotherapy drugs, however, means that surgery is delayed by as much as eight to 10 weeks. If we can determine which patients are more likely to benefit from immunotherapy and which ones should go straight to surgery, we can potentially improve overall outcomes for our patients. We think that’s what (IFN)/MHC-II can do: predict how well patients will have a tumor response to immunotherapy.”

Puram is the corresponding author of the study. Co-senior authors are Douglas R. Adkins, MD, director of the Section of Head and Neck and Thyroid Medical Oncology in the Division of Medical Oncology at WashU Medicine and co-director of the Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman; Ravindra Uppaluri, MD, PhD, director of Head and Neck Surgical Oncology at Dana-Farber Cancer Institute; and Itay Tirosh, PhD, senior scientist in the Department of Molecular Biology at the Weizmann Institute of Science in Israel.

WashU Medicine researchers already have defined a new standard for the treatment for resectable LA-HNSCC in adults. In the pivotal global KEYNOTE-689 Phase 3 clinical trial, published in the New England Journal of Medicinein June 2025 and co-led by Adkins and Uppaluri, researchers found that the administration of pembrolizumab before and after surgery combined with adjuvant (chemo) radiation therapy resulted in tumor cell death in the surgical specimen and significantly improved the event-free survival (EFS) for these patients.

Perioperative pembrolizumab was approved by the FDA in June 2025 and changed the standard treatment pathway for patients with LA-HNSCC.

“The KEYNOTE-689 trial was built on the favorable results of investigator-initiated trial testing of perioperative pembrolizumab that was developed and conducted at WashU Medicine (with participating sites at the Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center),” Adkins said. “In these trials, administration of pembrolizumab before surgery resulted in evidence of tumor cell death in the surgical specimen in up to 50% of patients, a finding linked to better EFS. However, a biomarker was needed that could predict which patients benefited from pembrolizumab before the immunotherapy drug was given. Tumor PD-L1 protein expression does predict potential benefit with pembrolizumab in these patients; however, this test is a very weak predictive biomarker. Predictive biomarkers with stronger links to benefit with pembrolizumab are needed to select patients a priori who may or may not benefit from pembrolizumab before and after surgery.”



To understand the underlying biology and what might drive tumor responses to immunotherapy, researchers used single-cell RNA-sequencing on tissue samples from 16 HNSCC patients, both pre- and post-neoadjuvant pembrolizumab treatment, who were enrolled in the phase 2 trials that represent the predecessors to KEYNOTE-689.



“Single cell approaches allowed us to profile the individual malignant cells and understand the specific genes expressed and how they change with immunotherapy,” Puram said. “Surprisingly, we found a subpopulation of malignant cells that were defined by MHC-II and interferon response genes that predicted immunotherapy response.”



The researchers believe that MHC-II and interferon expression by malignant cells reflects engagement of immune cells with T cells, which are positioned to kill the cancer but have been “turned off” — a state called T-cell exhaustion. Based on spatial techniques, they hypothesize that immunotherapy drugs like pembrolizumab “wake up” these T cells, with MHC-II and interferon identifying which tumors might be poised to then respond to the immunotherapy.



“These results suggest that for the first time, a clinically available strong predictive biomarker may become available to clinicians that can be used to decide whether to include perioperative pembrolizumab before and after surgery and adjuvant therapy for the treatment of patients with LA-HNSCC,” Adkins said. “This will be an important milestone to achieve for our patients.”



“What we’ve demonstrated is the importance of malignant cell states for immunotherapy response,” Puram added. “After more studies with more patients, we envision that a simple test could be developed that tells us if a patient expresses (IFN)/MHC-II and therefore would benefit from immunotherapy. We think this is a significant finding as we continuously try to predict which patients will respond and how to make treatments more effective.”

Historical Clinical and Research Breakthroughs

Siteman Cancer Center has a long history of improving outcomes and driving novel research into head and neck cancers. The WashU Medicine Department of Otolaryngology is among the top 10 recipients of NIH research funding among otolaryngology departments. Within the Robert Ebert and Greg Stubblefield Head and Neck Tumor Center, investigators and physician-scientists across a multidisciplinary team of otolaryngology, medical oncology and radiation oncology specialists oversee one of the largest basic, translational and clinical research portfolios in the country. In addition to paradigm-changing clinical trials such as the KEYNOTE-689 trials, researchers at the center have pioneered advanced reconstructive techniques and new therapies with radiation and chemotherapy, as well as immunotherapies and targeted therapies for head and neck cancers.

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Puram named Head of Otolaryngology

Leading physician-scientist and head and neck cancer specialist also revered as a mentor

Sidharth “Sid” V. Puram, MD, PhD, has been named the head of the Department of Otolaryngology — Head & Neck Surgery and the Lindburg Professor of Otolaryngology at Washington University School of Medicine in St. Louis. A nationally recognized physician-scientist specializing in head and neck cancer surgery, Puram currently serves as the Joseph B. Kimbrough Professor and director of the department’s Division of Head & Neck Surgery. He also is co-director of the Robert Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine. Puram’s new appointment begins Nov. 1, 2025.

His research has advanced understanding of tumor growth, treatment resistance and metastasis in head and neck cancers — discoveries that have opened new options for treating these challenging tumors.

“Dr. Puram is an exceptionally talented physician-scientist and mentor who was unanimously selected by our leadership team from an outstanding pool of candidates,” said David H. Perlmutter, MD, executive vice chancellor for medical affairs, the Spencer T. and Ann W. Olin Distinguished Professor and the George and Carol Bauer Dean of WashU Medicine, who announced Puram’s new appointment. “He will be leading a department that has always been esteemed but has grown in accomplishments and reputation in the last decade under the leadership of Dr. Craig Buchman. We believe Dr. Puram will inspire the otolaryngology team at WashU Medicine, with our partners at BJC HealthCare, to even greater impact and advance the science-based practice of care for patients with upper airways disorders in the coming decades.”

Puram’s research explores tumor heterogeneity — the complex ecosystem of diverse cells within a cancer and how they communicate with one another — a focus that has garnered significant funding from the National Institutes of Health (NIH). Understanding the cellular and genetic make-up of tumors can help scientists and clinicians identify and target the specific cells implicated in troubling behaviors seen in cancer such as tumor invasion, spread and resistance to therapy. His research has informed several innovative clinical trials and identified still other potential treatment avenues.

Detailing the diversity within tumors has pointed the way toward precision treatments for certain kinds of head and neck cancers and provides a foundation for developing therapies more tailored to the tumors of individual patients.

Through his leadership of the Division of Head & Neck Surgery at WashU Medicine, Puram has guided growth in both faculty and patient referrals while also establishing new collaborations with other departments to broaden the expertise offered to head and neck cancer patients with complex clinical needs. In his role as co-director of the Robert Ebert and Greg Stubblefield Head and Neck Tumor Center, Puram has overseen a coordinated clinical program including head and neck specialists, oral health services, ancillary care and mental health care, among other services, with care coordination driven by patient navigation. This innovative, multidisciplinary approach is designed to improve patient outcomes by supporting patients throughout their cancer treatment while improving communication among the care team.

These programs reflect the department’s broader leadership in research and patient care. The department is the fifth-highest recipient of NIH research funding for otolaryngology departments. Each year, its physicians care for more than 120,000 patients and perform more than 11,000 surgeries, including nose and sinus operations; cochlear implants and other procedures to restore hearing; facial reconstruction surgeries; procedures to improve voice and swallowing; pediatric upper airway surgeries; and cancer surgeries.

“Otolaryngology at WashU Medicine is like no other in the U.S. in terms of its academic rigor and the collegiality of the faculty and researchers, so it is a great honor to have been selected to lead the department,” said Puram. “We have a fantastic team of physicians, researchers and trainees here who are absolutely committed to delivering the highest standard of care for our patients today and to carrying out rigorous research that will benefit the patients of tomorrow. Our team continues to push the boundaries through innovative surgical techniques and research projects that will disrupt traditional paradigms of care. I’m very excited to be able to carry that mission forward.”

As a head and neck cancer specialist, Puram is in the rare position as a physician of being both his patients’ surgeon and primary oncologist. With a particular focus on reconstructive surgery after the removal of head and neck cancer, he helps many patients return to their lives and minimize damage to key functions such as speech, swallowing, taste, hearing and smell.

Puram earned his bachelor’s degree from the Massachusetts Institute of Technology and earned both his MD and PhD from Harvard Medical School in 2013. For his graduate research, Puram identified signaling pathways in brain cells that affect the shape of their dendrites, which are key recipients of information.

Puram chose otolaryngology as his medical specialty because it provided him the opportunity to perform a variety of anatomically intricate and challenging surgeries while also practicing as a cancer specialist. He completed a residency in otolaryngology in the Massachusetts Eye and Ear Infirmary/Harvard Combined Program in 2018. During his simultaneous postdoctoral fellowship at Massachusetts General Hospital/MIT Broad Institute, Puram published the first single-cell atlas of head and neck cancers. He then completed his training with a clinical fellowship in microvascular reconstruction/head and neck surgical oncology at The Ohio State University Comprehensive Cancer Center – James before coming to WashU Medicine in 2019.

Puram serves on the National Institute of Dental and Craniofacial Research special grants review study section. He is also on the editorial boards of Surgical Oncology Insight, Head & Neck and Frontiers in Oncology. Puram has been recognized by his peers for his teaching, science and clinical skills. He received the American Society for Clinical Investigation Young Physician Scientist Award in 2020 and was named a Fellow of the American College of Surgeons in 2021. He received the Department of Otolaryngology — Head & Neck Surgery Faculty Teaching Award earlier this year.