Article Topic: Immunotherapy

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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Innovative CAR-T cell therapy receives FDA breakthrough therapy designation

Immunotherapy for aggressive T-cell cancers developed by WashU Medicine researchers moves to faster approval pathway

A cell-based immunotherapy designed to treat rare and aggressive types of blood cancer has been granted Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA). Developed by researchers at Washington University School of Medicine in St. Louis, this innovative CAR-T cell therapy is licensed to Wugen, a WashU Medicine startup biotechnology company based in St. Louis’ Cortex Innovation District.

The immunotherapy was developed by WashU Medicine physician-scientists who treat patients at Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine.

The therapy — called WU-CART-007 (soficabtagene geleucel) — targets specific blood cancers called T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LL). These are aggressive forms of blood cancer that originate in the immune system’s T cells, a type of white blood cell important for the body’s immune response. These cancers often don’t respond at all to standard care or return after several rounds of treatment, leaving patients with few treatment options and poor prognoses. Stem cell transplantation is the only curative treatment for such cancers, but these patients rarely qualify for it because they must first achieve remission following early rounds of chemotherapy, which is rare for these blood cancers.

The FDA’s Breakthrough Therapy designation aims to speed up the development and regulatory review of treatments for serious or life-threatening conditions, especially therapies that may offer substantial improvements over existing options. The Breakthrough Therapy designation for Wugen’s immunotherapy is based on preliminary clinical evidence showing early success in treating these aggressive blood cancers. Early-phase clinical studies have demonstrated that the therapy can selectively target and eliminate cancerous T cells with manageable side effects.

About 1,000 people are diagnosed with T-cell cancers each year in the U.S. If the cancer does not respond to treatment or returns after initial treatment, patients survive an average of six months, and fewer than 7% are still living at the five-year mark.

“This therapy has the potential to enable long-term survival for this patient population by controlling the disease and allowing patients — who would otherwise not be eligible — to proceed to stem cell transplantation, the only potentially curative treatment for these blood cancers,” said WashU Medicine oncologist John F. DiPersio, MD, PhD, the Virginia E. & Sam J. Golman Professor of Medicine and director of WashU Medicine’s Center for Gene and Cellular Immunotherapy, who first developed the therapy in his lab at WashU Medicine. “We remain hopeful that the ongoing Phase 2 study will be completed soon, and we’ll have positive results — but we’ll need some time to see how the patients do in both short-term and long-term follow-up.”

DiPersio treats patients at Siteman Cancer Center and founded Wugen alongside other WashU Medicine investigators, including Matthew Cooper, PhD, who then was on the WashU Medicine faculty and now serves as Wugen’s chief scientific officer. The researchers worked with WashU’s Office of Technology Management (OTM) to launch the company in 2018.

The early-phase clinical trial that led to the Breakthrough Therapy designation was conducted in multiple study centers in the U.S., Australia and Europe. The Phase 1 study included 28 adult and adolescent patients with either T-cell lymphoblastic cancer that returned after several lines of therapy or that never responded to treatment. Of 11 patients who could be evaluated after treatment, the overall response rate was 91%, meaning 10 patients either showed no signs of cancer after treatment or their cancer cell burden was reduced significantly. Eight out of 11 patients (72.7%) achieved complete remission. At the study’s data cutoff, six who underwent a transplant remained in remission, with no evidence of disease six to 12 months later, according to the study published in the journal Blood.

“This FDA Breakthrough Therapy designation for soficabtagene geleucel highlights the role of Siteman Cancer Center, a leading NCI-designated Comprehensive Cancer Center, and WashU Medicine in advancing innovative CAR-T cell therapies for aggressive T-cell leukemias and lymphomas,” said Timothy J. Eberlein, MD, director of Siteman Cancer Center and the Spencer T. and Ann W. Olin Distinguished Professor at WashU Medicine. “The dedicated work of our physician-scientists and clinicians is translating the most cutting-edge cellular immunotherapy research into the newest treatment options for patients with relapsed or refractory T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma.”

The phase 2 trial is currently ongoing. At the Siteman site, the clinical trials have been led by principal investigator Armin Ghobadi, MD, a professor of medicine, director of cellular therapies at Siteman, and clinical director of WashU Medicine’s Center for Gene and Cellular Immunotherapy. Siteman Kids at St. Louis Children’s Hospital and WashU Medicine is a key site for the pediatric portion of the clinical trial, co-led by Thomas Pfeiffer, MD, an assistant professor of pediatrics. Ghobadi and Pfeiffer have no financial interest in Wugen.

A major advantage of the treatment is its “off-the-shelf” availability, eliminating the need to manufacture an individualized cell product for each patient. The cell therapy can be prepared in advance from cells donated by healthy individuals and used to treat any patient with a T-cell cancer. In contrast, already-approved CAR-T cell therapies are adapted from the patient’s own immune cells, a process that typically takes three to four weeks. The accelerated treatment timeline of the Wugen immunotherapy reduces logistical and financial barriers associated with most cell-based therapies. This speed can make a meaningful difference because it is not unusual for patients with these aggressive cancers to die while waiting for the therapeutic cells to be prepared.

These particular blood cancers present a unique challenge because the therapeutic cells and the cancer cells are both T cells, so DiPersio and his colleagues came up with further innovations to prevent the therapeutic T cells from mistaking one another for the cancer and causing CAR-T cell fratricide. All other approved CAR-T cell therapies target B cell cancers, which do not have this T cell self-targeting complication.

Siteman Kids is the first site of multicenter CAR-T trial for autoimmune diseases

Access to the novel immunotherapy ­­— which “has the potential for cure” — is the latest offering by the national leader in pediatric hematology, oncology, and cell therapies.

Siteman Kids at St. Louis Children’s Hospital, along with WashU Medicine, is the first site to test a novel immunotherapy drug for the treatment of autoimmune diseases such as systemic lupus erythematosus, juvenile myasthenia gravis, juvenile dermatomyositis, and ANCA-associated vasculitis in children and young adults.

The clinical trial, called HELIOS Descartes-08 (202510129), evaluates dosing levels of an autologous chimeric antigen receptor T-cell (CAR-T) therapy that targets the B-cell maturation antigen (BCMA). Significantly, no neoadjuvant chemotherapy is needed prior to the start of Descartes-08 therapy.

“We are the first site in a multicenter clinical trial that will offer qualified patients an infusion of mRNA-modified CAR-T cells that target plasma cells,” said WashU Medicine hematologist/oncologist Melissa Mavers, MD, PhD, site principal investigator and a leader on the childhood cancers specialist team at Siteman Cancer Center. “This trial is exciting because this is the first available therapy targeting plasma cells in autoimmune disease and has the potential for cure for these patients.”

Earlier results of the Descartes-08 therapy, developed by Cartesian Therapeutics, have been promising. The FDA has granted it Orphan Drug Designation and Regenerative Medicine Advanced Therapy Designation.

To be eligible for the clinical trial, a patient must:

  • Be age 12 or older
  • Diagnosed with systemic lupus erythematous, juvenile myasthenia gravis, juvenile dermatomyositis, or ANCA-associated vasculitis
  • Have undergone systemic treatment

The trial will be administered through the Pediatric Hematopoietic Cell Transplant and Cellular Therapy Program at Siteman Kids at St. Louis Children’s Hospital.

Other Major Advancements

The clinical trial launch follows these recent advances at Siteman Kids:

Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma (ALL/LBL)

The FDA granted Breakthrough Therapy Designation for WU-CART-007, an allogeneic CAR-T therapy for T-cell malignancies developed by WashU Medicine researchers at Siteman Cancer Center. WU-CART-007 is an off-the-shelf, anti-CD7 CAR T-cell therapy for children and adults diagnosed with relapsed or refractory T-cell lymphoblastic leukemia or T-cell lymphoblastic lymphoma (R/R T-ALL/LBL). The FDA designation, announced in January, came after global clinical trials found that WU-CART-007 (also known as soficabtagene geleucel, or sofi-cel), resulted in 73% of adults and adolescents in the trials achieving full remission after receiving a full dose of the cellular therapy. WashU Medicine pediatric hematologist/oncologist Thomas Pfeiffer, MD, co-led the pediatric component of the clinical trial at Siteman Kids.

Learn more: U.S. FDA Grants to Wugen’s WU-CART-007 Breakthrough Therapy Designation

Brain Tumors

Global consultations and referrals continue to expand the reach and impact of an International Neuro-Oncology Tumor Board that originated at Siteman Kids. WashU Medicine neuro-oncologist Mohamed Shebl Abdelbaki, MD, director of the Pediatric Neuro-Oncology Program at Siteman Kids, began the monthly tumor board meetings in early 2021. To date, more than 2,500 health care specialists from 71 institutions in 41 countries have participated in the meetings, which have resulted in several advancements in best care practices for the management of complex brain tumors in infants, children and young adults.

Also available at Siteman Kids is participation in the CONNECT1906: PEP-CMV vaccine phase II clinical trial that is testing a CMV-directed peptide vaccine in children with recurrent medulloblastoma or newly diagnosed high-grade gliomas or diffuse intrinsic pontine gliomas. The multicenter study advances investigations into whether CMV-targeted vaccines can serve as a novel immunotherapeutic approach and boost responses against these cancers in pediatric patients. Eligible patients will receive a single, 5-day course of oral chemotherapy followed by PEP-CMV injections. Siteman Kids’ site principal investigator is Eric Thompson, MD.

For patients with malignant brain tumors, Siteman Kids also is involved in a multicenter phase I trial investigating the safety and dosing of intra-tumoral injections of NK cells in patients with recurrent or progressive tumors located in the upper part of the brain. Siteman Kids is one of only seven institutions offering this trial through the Pediatric Neuro-Oncology Consortium. WashU researchers are known internationally for their breakthroughs in the development and use of NK cell immunotherapies. Site principal investigators are WashU Medicine neuro-oncologists Mohamed Shebl Abdelbaki, MD, and Michael Angelo Huang, MD, MS.

“These are just a few of the leading-edge research efforts and collaborations we have underway at Siteman Kids,” said Jorge Di Paola, MD, chief of the Division of Pediatric Hematology and Oncology and the Elizabeth Finney McDonnell Endowed Chair in Pediatric Hematology Oncology at Siteman Kids at St. Louis Children’s Hospital and WashU Medicine. “We have 12 basic and translational research labs solely dedicated to advancing understanding and treatments for a wide range of pediatric cancers and more than 280 clinical trials available.”

For more information regarding clinical trials at Siteman Kids, email [email protected] or call 800-600-3606 to make a referral.

Learn about all active trials.