Emerging translational center of excellence (TCE) for HPV-related oropharynx cancer at Penn

Surgeon/scientist, Devraj Basu, MD, PhD, FACS, recently led the creation of the HPV+ Head and Neck Cancer Translational Center of Excellence (TCE) at the Abramson Cancer Center (ACC). The center’s overarching goals are to (1) accelerate identification and clinical application of biomarkers that distinguish HPV+ head and neck cancer patients at high vs. low risk of tumor recurrence and (2) develop personalized therapeutic strategies that exploit the biologic differences among HPV+ head and neck cancers. 

Human papilloma virus-related (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) are rising in incidence in the United States, where they have surpassed cervical cancer as the most common HPV-related malignancy.¹ Despite the availability of HPV vaccination, HPV+ OPSCCs will likely become the most common head and neck cancer type by 2030 and are not expected to begin declining in incidence until 2060.^2,3

The current therapeutic landscape for HPV-related oropharynx cancer

The standard multimodality therapies for HPV+ OPSCC are generally effective for the majority of patients but have acute toxicities as well as lasting effects that leave permanent treatment-related disabilities in many survivors. This treatment toxicity justifies ongoing efforts to de-escalate therapy while maintaining high cure rates by using minimally invasive surgery, limiting radiation doses, and/or avoiding cytotoxic chemotherapy.^4,5

However, says Dr Basu, patient selection for therapy de-escalation mostly relies on clinical and pathologic features that have limited prognostic and predictive accuracy, and molecular biomarkers of therapy response and recurrence risk presently remain inadequate for standard clinical application. Dr. Basu is a head and neck surgeon and a cancer biologist focused on leveraging molecular understanding of HPV-mediated oncogenic mechanisms to develop predictive biomarkers and novel preclinical therapeutic approaches that can be advanced into clinical trials.

A sizable minority of HPV+ OPSCCs recur after standard therapy, Dr. Basu observes, and the mechanisms and markers of therapy resistance that distinguish these tumors from their more treatment-sensitive counterparts remain poorly defined. This recurrence risk prevents drastic reductions in toxic treatment for patients who are most easily curable. Moreover, the dramatic advances in immunotherapy for cancer in recent years have not yet produced major dividends for HPV+ OPSCC patients.

Parsing the Mechanisms of Therapy Resistance in HPV+OPSCC

Starting in 2005, Drs Bert O’Malley, Jr., and Gregory Weinstein of Penn Otorhinolaryngology developed transoral robotic surgery (TORS) for OPSCC and led its adoption into use across many other centers. Resulting FDA approval of TORS for T1/T2 OPSCCs in 2010⁶ subsequently impacted clinical practice patterns for this disease globally and has attracted many HPV+ OPSCC patients to Penn.

Although TORS changed the therapeutic landscape, most HPV+ OPSCC patients who receive it at Penn still need adjuvant radiation, and ~25% have indications for postoperative chemotherapy.⁷ In addition, up to half of HPV+ OPSCC patients seen in the Penn practice are presently not deemed suitable for TORS. Instead, these patients usually receive full dose (70Gy) radiation as primary therapy, and most also receive cytotoxic chemotherapy if they are deemed healthy enough to tolerate it.

The de-escalation of these treatments using a variety of approaches is a focus of completed, ongoing, and planned clinical trials at Penn Medicine and elsewhere.^8-10 However, the current design of current trials remains tempered by limited risk stratification tools, Dr. Basu notes, with the optimal design of these de-escalation studies hindered by the current inability to discriminate the cases prone to recurrence with sufficient accuracy. Moreover, he adds, the field continues to rely primarily upon TNM staging plus certain other pathologic features that have limited predictive ability to guide definitive therapy, and treatment for patients who subsequently recur also remains minimally personalized.

The ACC Transitional Center of Excellence for HPV+ OPSCC

In planning the Abramson Cancer Center HPV+ Head and Neck Translational Center of Excellence (TCE), Dr. Basu and colleagues hoped to address a number of unanswered concerns, including questions relevant to HPV+ OPSCC recurrence and the mechanisms of resistance.

“Many of these questions are foundational,” Dr. Basu says. “For example: Which patients are destined to recur? Which patients could benefit from therapy de-escalation, and which would instead need intensified therapy? What are the molecular mechanisms underlying sensitivity vs. resistance to standard therapy? What are the genetic features and transcriptional profiles linked to high risk of treatment failure? Can such molecular traits be integrated with clinical, radiographic, and pathologic features to produce robust, generalizable predictive biomarkers? Finally, how can these traits be leveraged to personalize therapy though innovative clinical trial designs at Penn?”

A durable program that integrates basic and clinical HPV+OPSCC research

To leverage the resources at Penn relevant to these questions in the context of the ACC HPV+OPSCC TCE, Dr. Basu assembled a team of faculty members with complementary expertise in molecular epidemiology, cancer biology, virology, DNA damage responses, tumor immunology, preclinical therapeutic studies, and clinical trials.

This team includes Jianxin You, a tumor virologist positioned to answer mechanistic questions linking HPV oncogene function to therapy response and clinical outcomes. Dr. You is also developing a new lipid nanoparticle-based strategy to reverse STING pathway suppression by HPV, which limits the immune system’s ability to detect this cancer type. A DNA damage response expert in the department of Cancer Biology (Dr. Eric J. Brown) is working characterize the DNA repair defects in this disease and exploit them for preclinical therapeutic trial design. Another cancer biologist (Dr. Ahmed Diab) is further exploring the interface of HPV+ OPSCCs with the immune system and working to activate anti-tumor immunity by targeting mechanisms of DNA repair in the tumor.

Preclinical therapeutic studies are ongoing using multiple novel small molecule inhibitors of proteins involved in DNA repair signaling in combination with radiation and anti-PD1 drugs (Dr. Brown, Diab, and Basu). To identify cases in which targeting these molecular pathways may be most relevant, genetic and transcriptomic data is being compared by Dr. Basu’s team between TORS-treated tumors that later recurred and carefully matched non-recurrent control tumors. Dr. Basu has also developed and characterized a unique set of patient-derived models that are useful for evaluating therapeutic efficacy against distinct molecular subtypes of HPV+ OPSCC found in patients.¹¹

To bring this preclinical work to fruition in prospective human studies, Dr. Basu is working closely with head and neck medical oncologists Drs. Roger Cohen and Lova Sun and radiation oncologist Dr. Nick Lukens, who are actively designing new trials based on the molecular biomarkers and novel therapeutic agents being explored in the lab. These investigators also provide a critical bridge to industry partners and the national cooperative groups for trial development at Penn Medicine and other collaborating centers. These efforts, supported by the ACC, provide a robust platform to advance cutting-edge care for HPV+ head and neck cancer patients over the coming years.

References

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8. Hargreaves S, Beasley M, Hurt C, Jones TM, Evans M. Deintensification of Adjuvant Treatment After Transoral Surgery in Patients With Human Papillomavirus-Positive Oropharyngeal Cancer: The Conception of the PATHOS Study and Its Development. Front Oncol 2019; 9:936.
9. Ferris RL, Flamand Y, Weinstein GS, Li S, Quon H, Mehra R, Garcia JJ, Chung CH, Gillison ML, Duvvuri U, et al. Phase II Randomized Trial of Transoral Surgery and Low-Dose Intensity Modulated Radiation Therapy in Resectable p16+ Locally Advanced Oropharynx Cancer: An ECOG-ACRIN Cancer Research Group Trial (E3311). J Clin Oncol 2022; 40:138-49.
10. Swisher-McClure S, Lukens JN, Aggarwal C, Ahn P, Basu D, Bauml JM, Brody R, Chalian A, Cohen RB, Fotouhi-Ghiam A, et al. A Phase 2 Trial of Alternative Volumes of Oropharyngeal Irradiation for De-intensification (AVOID): Omission of the Resected Primary Tumor Bed After Transoral Robotic Surgery for Human Papilloma Virus-Related Squamous Cell Carcinoma of the Oropharynx. Int J Radiat Oncol Biol Phys 2020; 106:725-32.
11. Facompre ND, Rajagopalan P, Sahu V, Pearson AT, Montone KT, James CD, Gleber-Netto FO, Weinstein GS, Jalaly J, Lin A, et al. Identifying predictors of HPV-related head and neck squamous cell carcinoma progression and survival through patient-derived models. Int J Cancer 2020; 147:3236-49.