Summary authored by Joshua Smith, MD

Toxicity Associated with Immune Checkpoint Inhibitors

Joshua Smith, MD

In the past several years, the use of immune checkpoint inhibitor (ICI) therapy for head and neck squamous cell carcinoma (HNSCC) has rapidly proliferated, inspired by a signal of durable response and survival benefit in a subset of patients with recurrent and/or metastatic disease. Our field (i.e., head and neck surgical oncology) has now directed attention towards clinical trial validation of ICI therapy in the neoadjuvant and adjuvant settings, with profound implications for surgical and perioperative care of our patients. Initial Phase I/II trials of ICI therapy for patients with surgically curable HNSCC have shown promising pathologic response rates and safety profiles. However, there exists substantial uncertainty regarding survival benefit, optimal treatment duration, and acute- and long-term toxicities of ICI therapy when used in neo-adjuvant and adjuvant settings for HNSCC.

As this is a particular clinical and research interest of mine, I really enjoyed Dr. Alexandra-ChloéVillani’s talk on toxicities of ICI therapy. Her group’s groundbreaking research on predicting and mitigating immune related adverse events (irAEs) of ICI therapy has numerous exciting applications in my field. In HNSCC translational research, much work is focused on identifying predictive biomarkers of ICI response. There is a paucity of published work on precision strategies to identify those patients who may suffer significant irAEs that demand cessation of ICI and thus limit their therapeutic potential in patients at all stages of disease. Thus, I found several key points in her talk especially intriguing and applicable to my practice. 

First is Dr. Villani’s focus on single cell omics technologies to better understand immune-cancer interactions and impact of individual cell types on irAEs and response to ICI therapy. Her lab’s single-cell (sc)RNA sequencing work on human blood dendritic and monocyte cell lineages illustrates the potential complexity of the immune response to cancer and ICI therapy. HNSCC is a deeply immunosuppressive malignancy with impressive intra- and inter-tumoral cellular heterogeneity. Application of her single cell omics experimental and analytical frameworks to HNSCC may help to supplant current biomarkers of response to ICI therapy and mitigation of irAEs by deciphering the complexity of this disease. 

Second is Dr. Villani’s truly inspiring focus on identifying candidate cellular mechanisms that may be targeted to mitigate irAEs, either primarily or secondarily, while preserving the durability of response to ICI therapy. Similar to other cancers, we have no reproducible nor reliable strategy to predict which patients will suffer irAEs to ICI therapy, thus limiting their options to cytotoxic therapies with palliative intent. IrAEs to ICI therapy are of particular concern in HNSCC when using these therapies in a neoadjuvant or adjuvant setting, as timely surgical care and avoidance of wound complications is paramount importance. Application of her researchstrategies to identify predictive and clinically useful markers of irAEs in HNSCC specifically would have tremendous impact on our patients. 

Third is her description of the inception and maintenance of the Severe Immunotherapy Complications Service at Massachusetts General Hospital. This is a truly unique service that utilizes multi-disciplinary expertise of multiple clinical and pre-clinical specialties to better understand and treat severe irAEs in the acute setting. Having personally taken care of several post-operative patients with HNSCC suffering from severe acute irAEs, I can attest to the likely profound benefit of such a service at a major academic medical center. Further, the framework for seamless procurement of invaluable biospecimens for translational study in a bedside-to-bench paradigm is truly unique. As I transition to surgical fellowship and to my first faculty job, I hope to practice at an institution with such a service. 

In summary, Dr. Villani’s talk certainly inspired me to become more sophisticated in my understanding of irAEs in ICI therapy and her strategies for translational research may be applied to surgical care of patients with HNSCC specifically. This was simply an invaluable experience.