2020 Systemic/Toxic Effects

Solving the Achilles Heel of Cancer Immunotherapy

Chloé Villani, PhD, Harvard Medical School, Massachusetts General Hospital Charlestown, Massachusetts, USA

Fellow Summary

Authored by Adam DuVall

Dr. Villani presented very interesting work describing immune related adverse events (irAEs) associated with the use of immune checkpoint inhibitor (ICI) therapies and how they have subsequently developed a multi-disciplinary care team and translational research to manage and understand the mechanism driving irAEs.

Dr. Villani first presented a brief history of ICI, recounting the mechanism of action (“releasing the brakes” of the immune system) and current approved therapies, including anti-CTLA4, anti-PD-1, and anti-PD-L1 agents and their currently approved uses. In total, by 2019, there were 41 approvals in 31 different diseases. This has obviously resulted in a massive increase in the number of patients treated with ICI over the last 10 years. The lecture then transitioned to a general background on irAEs including a demonstration on how they can impact every organ system, graphically representing the organ systems most commonly involved based on type of ICI used, grade of irAE, and point post initiation of therapy at which the irAE presented. Dr. Villani presented previously published data showing that a higher response rate to therapy was associated with >3 irAEs and cutaneous irAEs but that this has not been consistent over all studies of ICI. Additionally, treating irAEs with high doses of steroids may actually have a detrimental effect on anti-cancer response making the management of irAEs. This section of the presentation clearly delineated the difficulties in managing the toxicities of ICI while also maximizing the potential benefit in a population whose therapeutic options are very limited.

Dr. Villani then transitioned to discussing the multi-disciplinary care team that they have developed at MGH, which includes 49 different physicians across 6 departments and 10 divisions of medicine.  They round on patients admitted with irAEs, have created a conference series focused on irAEs, and most importantly have a designated person in each specialty who can act as a point person for all irAEs. Their translational research program has the goal of developing rapid diagnostic tools, biomarkers, and better targeted therapies for irAEs, which leverages their multi-disciplinary environment to truly create a bench to bedside and back program.

Fellow Summary

Authored by Kenji Tsuchihashi

  1. Describing immune related adverse events (irAEs) associated with the use of immune checkpoint inhibitor (ICI) therapies for cancer treatment
  2. The importance of understanding the clinical challenges associated with managing irAEs and the need for multi-disciplinary care teams
  3. The importance of understanding how translational efforts could be used to infer biological mechanisms driving irAEs and identify novel therapeutic targets

In Dr. Villani’s talk, she focused on three important topics regarding the Achilles’ heel of cancer immunotherapy:

Firstly, she explained the actionable mechanism of immune checkpoint inhibitors (ICI). ICI such as anti-CTLA4, anti-PD-1 and anti-PD-L1 are approved for various types of cancers. The combinatory therapy with ICI and conventional therapies are thought to raise the survival curve compared with each one in non small-cell lung cancer. Further, combinatory therapy with anti-PD-1 and anti-CTLA-4 also raise survival compared with each one in melanoma. However, the life-saving potential of ICI therapy is severely limited by immune related adverse events (irAEs). IrAEs may happen in any part of the body. The distribution of IrAEs is different in part between anti-CTLA4 and anti-PD-1/PD-L1. The timing of IrAEs is different between organs. IrAE in skin such as thrush and pruritis happen earliest. Next, she showed MGH experiences of IrAEs. Colonic events are most common, occupying about 44%, followed by hepatic events at 15%. Whether the occurrence of irAEs is a biomarker of treatment response is still controversial. The general guidelines for management of irAEs are shown by ESMO, SITC, and ASCO/NCCN. Steroids are used for management of irAE ≥grade2. However, high dosage of glucocoriticoids may impair the improved survival by ICIs. Further data is expected to be published soon. The vision of MGH for the care of irAEs is:

  • to develop expertise in the clinical recognition of these atypical presentations and the management of toxicity,
  • to identify biomarkers with enormous need, and
  • to develop better therapies to treat irAE while maintaining anti-tumor immunity.

MGH has a team for Severe Immunotherapy Complication (SIC) Service which consists of 13 oncologists across all areas of cancer. She also introduced the SIC translational program. This program seeks to understand the causes of irAEs to develop rapid diagnostic tools, biomarkers, and better targeted therapies. This program consists of many clinical departments and translational research teams. One of the efforts is to analyze paired body fluid, blood, and tissues through different sampling strategies from core biopsies to rapid autopsy. Finally, she discussed envisioned outcomes of the SIC translational research program: identifying a set of biomarkers to be implemented in clinic, development of better therapy strategies to treat autoimmune-toxicities while maintaining anti-tumor immunity to inform next-generation mechanism-based clinical trial, further understanding of early mechanisms leading to autoimmune diseases, identifying novel druggable targets with immunosuppressive potential, and training the next generation of physician and scientists to embrace precision medicine.