Immune Checkpoint Inhibition in Advanced Cancer
Kerry Reynolds, MD, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA
Authored by Catherine Spina, MD, Columbia University Medical Center, New York, New York, USA
With the rapid adoption of checkpoint inhibitors into oncology practices, providers continue to learn about the risks, predispositions, and underlying mechanism behind immunologic adverse effects (irAEs) from this new class of drugs. Dr. Reynolds reviewed our current understanding of response rates by our patients (RR: 20-30% for solid tumors, 65-85% Hodgkin’s Lymphoma, 60% MSI malignancies), highlighting the paucity of reliable clinical biomarkers or predictors to improve patient selection.
Existing data was reviewed regarding the incidence of irAEs in the setting checkpoint inhibitor monotherapy versus combination therapy, underscoring a significantly increased risk to our patients when multiple checkpoint inhibitors are combined. Dual checkpoint inhibition induces irAEs in as many as 60% of patients up to 4-5 months after completion of treatment.
Dr. Reynolds discussed the institutional experience at MGH, highlighting the dramatic rise in checkpoint inhibitor use from 94 patients in 2011 to more than 6,000 in 2017. As expected, the rates of irAEs have correspondingly risen, affecting nearly all organ systems. To illustrate the potential severity of irAEs, Dr. Reynolds presented Mr. DM, a 64 year-old gentleman with metastatic melanoma treated with dual checkpoint inhibition. Mr. DM suffered from pneumonitis, colitis, neuropathy, and fungal pneumonia, ultimately succumbing to the multitude of checkpoint blockade complications just three months after initiation of therapy. This case underscored the challenge of knowledgeably balancing the risks and benefits of aggressive treatment in the setting of poor biomarkers for risk stratification and the potential catastrophe than can ensue from the toxic combined regimen.
The treatment of irAEs was discussed, including use of high-dose steroids but also reliance on multidisciplinary teams to effectively and efficiently diagnose and manage complications to improve outcomes. The MGH Immunotherapy Toxicity Service was discussed as an example of the type of team-based innovations that may be necessary to effectively manage the vast set of potential severe complications.
Dr. Reynolds described efforts underway to develop irAE predication modes using translational correlates, including single cell analysis, mutation burden at the level of TCRs, and epigenomics. Clearly, there is an urgent need for research investigating molecular mechanisms driving the potentially devastating irAEs to facilitate biomarker discovery and clinical management of toxicity syndromes and thus decrease the risks of treatment using checkpoint blockade for our patients.
Authored by Michelle Ting, MD, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas, USA
The immune system plays an important role in controlling and eradicating cancer, and we are in the midst of an exciting revolution in the treatment of cancer. Many advances have been made in cancer immunotherapy since the discovery of checkpoint inhibition and use of CTLA-4 and PD-1 blockade. Although these therapies can be associated with substantial benefits (including decreased tumor burden and, sometimes, long-lasting remission), disruption of the immune system function using immune checkpoint inhibitors can lead to inflammatory side effects called immune-related adverse events (irAEs). IrAEs can affect nearly every organ system but most commonly involve the gastrointestinal tract, endocrine glands, skin, and liver. Less often, the central nervous system, cardiovascular, and pulmonary systems are involved. Due to the very wide range of potential presentations, management of irAEs requires multidisciplinary, collaborative management by providers across the clinical spectrum.
In this very engaging talk, Dr. Kerry Reynolds presented the Massachusetts General Hospital (MGH) experience with irAEs. The number of patients treated with immune checkpoint inhibitors has increased impressively in the recent years from 94 patients in 2011 to over 6000 patients in 2017. As the use of these antibodies expands, the principles of irAE recognition and management are becoming increasingly important. However, many questions remain unanswered. The precise pathophysiology underlying irAEs has not yet been clearly elucidated, and optimal treatment regimens for irAEs have not yet been established. While the current mainstay of treatment includes systemic immunosuppression with high dose steroids, it is currently unclear whether immunosuppression also reduces the antitumor efficacy of immune checkpoint blockade. Furthermore, can immune checkpoint inhibitors be safely given in all patient populations (including patients with autoimmune disease), and can we uncover predictors for the development of severe toxicity?
To answer some of these questions, Dr. Reynolds spearheads the Severe Immunotherapy Complications Service, which provides expert multidisciplinary clinical care and supports the necessary infrastructure to empower specimen collection and facilitate translational research efforts. This service is a paradigm of a translational research program in which a variety of clinicians and scientists across the institution band together to tackle an increasing problem facing many cancer patients today.
Authored by Kartik Sehgal, MD, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
Cancer immunotherapies have been the major scientific breakthrough of this decade and are especially exciting for the durability of clinical responses in many instances. The list of cancers with FDA-approved indications has been growing rapidly. Although the immune checkpoint inhibitors don’t cause the traditional adverse effects associated with chemotherapy, they do cause a distinct set of immune-related adverse events (irAEs).
Dr. Reynolds provided a comprehensive presentation on managing immunotherapy complications and the future directions in this field. Immune-related adverse events can affect any organ of the body and are seen with a higher frequency when checkpoint inhibitors are combined (e.g. anti-PD-1 and anti-CTLA-4 drugs). The kinetics of the different types of immune-related adverse events have been described, although it is of utmost importance to realize that these can occur even months after the drugs have been discontinued.
Dr. Reynolds then described her experience at MGH Cancer Center, where a registry has been built to collect data on immune-related adverse events. All of the hospital admissions for irAEs have been recorded since 2011, and the incidence has been increasing every year, likely reflecting the increased number of patients being treated with these agents. She also shared a personal story of her patient who developed colitis, pneumonitis, and sensory ganglionitis after treatment with combination immune checkpoint inhibitors. She stressed the importance of a multi-disciplinary team to avoid delays in diagnosis and treatment of these potentially life-threatening events. She stressed the importance of open communication with patients regarding the possibility of severe toxicities with immunotherapies and developing better predictors and biomarkers. She also shared the emerging data correlating irAEs (including cutaneous) with better responses in melanoma and lung cancer patients.
Towards the end, she talked about the immunotherapy toxicity service at MGH, which has brought together oncologists, clinical sub-specialists, clinical researchers, and translational researchers under one umbrella. This group, under her leadership, is involved in clinical care of patients via immunotherapy toxicity clinical conference and consults service, as well as translational research, to better identify sets of biomarkers and therapeutic strategies against immune-related adverse events.
Authored by Nazli Dizman, MD, City of Hope Comprehensive Cancer Center, Duarte, California, USA
In this presentation, Dr. Reynolds relates the complications caused by immunotherapies and treatment strategies. Her presentation started with the indications for immunotherapies, the mechanism of action of particular agents, the frequencies of immune-related adverse events, and management strategies. She also gave an overview of her experience in Massachusetts General Hospital inpatient oncology units.
The treatment landscape in oncology shifted broadly within the last 15 years from cytotoxic chemotherapies to contemporary immunotherapeutic approaches. This shift was based on improved response rates and survival outcomes as well as proper safety profiles observed with immunotherapies. Currently, there are more than ten immunotherapies approved by the United States Food and Drug Administration for the treatment of various cancer types. The mechanism of action of immunotherapies is mainly the blockade of the immune checkpoint proteins to activate immune response against the main escape mechanism of cancer cells. Despite showing an impressive safety profile, immunotherapies are responsible for overt immune activation against normal functioning cells of different organs, causing autoimmune destruction. The most commonly involved organ systems are the gastrointestinal system (including colon and liver involvement), skin, lungs and endocrine structures such as thyroid and pituitary glands. The immune-related adverse events can be seen at any time during treatment and may cause continued destruction despite discontinuation of immunotherapies. Real world observation from Massachusetts General Hospital inpatient oncology wards reflects the increasing use of immunotherapies and an increasing number of admissions due to immune related adverse events. Recommended approach in the management of immune related adverse events is based on the severity of the event and may include discontinuation of the immunotherapy, steroid initiation, and immune modulator agents. Of note, high dose steroid use was shown to deteriorate the response to immunotherapies. Therefore treatment of immune related adverse events while maintaining anti-tumor immunity may be challenging. In this area of an urgent and unmet need, further understanding of early mechanisms leading to immune-related adverse events and development of novel druggable targets with immune suppressive potential is of great importance.