RFA: Understanding, Preventing, and Managing Immunotherapy-related Adverse Events (irAEs) Associated with Checkpoint Inhibition for Melanoma and Other Cancers

In recognition of the immense potential of checkpoint inhibition in combatting multiple cancers, and the reality that immune-related adverse events (irAEs) pose a challenge that, if addressed, could lead to better overall outcomes for patients and broader use, the American Cancer Society (ACS) and the Melanoma Research Alliance (MRA) have partnered to support research leading towards reduction of irAEs and improvement of overall outcomes for cancer patients treated with checkpoint immunotherapy.

This Request for Applications (RFA) offers funding for grants to test feasibility and generate preliminary data in the form of Pilot Awards and at least one Multidisciplinary Team Award. MRA and ACS have each committed $1 million for the awards. The combined $2 million will be used to fund at least one Multidisciplinary Team Award at $1 million for up to three years and up to five Pilot Awards at $200,000 each for two-year periods.

Team Awards are designed to foster interdisciplinary collaborative research to promote transformational advances with the potential for rapid clinical benefit.
Pilot Awards are intended to help seed the ground in this relatively young area of checkpoint irAE research.

About This RFA

Purpose: To facilitate research focused on prevention, risk, early detection, and management of short- and long-term immune-related adverse events (irAEs) associated with FDA-approved or late-stage development checkpoint cancer immunotherapies for melanoma and other cancers.

Expected outcome: The funded research is expected to inform approaches that will improve the overall benefits of checkpoint inhibition for patients with melanoma and other metastatic cancers and lay the groundwork for more effective use of these life-saving treatments.

Focus of the RFA: Research towards the prevention, early detection, reduction and/or management of life-altering and/or outcome-limiting side-effects of checkpoint inhibitor therapy is needed. A critical gap in management of irAEs is early identification of which patients are at greatest risk for various irAEs, which patient features are indicative of irAEs, the time course of clinical manifestation and if prevention strategies can limit side-effects without diminishing efficacy.

Background: Immunotherapies are playing a growing and critical role in advancing cancer treatment and while melanoma has served as the proving ground for immunotherapy, many diseases are benefiting. Specifically, approved checkpoint immunotherapies that target cytotoxic T-lymphocyte-associated-protein 4 (CTLA-4), programmed cell death inhibitor 1 (PD-1) receptor, and programmed cell death-ligand inhibitor 1 (PD-L1) have transformed outcomes for patients with melanoma, lung, kidney, bladder, and other cancers. The population of patients likely to be exposed to a regimen containing a checkpoint inhibitor such as ipilimumab, nivolumab, pembrolizumab, atezolizumab and avelumab is large and growing. To achieve complete remission and improve survival, clinical trials are underway using single agents and combination therapies of either: 

  • multiple checkpoint inhibitors;
  • checkpoint inhibitors with conventional or targeted therapy;
  • or checkpoint inhibitors with new immunotherapies that target other pathways. 

While safe and well-tolerated for many advanced cancer patients, a significant number of patients experience an array of inflammatory and immune side effects across organ systems that resemble autoimmune diseases. Immunotherapy related adverse events (irAEs) may range from mild to severe and life-threatening. These irAEs include dermatologic disorders, colitis, cardiotoxicity, hematologic toxicities, hepatoxicity, neuropathies, pneumonitis, renal toxicity, and a range of endocrinopathies. The potential for irAEs stands as one of the challenges to broader use of these medicines beyond metastatic disease and in the adjuvant or neoadjuvant treatment settings.

In the absence of clear diagnostics or biomarkers, management of irAEs relies on both patient self-report and the acumen of the primary oncologist to recognize clinical symptoms early, respond appropriately with treatment interruption and/or immunosuppressive therapy, and initiate early referral to subspecialists. A major clinical dilemma is being unable to predict in advance which patients will develop these symptoms and when. Symptoms that may appear subtle at the onset are best managed by organ-specific specialists familiar with symptom clusters and other specialists trained in co-managing multiple symptoms and co-morbid chronic conditions.

Examples of research included in the scope of this RFA

Areas of interest: Proposals should focus on research leading to mitigation of irAEs while preserving or enhancing checkpoint blockade effectiveness. Research topics of interest include, but are not limited to:

Research topics of interest include, but are not limited to:

Biological basis and mechanism of irAEs: Molecular, epigenetic, and genetic factors causing adverse events

  • Elucidation of the molecular, cellular, or microenvironmental mechanisms underlying irAEs
  • Biobehavioral mechanisms connecting metabolic pathways with symptom and symptom clusters to inform interventions to reduce adverse events and improve the management of symptoms

Prevention: Causes, risk factors, drug interactions

  • Elucidation of environmental, epidemiological, biological factors and the temporal nature in which they influence irAEs that lead to prevention or early intervention strategies.
  • Exploring links between the biological mechanisms and manifestations of symptom clusters, their onset and severity over time

Detection and biomarkers: Identification and use of biomarkers and personal characteristics (e.g. demographics, inherited mutations status, pre-existing diseases) to better predict which patients are at greatest risk and tailor care.

  • Development of screening methods and identification and validation of diagnostic, predictive or prognostic biomarkers.
  • Using existing or new data sources to understand irAE causes and management

Measurement of symptom clusters: Distinguishing symptoms related to immunotherapy vs. the cancer itself or other co-morbid chronic disorders require measurement tools to assess and quantify the magnitude of adverse events.

  • Characterizing symptom clusters to include patient’s symptom experience, temporal characteristics of the symptoms within a cluster, and phenotypic and molecular mechanisms associated with symptoms within the cluster.
  • Changes in symptom clusters over time, measurement of and severity and corresponding analytic strategies

Clinical translation: Enhancing care to improve tolerability of therapy and manage adverse events

  • Projects emphasizing the translation of scientific findings to new strategies for the clinical management of irAEs
  • Test novel methods for care delivery to managing irAEs
  • Comparative analysis of side effect profiles of different checkpoint inhibitors, different disease settings or different dosing schedules   
  • Development of pharmacological approaches with existing or new agents that improve tolerability and preserve efficacy.

Application Deadline:

  • October 16, 2017 for Pilot Award Proposals.
  • For Multidisciplinary Team Award Proposals, a letter of intent (LOI) is required. LOIs are due August 1 and if invited to apply, full applications are due October 31, 2017.

Application Materials

Multidisciplinary Team Award policies and instructions (PDF)

Pilot Award policies and instructions (PDF)

Electronic LOI and Grant Application instructions and forms are available on proposalCENTRAL.


Additional Questions

For questions about this mechanism please contact grants@cancer.org