Key Dates

Related Announcements

• February 09, 2024 - The NCI Transition Career Development Award (K22 Independent Clinical Trial Optional). See NOFO PAR-24-117.
• April 24, 2024 - NIH Pathway to Independence Award (Parent K99/R00 – Independent Clinical Trial Not Allowed). See NOFO PA-24-194.
• April 24, 2024 - Mentored Clinical Scientist Research Career Development Award (Parent K08 – Independent Clinical Trial Not Allowed). See NOFO PA-24-182.
• April 24, 2024 - Mentored Research Scientist Development Award (Parent K01 - Independent Clinical Trial Not Allowed). See NOFO PA-24-176.
• May 08, 2024 - Academic Research Enhancement Award (AREA) for Undergraduate-Focused Institutions (R15 Clinical Trial Not Allowed). See NOFO PAR-24-152.
• August 18, 2023 - Research Projects to Enhance Applicability of Mammalian Models for Translational Research (R01 Clinical Trial Not Allowed). See NOFO PAR-23-281.
• December 20, 2023 - Stephen I. Katz Early Stage Investigator Research Project Grant (R01 Clinical Trial Not Allowed). See NOFO PAR-24-075.
• January 10, 2022 - NIDCR Dual Degree Dentist Scientist Pathway to Independence Award (K99/R00 Clinical Trial Not Allowed). See NOFO PAR-22-041.
• February 11, 2022 - NIDCR Mentored Career Development Award to Promote Diversity (K01 Independent Clinical Trial Not Allowed). See NOFO PAR-22-050.
• August 17, 2021 - Maximizing Opportunities for Scientific and Academic Independent Careers (MOSAIC) Postdoctoral Career Transition Award to Promote Diversity (K99/R00 Independent Clinical Trial Not Allowed). See NOFO PAR-21-271.
• August 31, 2021 - NCI Mentored Research Scientist Development Award to Promote Diversity (K01 Independent Clinical Trial Not Allowed). See NOFO PAR-21-295.
• September 10, 2021 - NCI Mentored Clinical Scientist Research Career Development Award to Promote Diversity (K08 - Independent Clinical Trial Not Allowed). See NOFO PAR-21-300.
• September 10, 2021 - NCI Transition Career Development Award to Promote Diversity (K22 Independent Clinical Trial Not Allowed). See NOFO PAR-21-301.
• May 05, 2020 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed). See NOFO PA-20-185. 
• May 07, 2020 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed). See NOFO PA-20-195.
• November 25, 2020 - NIDCR Small Grant Program for New Investigators (R03 Clinical Trial Not Allowed). See NOFO PAR-21-084.

Issued by

National Cancer Institute (NCI)

National Institute of Allergy and Infectious Diseases (NIAID)

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

National Institute of Dental and Craniofacial Research (NIDCR)

Office of The Director, National Institutes of Health (OD)

Purpose

The overall goal of this Notice of Special Interest (NOSI) is to promote mechanistic research aimed at better understanding the pathophysiology of immune-related adverse events (irAEs). It is anticipated that the mechanistic research supported through this NOSI will build the foundational knowledge which will ultimately lead to better strategies to predict, prevent and/or ameliorate toxicities that can arise as a consequence of current immunotherapeutic regimens, and improve treatment outcomes. The proposed research can be basic or translational but should be focused on revealing the mechanisms underlying irAEs. Single investigators and/or multidisciplinary teams with relevant expertise in the research area proposed and/or patient characterization and selection are encouraged to apply.

Background

Cancer immunotherapies including checkpoint inhibitors, adoptive cell transfer, and other immune modulators have led to durable long-term survival in subgroups of adult and pediatric cancer patients. However, these therapies can also lead to a breach of balance between immunity and immunopathology, resulting in mild to severe inflammatory reactions or autoimmunity, some of which can be life threatening. The specific manifestation of irAEs varies due to the different immunotherapy modalities used; for example, immune checkpoint blockade therapies can lead to inflammation and damage to various organ sites; while CAR-T cell therapies can result in cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and on-target, off-tumor toxicity. irAEs occur in only a subgroup of patients, at different organ sites, either early or late in the course of the therapy. There is currently no clear understanding of the complexity and heterogeneity of irAEs, nor ways to predict those patients who will go on to develop an irAE in response to a given immunotherapy. With the increasingly widespread use of cancer immunotherapies and in ever-more-effective combinations, the cases of irAEs have skyrocketed in recent years and likely will continue to increase with more complexity and severity, representing a major barrier to delivering effective immunotherapies to cancer patients. Furthermore, whether health disparities affect the trajectory or severity of any given irAE is also an important issue which has been scarcely investigated. Given that there is clear evidence of health disparities in autoimmune diseases and cancer and that the biological and socioeconomical determinants are yet to be fully delineated, health disparities in irAEs would be expected. The incidence and severity of irAEs has been shown in some cases to correlate with overall patient response and survival following immune checkpoint blockade, suggesting that the anti-tumor and autoimmune responses share common underlying mechanisms. Immune suppression can sometimes reverse these adverse events but can also compromise the anti-tumor activity of the immunotherapy. To uncouple irAEs from anti-tumor immunity, more specific and targeted approaches for management of irAEs are needed, for which a clear understanding of the immune mechanism of irAEs is essential.

Research Objectives

This NOSI calls for research proposals to investigate irAEs. Specifically, research is encouraged in understanding the mechanisms of immune and/or autoimmune pathways that could be applied to improving immunotherapeutic approaches while simultaneously eliminating or reducing the severity of inflammatory or autoimmune responses. A related area of interest is studies designed to enhance the target specificity of immunotherapeutic reagents, to reduce or prevent adverse events. An additional area of interest is the identification of predictive immunophenotypes of cancer patients at risk for developing irAEs. Understanding the risk factors for developing irAEs would better inform patient stratification at the start of therapy and lead to improved treatment outcomes. Achieving the goals of this NOSI should establish a deeper understanding of the origins and activation pathways leading to inflammatory or autoimmune adverse events that currently limit the use of various immunotherapy regimens in patients. 
Studies focused on mechanisms of irAEs for both adult and pediatric cancers are encouraged. Understanding the mechanisms of irAEs involves diverse expertise, including cancer biology, tumor immunology, autoimmunity and organ physiology. Given the complexity, multi-disciplinary approaches are encouraged. Research may include, but is not limited to:

Specific Areas of Research Interest to NCI

• Developing model systems (in vitro tissue models, animal models, in silico and computational models, synthetic and engineered immune model systems, etc.) to study the regulation of immune responses affected by immunotherapy strategies and leading to adverse events; 
• Investigating the role of the microbiome in the generation or prevention of irAEs resulting from cancer immunotherapies;
• Investigating the role of obesity, aging and other co-morbidities in developing irAEs;
• Revealing the biological mechanisms underlying racial/ethnic and socioeconomic health disparities in irAEs;
• Identifying tumor antigens and epitopes with minimal or tolerable expression on normal tissues as potential immunotherapeutic targets to minimize off-target toxicities;
• Achieving a mechanistic understanding of critical cell participants, or new cellular functions of known cell participants, in tumor-directed immunity and its regulation affected by immunotherapy strategies and leading to adverse events;
• Identifying and generating a mechanistic understanding of critical components of the tumor microenvironment (TME) as potential therapeutic targets to mitigate irAEs during cancer immunotherapy;
• Identifying and generating a mechanistic understanding of key immunotherapy-relevant immune modulators as potential therapeutic targets to overcome adverse events; 
• Interrogating immune mechanisms at the intersection of anti-tumor immunity and autoimmunity; and
•  Developing and evaluating candidate agents for mitigation of adverse events that do not limit the anti-tumor activity of immunotherapy regimens.
   

Specific Areas of Research Interest to NIDCR: NIDCR is interested in supporting basic and translational studies of immunotherapy-related adverse events that are relevant to the NIDCR's mission and strategic plan. Research may include, but is not limited to:

• Understanding mechanisms related to irAEs that manifest in dental, oral, and craniofacial tissues
• Investigating how biological variables (e.g., sex/gender, age) and racial/ethnic and socioeconomic health disparities alter the risk for adverse effects in oral and salivary irAEs; 
• Identifying tolerance pathways and regulating "off-target" non-specific inflammatory and autoimmune responses while using checkpoint blockade, other types of immunotherapies, or combinatorial therapies without impeding anti-tumor immune responses;
• Addressing the complexity and heterogeneity of irAEs and identifying genetics, epigenetics, oral microbiome, metabolic and immune biomarkers for the onset of irAEs.

Potential applicants are encouraged to speak with a NIDCR program official to discuss the relevance of proposed research topic(s).

Specific Areas of Research Interest to NIAMS: NIAMS is interested in supporting basic and/or translational studies focused on:

• Understanding mechanisms related to irAEs that are covered under NIAMS mission areas (i.e. rheumatological, skin-related, musculoskeletal); and
• Investigating the role of underlying rheumatic, musculoskeletal and/or skin diseases in the development of irAEs.

Specific Areas of Research Interest to NIAID: NIAID is interested in supporting basic and/or translational studies that focus on understanding mechanisms regulating immune tolerance and autoimmunity associated with irAEs. Examples of NIAID’s interests include the following types of research:

• Understanding regulatory, signaling, or other pathways modulated by immunotherapy that lead to autoimmunity;
• Identifying tolerance pathways that could be exploited to prevent autoimmunity resulting from adverse events caused by immunotherapy;
• Regulating "off-target" non-specific inflammatory and autoimmune responses while using checkpoint blockade without impeding anti-tumor immune responses;
• Addressing cancer immunotherapy in patients with underlying autoimmune diseases, including those, like lupus, that disproportionately affect racial and ethnic populations; and
• Identifying predictive biomarkers for the onset of irAEs (e.g., genetics, epigenetics, microbiome, and overall immune status).
   

Responsiveness

This NOSI calls for research projects to study the basic mechanism of irAEs. Clinical research directly related to treatment strategies and outcomes in patients is not responsive to this NOSI.

Examples of projects NOT responsive to this NOSI:

1. Projects solely focused on developing biomarkers for patient stratification and predicting treatment outcomes.
2. Patient cohort studies for treatment outcomes.
3. Clinical development of therapies for irAEs with well-understood mechanisms.

Application and Submission Information

Submit applications for this initiative using one of the following Notice of Funding opportunities (NOFOs) or any reissues of these announcements through the expiration date of this notice.

Applicants must select the IC and associated NOFO to use for submission of an application in response to the NOSI. The selection must align with the IC requirements listed in order to be considered responsive to that NOFO. Non-responsive applications will be withdrawn from consideration for this initiative.

In addition, applicants using NIH Parent announcements (listed below) will be assigned to those ICs on this NOSI that have indicated those NOFOs are acceptable and based on usual application-IC assignment practices.

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-CA-24-055” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Although NCI, NIAID, NIAMS, NIDCR, and OD is not listed as a Participating Organization in all the NOFOs listed above, applications for this initiative will be accepted.

Applications nonresponsive to terms of this NOSI will be withdrawn from consideration for this initiative.

Inquiries

Please direct all inquiries to the contacts in Section VII of the listed notice of funding opportunity with the following additions/substitutions:

Scientific/Research Contact(s)

Yin Liu, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6251
Email: liuy@mail.nih.gov

Shoba Thirumangalathu, Ph.D. (Training and career development)
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone:301-594-0652
Email: shoba.thirumangalathu@nih.gov

Preethi Chander, Ph.D. (autoimmune diseases)
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-827-4620
E-mail: preethi.chander@nih.gov

Zhong Chen, MD, Ph.D. (oral, oropharyngeal, and salivary gland cancer)
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-529-7083
E-mail: zhong.chen@nih.gov

Marie Mancini, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-5032
E-mail: mancinim2@mail.nih.gov

Maggie A. Morris Fears, Ph.D. (program contact)
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-761-5444
E-mail: maggie.morrisfears@nih.gov

Tamia Powell ( grant management contact)
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-2982
Email: tamia.powell@nih.gov