This Notice of Special Interest (NOSI) from the National Cancer Institute (NCI) announces an opportunity for administrative supplemental funding to support the development of an "Immune Radiation Response Index (i-RRI)" for immune cells from normal and tumor microenvironments.
Recent evidence indicates that ionizing radiation can enhance immune responses to tumors. Advances in radiation delivery techniques allow hypo-fractionated delivery of conformal radiotherapy. Hypofractionation or other modifications of standard fractionation may improve radiation's ability to promote immune responses to tumors. Other novel delivery options may also affect immune responses, including T-cell activation and tumor-antigen presentation changes. However, there is limited understanding of the immunologic impact of hypo- and unique multi-fractionated radiotherapy regimens, as these observations are relatively recent. Divergence of approaches and findings between preclinical studies and clinical trials highlights the need for evaluating the design of future clinical studies with particular emphasis on radiation dose and fractionation, immune biomarkers, and selecting appropriate endpoints for combination radiation/immune modulator trials, recognizing that direct effect on the tumor and potential abscopal effect may well be different. Similarly, preclinical studies should be designed as much as possible to model the intended clinical setting.
Specific Research Objectives
The impact of radiation on the immune response is complex. There is a lack of systematic evidence to understand the effects on the tumor immune microenvironment in response to various radiation doses and fractionation. Hence, this concept seeks to understand the comparative i-RRI for normal immune cells and immune cells in the tumor microenvironment that can inform the mechanisms underlying radiation-induced disturbances of innate and adaptive immune modulation. Radiation response index is defined as a dose scale (in Gy) to categorize all types of normal and tumor-infiltrate immune cells based on either "intrinsic radiation sensitivity" or "intrinsic radiation resistance".
In particular, such studies can address the major translational question:
- Do immune cells expanded in vitro predict i-RRI for immune cells infiltrating normal or tumor tissues?
- Can such an i-RRI be utilized in designing clinical trial concepts?
A short-term goal of NCI is to identify optimal radiation dose and fraction that will synergize with immunotherapy for the management of solid tumors. This will create a dose-fraction response scale for tumor immune infiltrate and normal immune cells that can help characterize different doses and fractionations of RT as distinct immunomodulatory drugs.
The long-term goal is of the NCI to implement how the comparative i-RRI for normal immune cells and immune cells in the tumor microenvironment can be adapted in designing new combined clinical trial concepts.
- This administrative supplement requires a radiation oncologist/radiobiologist's collaboration with an immunologist actively involved in cancer immunotherapy investigations. The radiation oncologist/Immuno-therapist/Immunologist must be a Cancer Moonshot Investigator collaborating with an NCI-Cancer Center (CC) investigator.
- Only one application per Cancer Moonshot-NCI-CC parent award is allowed.
- The investigators should have access to in vitro and in vivo irradiation facilities for study. Studies should focus on the immunobiology of radiotherapy and should propose experiments that define or will contribute to a definition of an i-RRI.
- The awardees of these administrative supplements will be required to join the existing network such as the Immuno-Oncology Translational Network (IOTN) that will meet regularly to collaborate and accelerate research in this field.
Applications not permitted to this NOSI include:
- Applications submitted from only radiation oncologists or only immunologists are not responsive. For example, a partnership with an immunotherapist-Immunologist is not allowed as there should be a radiation expert investigator in the partnership.
- Proposals that cannot reasonably be completed in one year of supplemental funding with the second year of a no-cost extension.
All applicants are encouraged to discuss their applications with the scientific/research contact listed in this NOSI (below) prior to submission.
Application and Submission Information
Applications for this initiative must be submitted using the following opportunity or its subsequent reissued equivalent:
PA-20-272 - Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional).
All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:
Only existing awardees of the programs https://www.cancer.gov/research/key-initiatives/moonshot-cancer-initiative/funding; these include:
- For supplements to parent awards that include multiple program directors/principal investigators (PDs/PIs), the supplement may be requested by any or all of the PDs/PIs (in accordance with the existing leadership plan) and submitted by the awardee institution of the parent award.
- If the PD/PI of the supplement application is not the PD/PI of the parent award, a letter of support from the contact PI of the parent award must be provided.
- The project period for the parent award must be active, and cannot be in a no-cost extension, for the 1 year of the administrative supplement application/project/award.
Application Due Dates:
July 30, 2021 until 5:00 PM local time of applicant organization, for possible funding in FY2021.
The Expiration Date of this NOSI is July 31, 2021.
- Each parent award supplement budget request cannot exceed $125,000 in direct costs. In addition, the budget cannot exceed the direct costs of the current parent award. Direct award cost in collaborative settings (two joint parent award supplements) should not increase $250,000 with a total cost not exceeding $400,000.
- Allowable costs include funding for consumables, post-docs, graduate students and technicians. No salary support for PIs and Co-Investigators.
- Requests must reflect the actual needs of the proposed project.
- Administrative supplements can cover cost increases associated with achieving specific new research objectives as long as the research objectives are within the original scope of the peer-reviewed and approved project, or the cost increases are for unanticipated expenses within the original scope of the project.
- Requests are permitted for one year of support only.
- Modular and categorical budgets are permitted.
- The earliest anticipated start date is September 1, 2021.
- Applicants should begin the supplement application abstract by stating “This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-21-083.”
- For funding consideration, applicants must include “NOT-CA-21-083” (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.
- Page limits: The Research Strategy section of the application is limited to 6 pages.
Review and Selection Process:
NCI will conduct administrative reviews of applications and support the most meritorious applications submitted for consideration, based on funds' availability.
Additionally, NCI program staff will evaluate applications using the following selection factors:
- Is the proposed work within the scope of the parent award but beyond the original recruitment plans?
- Does the administrative supplement plan reasonably allow the proposed project to be completed, given the time and budget requested?
- Is the strategy ready to be initiated as described?
- Are the identified end-user(s) appropriate?
- Does the proposed project include strategies to ensure a robust and unbiased approach, as appropriate for the work proposed?
- Are potential problems, alternative strategies, and benchmarks for success presented?
- For previously used strategies, is a justification for the use of the tool provided?
- For new strategies, are the innovative aspects of new approaches highlighted?
- Will the strategy/assays/approaches be generalizable or adaptable in this cross-disciplinary setting?
- Does the application include a prospective plan to evaluate the performance of the proposed work and the effectiveness of the proposed strategy with pre-defined metrics such as development of i-RRI scale?