Expired PAR-14-086: Revision Applications for Research on Metabolic Reprogramming to Improve Immunotherapy (U01)

Part 1. Overview Information

Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Cancer Institute (NCI)
Funding Opportunity Title	Revision Applications for Research on Metabolic Reprogramming to Improve Immunotherapy (U01)
Activity Code	U01 Research Project Cooperative Agreements
Announcement Type	New
Related Notices	NOT-OD-16-004 - NIH & AHRQ Announce Upcoming Changes to Policies, Instructions and Forms for 2016 Grant Applications (November 18, 2015) NOT-OD-16-006 - Simplification of the Vertebrate Animals Section of NIH Grant Applications and Contract Proposals (November 18, 2015) NOT-OD-16-011 - Implementing Rigor and Transparency in NIH & AHRQ Research Grant Applications (November 18, 2015) June 4, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same.
Funding Opportunity Announcement (FOA) Number	PAR-14-086
Companion Funding Opportunity	PAR-14-085, R01 Research Project Grant PAR-14-087, P01 Program Project Grant
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.396
Funding Opportunity Purpose	This Funding Opportunity Announcement (FOA) invites research project - cooperative agreement (U01) revision applications from investigators with active NIH U01 research project - cooperative agreement awards to support an expansion of the scope of the funded U01 research project through the addition of one or more new specific aims. Revision applications are expected to stimulate collaborative research projects to generate a mechanistic understanding of the metabolic processes that support robust anti-tumor immune responses in vivo, determine how the metabolic landscape of the tumor microenvironment affects immune effector functions, and use this information to manipulate (or reprogram) the metabolic pathways used by the tumor, the immune response, or both to improve cancer immunotherapy.

Key Dates

Posted Date	February 4, 2014
Open Date (Earliest Submission Date)	June 10, 2014
Letter of Intent Due Date(s)	30 days before the due date
Application Due Date(s)	July 10, 2014; December 11, 2014; July 10, 2015; December 11, 2015, July 11, 2016; December 14, 2016, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
AIDS Application Due Date(s)	July 10, 2014; December 11, 2014; July 10, 2015; December 11, 2015; July 11, 2016; December 14, 2016, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
Scientific Merit Review	October-November 2014; February-March 2015; October-November 2015; February-March 2016; October-November 2016; February-March 2017
Advisory Council Review	January 2015; May 2015; January 2016, May 2016; January 2017, May 2017
Earliest Start Date	April 2015; July 2015; April 2016; July 2016; April 2017; July 2017
Expiration Date	December 15, 2016
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Table of Contents

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

This Funding Opportunity Announcement (FOA) invites research project - cooperative agreement (U01) revision applications from investigators with active NIH U01 research project - cooperative agreement awards to support an expansion of the scope of the funded U01 research project through the addition of one or more new specific aims. Revision applications are expected to stimulate collaborative, cross-disciplinary research projects to (1) generate a mechanistic understanding of the metabolic processes that support robust anti-tumor immune responses in vivo, (2) determine how the metabolic landscape of the tumor microenvironment affects immune effector functions, and (3) use this information to manipulate (or reprogram) the metabolic pathways used by the tumor, the immune response, or both to improve cancer immunotherapy.

This FOA will utilize the NIH research project - cooperative agreement (U01) mechanism and target revision applications from currently funded NIH U01 research project grants with at least two years of support remaining on the parent grant at the estimated time of award.

Background

One of the critical adaptations that enables cancer growth and survival is the ability to reprogram metabolism from primarily oxidative phosphorylation (OxPhos), observed in normal resting cells, to aerobic glycolysis (or Warburg metabolism). This reprogramming is associated with an increase in glucose receptor expression, uptake of glucose (and other environmental nutrients), diversion of glycolytic intermediates to various biosynthetic pathways required for cell growth, and the export of lactate and other metabolites. Taken together, these processes dramatically alter the metabolic landscape of the tissue in which the tumor resides. Recent advances in immunology have demonstrated that lymphocytes undergo a similar reprogramming to Warburg metabolism to meet the metabolic demands of clonal expansion following antigen stimulation. Whereas na ve T cells generate ATP through OxPhos to maintain basic cellular functions (such as ion transport, membrane maintenance, and protein turnover), following exposure to antigen they switch to Warburg metabolism. This metabolic shift, besides supporting clonal expansion, is also critical for lineage differentiation, acquisition of lineage-specific effector functions, and the generation of long-lived memory T cells capable of self-renewal. The presence of memory cytotoxic T cells in tumors is associated with an optimum and durable anti-tumor immune response. Thus, there is a growing recognition that metabolic manipulation can skew immune responses toward desirable outcomes (i.e. generating a more robust memory CTL response) and has the potential to dramatically enhance immunotherapy.

The ability to capitalize on this opportunity, however, will require a more complete understanding of the metabolic pathways that lead to optimum anti-tumor immune responses, how to manipulate those pathways to generate specific outcomes, and lastly how the anti-tumor immune response, once generated, is affected by the altered metabolic landscape of the tumor microenvironment. Tumors, both as a direct consequence of cancer cell behavior and through the recruitment of immunosuppressive cells, are characterized by perturbed chemical (hypoxia and acidosis) and nutrient/metabolite profiles that can have a profound impact on the ability of anti-tumor immune cells to proliferate, acquire and engage effector capabilities, and home to tumors. At present, there is a knowledge gap with regard to the similarities, differences, and functional consequences of the metabolic pathways utilized by activated immune cells and cancer cells that would guide the development of novel metabolic interventions to improve immunotherapy. Overall, future studies need to develop (a) approaches to reprogram the metabolic qualities of anti-tumor immune cells (either ex vivo or in vivo) to improve immunotherapy (effector function, homing, or persistence) and/or, (b) approaches that target cancer cell metabolic pathways to impair cancer cell survival without compromising anti-tumor immunity.

Specific Research Objectives

This FOA will support collaborative, cross-disciplinary projects focused on integrating the knowledge and expertise of diverse Program Director(s)/Principal Investigator(s) (PDs/PIs), or collaborating units, to investigate the metabolic pathways utilized by anti-tumor immune responses in the setting of cancer for the purposes of improving cancer immunotherapy. Synergistic collaborations, as described below, are expected to stimulate innovative approaches, spur the development of new tools, technologies and computational models, and facilitate bringing new researchers into cancer immunotherapy. Revision applications that are appropriate for this FOA should address the scientific areas listed below.

Scientific Areas Appropriate for Revision Applications to this FOA:

Applicable research directions could include, but not be limited to, the following:

Integrate the crosstalk between different metabolic platforms that may be operating in any given cell to generate a more complete metabolic profile at the single cell level;
Determine the relationship between metabolism and self-renewal capacity;
Generate a better understanding of how the metabolic environment (or nutrient repertoire) in normal tissues, immune tissues, and in the setting of pathology (i.e. tumors) affects immune cell development and/or effector function;
Studies to elucidate how specific metabolites affect various immune states such as activation, energy, development of long-lived memory cells versus short-lived effector cells, and homing to their proper niche are needed;
Generate a better understanding of metabolites as signaling molecules in transcription that effect cellular differentiation;
Optimize and translate new technology, instrumentation, or novel approaches that are needed to parse the metabolic heterogeneity of tissues in vivo and how the metabolic characteristics of the tumor microenvironment affect the anti-tumor immune response;
Generate computational models to better understand which metabolic pathways are hard-wired and when perturbed lead to cell death and which are flexible and can be experimentally manipulated need to generated;
Development of small molecule inhibitors of glycolysis, FAO, and other metabolic pathways for therapeutic intervention;
Perform comprehensive analysis of the metabolic heterogeneity (metabolic flux/metabolomics) of different immune subsets and a full description of the functional consequences of differential utilization of metabolic pathways in supporting immune cell differentiation.

Examples of Synergistic Collaborations Appropriate for this FOA:

collaborations should align cancer biologists, immunologists, and tool or technology specialists to develop complementary approaches to utilize metabolic reprogramming to improve cancer immunotherapy. For example, a cancer biologist, with an active NCI funded U01 cooperative agreement, could propose a revision application with an immunologist aimed at complementary areas of metabolic research and, if justified, a metabolomics, computational tools, or in vivo metabolic imaging;
collaborating PDs/PIs should have specific expertise not present in the parent grant;
collaborations that enable the participants to move into novel emerging areas related to metabolic regulation of immunotherapy and/or recruit unique expertise from other research fields and thereby have the potential to expand the pool of cancer researchers.

Research projects that are not appropriate for this FOA:

This FOA will NOT support the development of approaches aimed at biomarker discovery.

Section II. Award Information

Funding Instrument	Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.
Application Types Allowed	Revision applications from active NIH U01 awardees Resubmission (only of Revision applications originally submitted in response to this FOA). The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Award Budget	Application budgets are not limited but need to reflect the actual needs of the proposed project.
Award Project Period	The parent cooperative agreement must be active when the application is submitted. There must be a minimum two years of support remaining on the parent award (not to include a no cost extension) at the estimated time of award.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

Public/State Controlled Institutions of Higher Education
Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

Hispanic-serving Institutions
Historically Black Colleges and Universities (HBCUs)
Tribally Controlled Colleges and Universities (TCCUs)
Alaska Native and Native Hawaiian Serving Institutions
Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

Small Businesses
For-Profit Organizations (Other than Small Businesses)

Governments

State Governments
County Governments
City or Township Governments
Special District Governments
Indian/Native American Tribal Governments (Federally Recognized)
Indian/Native American Tribal Governments (Other than Federally Recognized)
Eligible Agencies of the Federal Government
U.S. Territory or Possession

Other

Independent School Districts
Public Housing Authorities/Indian Housing Authorities
Native American Tribal Organizations (other than Federally recognized tribal governments)
Faith-based or Community-based Organizations
Regional Organizations
Non-domestic (non-U.S.) Entities (Foreign Institutions)

Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Required Registrations

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

The parent project must be an active NIH U01 project. There must be at least two years (24 months) remaining on the project at the estimated time of award. The PD(s)/PI(s) on the revision must be the same as the PD(s)/PI(s) on the parent grant.

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
Of an application with a changed grant activity code.

Section IV. Application and Submission Information

1. Requesting an Application Package

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

Descriptive title of proposed activity
Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
Names of other key personnel
Participating institution(s)
Number and title of this funding opportunity

The letter of intent should be sent to:

T. Kevin Howcroft, Ph.D.
National Institutes of Health
National Cancer Institute (NCI)
Division of Cancer Biology
9609 Medical Center Dr.
Room 6W560
Bethesda, MD 20892-9748
Phone: 240-276-6229
Email: [email protected]

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

Required and Optional Components

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

Instructions for Application Submission

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

SF424(R&R) Cover