It is critical that applicants follow the Research (R) 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.

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

The purpose of this funding opportunity announcement (FOA) is to promote the discovery of novel small molecules that could enhance the ability of the immune system to selectively recognize and attack cancer cells. These small molecules could be further developed into stand-alone immunotherapeutics or synergistic partners for existing therapies, or as chemical probes for the discovery and validation of novel targets involved in anti-tumor immunity. Investigators from multiple scientific disciplines (immuno-oncology, tumor biology, screening technology, medicinal chemistry, and pharmacology) are encouraged to establish collaborative teams to discover and develop novel small molecule immunomodulators for cancer therapy. This FOA encourages the design of research projects that utilize the following phases of discovery research: 1) assay development specifically designed for immuno-oncology targets with the intent to screen for novel small molecule compounds that show potential as either probes or drugs, or as pre-therapeutic leads; 2) screen implementation for immunomodulatory targets to identify initial screening hits (from high throughput target-focused approaches or moderate throughput phenotypic- and fragment-based approaches); 3) hit validation through secondary orthogonal and counter screening assays, and hit prioritization; and 4) hit-to-lead optimization.

Applicants who propose basic studies that involve the identification and analysis of mechanisms contributing to tumor immune evasion are encouraged to apply for PA-17-330.

Cancer immunotherapy development to date has predominantly focused on biological agents that modulate the efficiency of cytotoxic T lymphocytes (CTLs) e.g. monoclonal antibodies that block inhibitory checkpoint molecule signaling in T cells and genetically engineered T cells with specific T cell antigen receptors to boost the recognition of tumor-associated antigens. Despite the impressive clinical efficacy observed in the immunotherapy of some cancers, only a limited number of patients respond to these therapies.

Increasing evidence suggests that tumor cells can evade the potent cytotoxic T lymphocyte (CTL) responses augmented by biological immunotherapies through an immune-suppressive microenvironment, which consists of a variety of interacting cell types, proteins and pathways. Many potential therapeutic targets have recently been identified in the tumor microenvironment that may be amenable for intervention using small molecules (e.g. cytokines, suppressive metabolites, stromal factors and cell surface molecules expressed on immune suppressor cells).

Modulating the immune system or the tumor microenvironment through a small-molecule approach offers advantages that are complementary to and potentially synergistic with the use of protein and cell immunotherapies as well as conventional chemotherapy. The advantages include the capability to tackle intracellular targets, the feasibility of oral bioavailability, the potential of improved tissue penetration, and the adaptability to combination therapies. Small molecules could also serve as chemical probes to discover, characterize and validate novel mechanisms involved in anti-tumor immunity. Because of their ability to bind specific protein domains and reversibly inhibit protein-protein interactions, small molecules are particularly suitable for the investigation of the diverse mechanisms and pathways contributing to immune suppression in the tumor microenvironment.

Although small molecule libraries, either generated through combinatorial chemistry or derived from natural sources, have been extensively screened against a variety of targets in tumor cells for direct inhibition of tumor growth, they have rarely been screened against targets in immune cells responding to tumor antigens or against targets in the tumor microenvironment, providing potential for modifying immune responses to tumor. Another key challenge of using high throughput screening (HTS) approaches for the discovery of small molecule immunomodulators is the development of robust, sensitive and scalable assays to address the complexity of measuring and enhancing anti-tumor immune responses. While target-based screenings would allow rapid identification of small molecules modifying a specific protein target with defined function, phenotypic screenings could potentially be more productive in addressing the complex immune response network and in identifying agents that enhance the antitumor immune response via novel mechanisms. Follow-up hit confirmation and lead development also require assays that are carefully designed with consideration of the complexity of antitumor immunity, including interplay between cancer cells and immune and non-immune cell types in the tumor microenvironment. Finally, selection of specific tumor model systems is also a critical element for the development of anti-cancer small molecule immunomodulators, as such immunomodulators will not necessarily exert the same effects across different types of tumors. Therefore, the discovery of small molecule drugs capable of engaging the immune system to inhibit tumor growth requires innovative thinking along with enabling models and technologies, which is the emphasis of this funding opportunity.

The primary objective of this FOA is to facilitate the discovery of small molecule immunomodulators for cancer therapy. Projects focusing on immune targets amenable for small molecule intervention may span any of the following stages of drug discovery research: 1) assay development; 2) primary screen implementation; 3) hit validation; and 4) hit to lead optimization. For applications requesting support for more than one stage, with some exceptions (see below), demonstration of feasibility is needed. Applicants are expected to provide strong rationale and preliminary data to justify the stage of the discovery research and to predict the feasibility of the proposed stage of the discovery research to move on to the next stage of the drug discovery process. Areas to be considered for each stage are described below and instructions are given in Section IV.

1. Assay Development for Novel Small Molecule Immunomodulators

This FOA encourages the development of assays for immunomodulatory targets and pathways that would result in the eventual discovery and development of novel small molecules as useful drug leads for cancer immunotherapy. Projects for assay development should emphasize the design and validation of creative approaches to assay valid and relevant immune response readouts that have potential to be used for chemical probe and drug discovery for cancer therapy.

Primary assays may be target-, pathway-, or phenotype-based. Some examples of targets or pathways involved in host tumor immune responses include, but are not limited to: (i) immune checkpoint molecules that inhibit anti-tumor responses; (ii) enzymes involved in reprogrammed metabolic pathways within the tumor microenvironment that in turn modulate tumor-infiltrating immune cells; (iii)chemokine receptors on cells in the tumor microenvironment that modulate the activity of immunosuppressive lymphocytes; (iv) signal transduction pathway modulators expressed in lymphocytes and myeloid lineage cells that regulate immune responses to tumor; and (v) toll-like receptors (TLRs) involved in immune surveillance of tumors.

For phenotype-based assays, the primary assay should model anti-tumor immune response and be suitable for medium or high throughput screening. For example, the reactivation of exhausted T cells could be measured in the context of environmental cues coming from suppressor cells or their soluble suppressor products. Direct activation of exhausted T cells (e.g. by stimulating T cells through the TCR in the absence of TME suppressive factors) could also be tested. Direct inhibition of the activation and/or proliferation of immunosuppressive cells (e.g. T regulatory cells, myeloid derived suppressor cells, or tolerogenic monocytes) could also be assayed. Preference will be given to assays that are most representative of the activation of T cells in a complex suppressive tumor microenvironment.

Applicants are encouraged to collaborate with an experienced screening facility to determine the feasibility of assays for high- or medium-throughput screening (see Academic Screening Facilities Directory; Academic Drug Discovery Consortium). Additional considerations for the design and testing of a primary assay may be found in Section IV under PHS 398 Research Plan.

2. Primary Screen Implementation

Projects focusing on primary screen implementation of small molecule immunomodulators are expected to provide preliminary data demonstrating that a primary screen has been developed, fully characterized, and tested in a pilot format. In addition, primary screen implementation projects should be proposed in conjunction with assay development or hit validation (if a well-developed primary assay is already available). Applicants are encouraged to collaborate with an experienced screening facility, particularly if high throughput screening (HTS) is planned. The screening facility may provide advice such as identification and selection of commercial HTS assay reagents, and suitable HTS assay format and readout.

See Section IV (PHS 398 Research Plan) for further details on expected information prior to the Primary Screen Implementation stage.

3. Hit Validation

For validating small molecule immunomodulators obtained from primary screens, investigators may conduct advanced cheminformatics analysis and chemistry inspection to prioritize the hit series. Development of orthogonal and counter screen assays to triage the hits are expected. Applicants are encouraged to collaborate with an experienced screening facility for developing orthogonal assays to validate the screening hits and chemical improvement of the initial hits via a structure-activity relationship (SAR) study following hit validation. Investigators should verify the purity and structure of hits using a combination of analytical methods and, when necessary, re-synthesis of selected hits.

4. Hit-to-lead Optimization

For chemical optimization projects, applicants should have a validated chemical hit as the starting point. The validated hit should have the following properties: (i) elicit a reproducible response in at least two assay types, and elicit a dose-response over a hundred-fold concentration range; (ii) be analytically validated in terms of integrity and purity (e.g., use of resynthesized powder sample of high purity in the preliminary assays); (iii) demonstrate adequate potency; and (iv) possess a tractable starting point of chemical optimization with no obvious major chemical liabilities. Investigators should implement SAR assays that measure target engagement, target selectivity, and functional assays quantifying immunomodulation of the analogues. Physicochemistry, in vitro Absorption, Distribution, Metabolism and Excretion (ADME) and biophysical characterization of derived analogues are strongly encouraged for this stage. If applicable, in vivo activity assays can be proposed in appropriate animal models that adequately reflect the complexity of host immune system.

This FOA is not intended to support the following types of research projects:

• Research focused on the discovery of small molecules with primary mode of action for inhibiting tumor growth that does not involve the host immune system;
• Research that involve analysis of immunomodulatory effects of currently approved chemotherapeutic agents or well established anti-inflammatory agents (e.g. NSAIDs);
• Research focused on extensive characterization of the mode of action of a small molecule immunomodulator;
• Research focused on pre-clinical development of an advanced small molecule drug lead, such as IND-directed toxicological testing and Good Manufacturing Practices (GMP) synthesis;
• Research proposing combination of conventional chemotherapies with immunomodulatory agents (e.g. existing small molecule chemotherapeutic agents with immune checkpoint inhibitors); and
• Research projects that propose human clinical trials.

Because of the complexity and diversity of the research areas that are being encouraged by this FOA, applicants are encouraged to contact the Scientific/Research Contact, listed in Section VII, to discuss the scope of their proposed research project

See Section VIII. Other Information for award authorities and regulations.

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.

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:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o 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)

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.

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. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. 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.

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.

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

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions 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.

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:

Sundar Venkatachalam, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-7304
Fax: 240-279-7894
Email: sundarv@nih.gov

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

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.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Research Strategy: Applicants should address the following topics as they pertain to the research project proposed:

Significance: Applicants should address why the chosen target or pathway or assay is significant to immunomodulation as cancer therapy. For specified targets, published information on the biological target or pathway and any other small molecule immunomodulators for the target should be mentioned, and a rationale for doing additional screening for molecules that address the target should be delineated.

Innovation: Innovative aspects of studying the proposed target or pathway, and of the proposed assay(s) and screening scheme(s) should be highlighted.

Approach: Applicants are highly encouraged to define the scope of the proposed research project within the context of the drug discovery and development phases outlined in Section I and to propose a timeline and budget in keeping with the scope. Preliminary data demonstrating the project has completed the stage before the proposed stage(s) are required to substantiate the proposed scope. For instance, if a project for primary screen implementation through hit validation is proposed (Stages 2 and 3), preliminary data should address the topics mentioned below under Assay Development, as appropriate to the project. Detailed guidelines for the four stages are as follows:

1) Assay development for Novel Small Molecule Immunomodulators: To increase the overall likelihood of a successful assay development project, applicants are encouraged to include the following topics in the grant application:

(i) provide scientific rationale for the primary assay selection with emphasis on how this assay measures/reflects the complex of immunomodulation of tumors. For example, how does the assay model immune cell attack on human tumors, ideally, in the context of a suppressive tumor microenvironment? If available, preliminary data supporting the choice of the primary screening assay should be included;

(ii) specify the scale of the intended screening campaign for the assay (i.e. low-, moderate- or high-throughput), for a specified target or phenotype;

(iii) demonstrate reproducibility of the primary screening assay in a low-to-moderate throughput setting. Some of the factors affecting reproducibility for consideration include time of treatment, temperature and protein concentration; tolerance to the effect of DMSO at 0.1-1%; and reproducibility between plates and day-to-day experiments;

(iv) consider assay adaption and miniaturization for automated, high-throughput screening and demonstrate reproducibility and robustness. High-throughput assay reproducibility and robustness should be assessed using multiple negative and positive controls including prior art compounds and/or control conditions. Multi-dose response testing may also improve assay robustness;

(v) assay responses to positive or negative controls will also help establish feasible threshold for positive responses and reasonable signal-to-basal ratio; and

(vi) elaborate on availability of reagents and controls necessary to perform the assay development and pilot screen.

2) Primary Screen Implementation: Applicants are encouraged to include preliminary data to address the topics described above in the Assay Development section. Primary screen implementation projects should be proposed in conjunction with assay development or hit validation (if a well-developed primary assay is already available). In addition, the research scope mentioned under Screen Implementation in Section I should be considered when writing the Approach section. Applicants are expected to include:

(i) preliminary data on the primary screening assay performance as tested in a small-scale pilot screen, including a scatter plot with a Z factor above 0.5 (see Assay Development section above);

(ii) discussion of the parameters critical for screening including but not limited to: anticipated hit rate (percentage of hits); strategy and feasibility of assessing hits and prioritization method (particularly for a large number of hits); screening concentrations; reagents and materials availability; and equipment used in configuring the assay;

(iii) rationale for selecting screening libraries;

(iv) if the applicant plans to utilize diversity libraries, the underlying strategy for their construction and criteria for compound selection should be included (e.g. Lipinski Rule of Five, privileged scaffolds, PAINS filtering, diversity space, drug-like criteria). If focused libraries are to be included, the rationale for selection of the libraries (e.g. target-based, compound class, bioactivity, repurposing) should be discussed;

(v) describe procedures that will be used to ensure the quality and integrity of the screening compounds (e.g. solubility, purity, identity, storage conditions); and

(vi) If achievable, a pilot screen for target validation from a small compound library may be performed as a highly desirable validation step for translation of the assay to HTS.

If appropriate, applicants can also consider utilizing the library resources available through the NCI Developmental Therapeutics Program and NeXT (NCI Experimental Therapeutics Program).

3) Hit Validation: Hits from a primary screen may be systematically assessed using a cascade of follow-up assays to efficiently and effectively remove false positives. Post-primary screening assays may include: a) an assay that is essentially identical to the primary assay but with an orthogonal detection scheme; b) a target-minus assay; c) cytotoxicity assays; d) target selectivity assay(s); (e) mode of action assays; (f) specificity assays to distinguish biological activities of chemical entities among orthologous targets across species; and (g) target identification assays.

For projects focusing on hit validation, applicants are expected to include the following in the Approach section:

(i) description of the primary assay and screening campaign that generate the hits and preliminary characterization of hits;

(ii) a clear rationale for the chosen hit validation scheme, considering the number of hits from the primary screen, anticipated false positives inherent in the primary assay format;

(iii) availability and suitability of secondary assays and if unavailable, elaboration on secondary assay development and validation. Description of planned or existing counter screen assays including cytotoxic assays and/or specificity/selectivity assays that will be used in the triage of hits; and

(iv) plan to conduct advanced cheminformatics analysis and medicinal chemistry inspection to prioritize the hit set.

It is expected that investigators will confirm hit compounds by testing powder samples and commercially available analog compounds. If commercial analogs are available, investigators may propose preliminary SAR studies. Investigators should verify the structure of hits using a combination of analytical methods and, if possible, re-synthesis of select hits.

4) Hit-to-lead optimization: For hit-to-lead optimization projects, a cascade of in vitro assays should be in place to efficiently test analog compounds derived from validated hits. The SAR assays may include target-, pathway-, and phenotype-based assays that are relevant to immunoregulatory role of the target. The assays farther downstream may also include appropriate in vivo models that reflect the complexity of host immune responses.

Applicants are expected to include the following in the Approach section:

(i) description of the properties of validated hit series and preliminary data if available;

(ii) definition of specific criteria that a compound must meet to be considered a drug lead or chemical probe that may include target specificity profile, potency, solubility, permeability and/or other properties as appropriate;

(iii) specification of assays or methodologies to define critical components in the iterative hit-to-lead process including SAR assays, medicinal chemistry capacity, drug design strategy, in vitro ADME profiling, preliminary in vitro toxicity testing, target engagement, biophysical and physicochemical characterizations, and/or in vivo pharmacokinetic characterization as appropriate to the stage of the process;

(iv) availability of SAR assays and rationale for assay selection including the relevance of the assays to anti-cancer immunomodulation and assay validation;

(v) criteria for disqualifying a hit series for further optimization and selection of back up series; and

(vi) if achievable, exploration of mechanism of action for hits obtained from pathway- or phenotype-based screening assays.

Critical path: The application should include a flow diagram to outline all critical steps in sequential and/or parallel manners with appropriate benchmarks and timelines, including but not limited to the primary assay to be implemented or previously implemented, alternative assay or approach (e.g., computational docking) to ensure success of the screening, hit selection criteria, cheminformatic analysis, chemical tractability assessment, all follow-up assays to validate screening hits, study of SAR, and assay responsibilities of each party involved in the project.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Appendix:

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

Form only available in FORMS-E application packages for use with due dates on or after January 25, 2018.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information
All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study: All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review, NIH. Applications that are incomplete or non-compliant will not be reviewed.

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

Applicants are required to follow the instructions for post-submission materials, as described in the policy.

Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Specific to this FOA: Are the chosen targets or pathways significant and relevant to immunotherapy of cancer in human patients? Do citations and/or data provided demonstrate validity of the target or pathway for immunotherapy? If successful, how will this study advance the field of cancer immunotherapy?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Specific to this FOA: Are the investigators knowledgeable and experienced about immunotherapy of cancer in the proposed areas of research: 1) biological targets and pathways; 2) the process of screening compound libraries, at the scale and format proposed (e.g. moderate, high-throughput, high content); 3) the conduct of proposed biological screening assays?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Specific for this FOA: Is the proposed research likely to discover novel small molecule immunomodulators for cancer therapy? Are the assay development or screening projects creative and novel to facilitate the discovery of small molecules for cancer immunotherapy?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

Specific to this FOA: Do proposed assays or screening schemes accurately test for the ability of small molecules to modulate an anti-tumor immune response? Are subsequent or orthogonal assays described? Are known immunomodulators included as controls in the proposed assays or screening schemes? How will the proposed assays or screening schemes enhance the success of finding small molecule immunomodulators relevant for cancer therapy? Does the Approach section of the application cover the topics delineated in Section IV, PHS398 Research Plan, as appropriate to the scale and stage of the project? If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Specific to this FOA: Are the collaborative teams and processes sufficiently feasible to complete the proposed research?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Not applicable.

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by Center for Scientific Review, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

Sundar Venkatachalam, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-7304
Email: sundarv@nih.gov

Thomas Peterson, Ph.D.
Center for Scientific Review (CSR)
Telephone:301-408-9694
Email: petersonjt@mail.nih.gov

Shane Woodward
National Cancer Institute (NCI)
Telephone: 240-276-6303
Email: Woodwars@mail.nih.gov

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.