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 encourage submissions of applications that propose early stage studies of novel microbial-based cancer therapies to treat cancers that are inadequately addressed by conventional cancer therapies, or their use as delivery vehicles for cancer treatment to complement or synergize with current therapies.

Examples include, but are not limited to poorly vascularized, hypoxic, solid tumors, dormant or slowly dividing cells resistant to current interventions, and brain tumors. Solutions may utilize bacteria, archaebacteria, bacteriophages and other non-virus microorganisms, Oncolytic virus-based cancer therapies are not supported by this FOA.

This initiative will support research projects on the underlying mechanisms of the complex interactions between microorganisms, tumor, and immune system, and their use as delivery vehicles for cancer treatment to complement or synergize with current therapies. This FOA will accept basic, mechanistic and/or preclinical studies in cell culture and animal models in accordance with the state of the science. Applicants responding to this FOA are encouraged to address both the microbial and the tumor aspects of microbial-based cancer therapy.

Applicants are encouraged to propose basic or applied research that require both microbiology and cancer research expertise. The proposed projects may involve considerable risk and should be aimed at producing breakthrough pre-clinical development of novel microbial-based anticancer therapeutic agents, or study the biology involved in the interplay of microbe-tumor-immune system. An application may propose design-directed, developmental, discovery-driven, or hypothesis-driven research, and should apply an integrative approach to increase our understanding of biological, or translational aspects of microbial-based anticancer therapeutic agents.

This FOA utilizes the R21 award mechanism for exploratory/developmental projects. The R21 mechanism is suitable for projects that are at their inception, conceptual, or idea-based phase where proof-of-principle of the proposed methodology has not been established with the aim to demonstrate core functional capabilities of the proposed approach. In this phase, technical feasibility of the proposed technology or methodology should not yet have been established. Preliminary data are not required but are accepted if available. If preliminary data are sufficient to suggest the feasibility of the approach is established, then consideration should be given to submitting to the companion R01 FOA PAR-19-193.

Exploratory/Developmental Research Grant applications should be distinct from those supported through the traditional R01 activity, which are generally more advanced, longer-term systematic investigations supported by extensive preliminary data and designed to increase knowledge in an established area. Studies submitted to this R21 FOA should break new ground or take previous discoveries in new directions. R21 applications should have well-defined goals with potential for future development.

This FOA runs in parallel with a companion FOA of similar scientific scope that invites projects ready for more advanced development, optimization, and validation work, PAR-19-193 which uses the Research Project (Grant R01) activity. It is the appropriate FOA for more mature applications that include preliminary data that demonstrate the feasibility of the specific aims.

Clinical observations as early as the 1880s suggested that tumor regression coincided with natural bacterial infections and led to the first use of microbes as antitumor agents. With development of more effective and better understood radiation therapy, and later, chemotherapy, this approach was largely abandoned in the 1930s, and microbial-based therapy has remained elusive. However, standard cancer therapies have several major disadvantages, including rarity of complete and sustained remissions of most solid tumors, development of resistance, relapse, and frequent failure to clear micrometastases.

There is a clinical need for new cancer therapies that will be effective under conditions where conventional cancer therapies are inadequate, such as poorly vascularized, hypoxic, solid tumors; dormant or slowly dividing cells resistant to treatment; or islands of microinvasive tumor cells buried within normal tissues. Among the most attractive characteristics of microbial agents for anticancer therapies are their capacity for tumor-specific targeting as well as ease of genetic manipulation to regulate selective cytotoxicity.

Recent research advancements in bacterial anti-cancer activities

A recent NCI Conference on Challenges and Opportunities of Microbial Anti-Cancer Therapy and Prevention summarized the potential of microbial anti-cancer based therapy, current status, and research advances and approaches to understanding microbial pathogenesis, host-microbial interactions, immuno oncology, mechanisms of activation of immune systems, tumor destruction, and other future approaches. These insights plus recent advances in genetic engineering and gene editing raise the possibility of deploying new concepts and strategies for microbial therapy developments to mitigate or solve unmet clinical needs. Microbes may be employed to augment multiple antitumor mechanisms, including selective tumor cell infection, killing and induction of systemic antitumor immunity. Microorganisms potentially could stimulate long lasting anti-tumor immune responses and broaden tumor targeting. Most cancer therapeutics are costly, not widely available, nor accessible to most patients in low and middle-income countries (LMIC). Microbial-based therapy has unique capacity to self-regenerate, which may offer new therapeutic opportunities for cancer patients worldwide, including LMIC that account for most of the world population.

Obligate or facultative anaerobic bacteria such as Bifidobacterium, Clostridium, Salmonella, or Escherichia coli can specifically colonize and proliferate inside anaerobic tumor tissues, kill tumor cells or activate anti-tumor immunity. Multiple studies have demonstrated that anaerobic microorganisms have the capacity to grow selectively in hypoxic and anaerobic areas of solid tumors often not accessible to drugs. While many anaerobic bacteria are facultative anaerobes (capable of infecting non-tumor tissue), molecular manipulation can create attenuated, strictly anaerobic Salmonella and Clostridium novyi able to infect only hypoxic tumor tissues because they are non-viable outside hypoxic tumor micro-environments.

For example:

• Clostridium novyi spores are being used in a Phase I clinical trial to treat patients with solid tumors.
• Salmonella have the potential to activate dormant cells normally resistant to treatment, enabling treatment as activated cells with conventional therapy.
• A Trojan Horse strategy that uses attenuated Salmonella expressing aquatic flagellin as a foreign antigen can activate the immune system against tumor cells infected with Salmonella.
• Bifidobacterium and several other commensal bacteria have been shown to enhance the efficacy of checkpoint inhibitors in both mouse and human.
• Listeria monocytogenes bacteria have been engineered to deliver recombinantly expressed tumor-specific antigens that can activate tumor-specific cytolytic T lymphocytes (CTL) with the goal of inducing long-lasting tumor-specific cytolytic T lymphocyte responses.

While recent research demonstrates the potential of microbial-based cancer therapy, more research is needed to realize this potential and bring this novel class of therapies to the clinic, especially for conditions where conventional cancer therapies are inadequate.

The complex nature of interactions between the microbe, tumor, and immune system requires both microbiological and cancer expertise to understand these systems and develop innovative approaches for cancer therapy. This initiative offers competitive support of studies to understand microbe-tumor interactions necessary to develop and deliver new cancer therapies for clinical needs for which conventional cancer therapies are inadequate.

Applicants responding to this FOA are encouraged to address both the microbial and the tumor aspects of microbial-based cancer therapy. Research topics supported by this FOA may include, but are not limited to:

• Microbe-tumor interactions;
• Novel microbial species that might have therapeutic potential;
• Novel cancer targeting approaches;
• Approaches for targeting or treating poorly vascularized hypoxic solid tumors or islands of microinvasive tumor cells buried within normal tissue;
• Activation of anti-tumor immunity (including expressing foreign proteins on the surface of the tumor cell to induce a strong immune response, developing long lasting immunity, overcoming immune suppression, etc.);
• Tumor cell inactivation (including colonization, disrupting cell function, activation of cell death programs etc.);
• Activation of dormant tumor cells;
• Novel drug delivery approaches;
• Preclinical research on microbial based cancer therapies aimed to provide new cancer therapy options for cancers prevalent in low to middle income countries, which are compatible with available local medical/health infrastructure.

Projects advanced beyond the exploratory stage should be submitted to either the companion R01 FOA PAR-19-193 or to the Bioengineering Research Grant FOA PAR-18-206 or to the Parent NIH R01 FOAs PA-18-484 and PA-18-345.

Investigators are expected to conduct cutting-edge research within the scope of the FOA (see above) and aimed at advancing pre-clinical development of novel microbial-based anticancer therapeutic agents, or to study the complex biology involved in the interplay of microbe-tumor-immune system interactions. Applicants responding to this FOA are expected to address both the microbial and the tumor aspects of microbial cancer therapy. The goal is to conduct research that could have a major impact on cancer therapy and related research.

Potential areas of research may include, but are not limited to:

• Mechanisms of tumor-microbes-host interactions, such as tumor-specific targeting, microbial and tumor cell signaling, interaction with the immune system against tumors, microbial-specific tumor cell lysis and other basic aspects of microbial-based cancer therapy.
• Natural or engineered non-pathogenic microbes with therapeutic potential to selectively infect and treat cancers of various organs, solid tumors, metastasis, microinvasion, hypoxic or poorly vascularized tissues not accessible to chemical or monoclonal antibody drugs;
• Novel microbes, e.g., soil, aquatic and plants bacteria, archaebacteria, bacteriophages and other non-virus microorganisms as potential therapeutics to overcome the issues of microbial pathogenicity and clearance by the immune system;
• Targeting specificity for primary and metastatic tumors, hypoxic tissues, poorly vascularized tissues, neovascularization or slowly dividing/dormant cancer cells
• Microbial payload delivery of therapies, e.g., anti-cancer drugs, radiotherapy, other tumor relevant payloads.
• Microbial induction of specific antitumor immunity for primary and metastatic tumors including immune engagement, more robust tumor antigen presentation, immune-stimulatory constructs such as trojan horse delivery of novel antigen expressions to overcome immune suppression.
• Long lasting approaches to anti-cancer immunity, such as surface expression of foreign proteins to induce a strong response or overcome immune suppression.
• Tumor cell inactivation, such as colonization, cell function disruption, programmed cell death activation;
• Approaches to balance among microbe-initiated immune stimulation, cancer neoantigen presentation, therapeutic microbes' clearance, and microbial pathogenicity for more nearly optimal safety and efficacy of microbial-based anti-cancer agents;
• Strategies to prevent recurrence, such as prolonging microbial therapy efficacy with libraries of foreign antigens to re-stimulate the immune system after loss of initial antigen efficacy;
• Companion diagnostics to predict antitumor responses or improve microbial selections for patient treatment;
• Basic biology underlying microbe-tumor interactions such as invasion, lysis, antigen presentation, and other microbe-initiated tumor cell-death and immune responses;
• Preclinical research on new microbial based cancer therapies suitable for low resource settings, especially for cancers prevalent in LMIC and compatible with local medical/health infrastructure.

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 from 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) 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.
• o 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 to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. 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).

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace 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, 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.

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:

Avi Rasooly, PhD

National Cancer Institute (NCI)
Telephone: 301-276-6196
Fax: 240 276-7888
Email: rasoolya@mail.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:

Specific Aims: Include a brief sub-section "Statement of Potential Impact" describing the expected potential of the proposed approach to transform cancer therapy and clinical practice. The following questions should be addressed with this statement.

• How the new approach provided by the proposed research is potentially transformative and why may it be expected to have high impact on cancer therapy (i.e., describe the potentially transformative outcomes that might be realized should this approach succeed).
• If applicable, describe how will the proposed approach overcome limitations for currently available therapies or alternative approaches? (i.e., provide evidence to support the claim of effectiveness beyond currently available therapies).

Research Strategy:

The proposed investigative team are highly encouraged to include expertise in microbiology and cancer research. R21 applications may include preliminary data demonstrating the feasibility of the specific aims and data that demonstrates the capability of the investigators to conduct the proposed research may be included. Consequently, determinations of merit and feasibility will rely instead on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge and understanding. Applicants are encouraged to provide conceptual and technical feasibility for the proposed work through previous experience, literature citations, data from other sources, analytical and computational models. Since these grant applications could involve considerable risk such that the proposed work may not be successful, applicants are encouraged to clearly explain the significance of the proposed work, to allow the reviewers to determine whether the potential impact outweighs these risks.

Applicants are encouraged to address the following:

• Innovative, cancer-relevant approach with focus on initial development and demonstration of a novel therapy or targeting capability in a biologically relevant system: Describe metrics of success that would verify the technical capability proposed and its anticipated long-term use to advance cancer therapy, research and/or clinical practice. The proposed approach may target an unmet need in basic or clinical cancer research or may have potential for broad use in a field of cancer research. If the application involves adaptation of an existing approach, clearly describe the exploratory nature of the feasibility to be demonstrated to justify use of the exploratory R21 mechanism.
• Substantial Improvement, New Capabilities: All proposed research should offer the potential for substantial improvements over conventional approaches and/or add new therapy capabilities not provided by current therapies.
• Transformative Potential: Describe the unmet therapeutic need targeted by the approach or describe its anticipated use for laboratory research and/or in clinical settings. Claims for potential impact are expected to align with specific objective performance targets, also known as milestones (next bullet).
• Provide a Gantt chart of aims and time line for targets to be achieved.
• Objective Performance Targets (Milestones): Objective performance targets can help decisions on whether or not the R21 demonstration will justify support for further development (e.g., a future R01 project). Include objectively assessable measures as performance targets. They should be carefully selected, precisely defined, and clearly address the expected advantages of the proposed approach relative to existing technologies/approaches. Appropriate biological milestones require that the underlying experimental results meet appropriate assays and/or statistical tests for a reasonable level of certainty that the targeted level of performance has been achieved.
• Specific aims are not milestones. They describe the goals and intended path of the research. Performance targets provide the means for objectively assessing progress against those aims and substantiate the potential impact the approach might have on cancer research or clinical care. The project will be evaluated for success based on completion of the aims and comparison of results with the objective performance targets (milestones) proposed. For some specific aims, a single milestone may suffice. For others, multiple milestones may be more appropriate.

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:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) 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 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

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).

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.

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 How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. 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 are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Only the review criteria described below will be considered in the review process.

Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

The R21 exploratory/developmental grant supports investigation of novel scientific ideas or new model systems, tools, or therapeutics that have the potential for significant impact on biomedical or biobehavioral research.

An R21 grant application need not have extensive background material or preliminary information. Accordingly, reviewers will emphasize the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications; however, they may be included if available.

In the context of this FOA, innovation encompasses approaches to address well-defined, unmet needs of microbial based cancer therapy and may include the development of new methods, ideas, or technologies; early steps along the path toward delivery of a new capability or method for cancer therapy; and the integration of existing components in an unproven format.

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 the prior research that serves as the key support for the proposed project rigorous? 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 for this FOA: Does the application address a problem where conventional cancer therapies are inadequate, such as metastatic tumors, poorly vascularized, hypoxic, solid tumors, dormant or slowly dividing cells resistant to current interventions, islands of microinvasive tumor cells buried within normal tissues and brain tumors?

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 for this FOA: Does the investigative team include expertise in microbiology and cancer research, or clinical care delivery?

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: Does the application propose an early phase demonstration of feasibility and exploratory development with promise for future delivery of a mitigation or solution to a problem in basic, applied, preclinical or clinical research or clinical care delivery?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed 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 for this FOA: Does the application present a coherent plan to test the feasibility and/or accomplish exploratory development suitable for establishing promise of a mitigation or solution to a problem in basic, applied, preclinical or clinical research, or clinical care delivery? Are appropriate performance specifications described? For each stage of validation proposed, will the data acquisition support progression to the next stage of development? In light that there may be limited preliminary data to demonstrate the feasibility of the aims of the project, are there a robust conceptual framework and justification for the proposed work?

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 individuals of all ages (including children and older adults), 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?

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 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 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.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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 individuals of all ages (including children and older adults) 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

Not Applicable

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 submitted in response to this FOA. 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 https://www.hhs.gov/civil-rights/for-individuals/section-1557/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 https://www.hhs.gov/civil-rights/for-individuals/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, application errors and warnings, documenting system problems that threaten submission by the due date, and 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)

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

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Avi Rasooly, PhD
National Cancer Institute (NCI)
Telephone: 301-240-276-6196
Email: rasoolya@mail.nih.gov

(Cancer Therapy Applications)

Phil Daschner, PhD
National Cancer Institute (NCI)
Telephone: 240-276-6227
Email: daschnep@mail.nih.gov

(Cancer Biology and Basic Research)

Luis Alejandro Salicrup, PhD
National Cancer Institute (NCI)
Telephone: 240-276-5799
Email: luis.salicrup@nih.gov

(Global Health)

Min He, PhD
National Cancer Institute (NCI)
Telephone: 240-276-5928
Email: min.he@nih.gov

(Research Questions)

Miguel Ossandon, PhD
National Cancer Institute (NCI)
Telephone: 240-276-5714
Email: ossandonm@mail.nih.gov

(Companion Diagnostics for Microbial Based Cancer Therapy)

Houston Baker, PhD
National Cancer Institute (NCI)
Telephone: 240-276-5908
Email: bakerhou@mail.nih.gov

(General Questions)

Chiayeng Wang, Ph.D.
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-827-4647
Email: chiayeng.wang@nih.gov

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

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

Diana Rutberg, M.B.A.
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4798
E-mail: rutbergd@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.