Full Text PA-95-064 IMMUNOLOGIC RECOGNITION AND CONTROL OF TUMORS NIH GUIDE, Volume 24, Number 19, May 26, 1995 PA NUMBER: PA-95-064 P.T. 34 Keywords: Cancer/Carcinogenesis Immunology Vaccine National Cancer Institute PURPOSE The purpose of this initiative is to encourage applications that will provide for the continued expansion of a basic research foundation for ongoing efforts to develop cancer vaccines. The field of immunology continues to develop at a rapid rate. Emerging concepts of antigen recognition and cellular effector mechanisms have forced a reexamination of the theoretical bases of much of cancer immunology and have opened up major new research opportunities. These new concepts also provide new reasons to believe that vaccine approaches to the treatment or prevention of cancer may be of substantial benefit. As a result, a new generation of candidate vaccines for cancer has emerged and joined earlier cancer vaccines in clinical trials. While this represents important progress, there is still a great deal that is not known about the immune response to cancer. The number of promising targets for vaccine recognition remains limited and the factors that determine the quality and magnitude of the immune response to cancer are poorly understood. The goal of this Program Announcement is to promote investigator-initiated applications to study the basic mechanisms of antigen recognition, cytotoxicity and immune regulation that are critical to the immunotherapy of cancer. To be responsive to the Program Announcement, studies must involve tumor cells or tumor antigens. Basic studies of the immune response to non-tumor antigens fall within the interests of the National Institute of Allergy and Infectious Diseases. This represents a continuation of interest in this area, begun with the issuance of RFA CA-91-26 "Immunologic Recognition and Control of Cancer: A Basis for Cancer Vaccines" in 1991. The results of these studies will serve as the basis for developing future generations of cancer vaccines, although vaccine development, per se, is beyond the scope of this initiative. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This PA, Immunologic Recognition and Control of Tumors, is related to the priority area of Cancer. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00474-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (Telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign and domestic, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments and eligible agencies of the Federal government. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT Grants will be awarded as investigator-initiated research project grants (R01) and FIRST (R29) awards. FIRST Awards and R01s from new investigators are particularly encouraged. RESEARCH OBJECTIVES Tumor-rejection antigens were originally defined operationally by their ability to immunize against subsequent tumor challenge. Early attempts at vaccination against cancer were empirically guided, using modified or unmodified tumor cells or relatively crude fractions derived from them. The advent of hybridoma technology provided an impetus for the molecular definition of tumor-rejection antigens. These studies were very successful in identifying important differentiation antigens. They produced some important diagnostic reagents and still have treatment potential through immunotoxin and radioconjugate approaches. However, it became clear that approaches to the stimulation of active immunity against tumors required a broader approach, including attempts to stimulate the T-cell limb of the immune system. Current approaches to the development of cancer vaccines focus most commonly on the development of a specific T-cell response to the tumor. While the T cell may not be the ultimate effector of tumor destruction, it is viewed as the critical determinant of specificity and coordinator of subsequent cell-cell interactions. This focus became possible with the elucidation of the mechanisms of T-cell antigen recognition. The outline of these mechanisms has been clear for many years now, but critical details continue to be added, offering an ever-expanding number of points at which intervention might be expected to augment the immune response. The identification of tumor antigens that can be recognized by either CD4+ (helper/inducer) or CD8+ (cytotoxic/suppressor) T cells remains critical for mechanistic studies of antitumor responses and for many vaccine strategies. Important successes in antigen identification in some tumor types, especially melanoma, need to be expanded to other common human tumors. It is equally important to find ways of increasing the effectiveness of the immune response subsequent to antigen recognition by T cells. It is clear that the development of an effective immune response depends on proper communication among numerous immune cell subsets, mediated by local secretion of cytokines. An increasing amount is known about the cell-cell interactions and intracellular signaling pathways that control cellular activation and cytokine secretion, but much more information is required before it will be possible to predict what kinds of intervention will have beneficial effects in vivo. It is important to recognize that changes in the pattern of immune cells attracted to the tumor microenvironment and in the cytokines produced can either augment or depress the effector arms of the immune response. Certain patterns of recognition lead to tolerance, a long-lived paralysis of the immune system. New approaches are needed to prevent normal regulatory mechanisms (or tumor-derived substances) from curtailing an antitumor response before it destroys the tumor. Recent discoveries have provided a firm theoretical foundation for a new generation of studies in cancer immunology aimed at the development of vaccines to treat or prevent cancer. The emphasis is on specific recognition of tumors by T cells and the identification of cellular interactions and/or patterns of cytokine secretion that can translate recognition into an effective, cytotoxic response to the tumor. The techniques of molecular biology provide powerful tools with which to accomplish these new goals. There have been enough applications of new concepts and new methodology to cancer immunology to demonstrate continued promise. What is needed now is continued, high-quality research, involving not only established investigators in tumor immunology but also scientists who have been trained in the latest immunologic concepts and methods, but who may not appreciate the opportunities that tumor systems have to offer. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 9/91) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 6701 Rockledge Drive, Room 3032, MSC 7762, Bethesda, MD 20892-7762, telephone 301/710-0267. The title and number of the program announcement must be typed in Section 2a on the face page of the application. Applications for the FIRST Award (R29) must include at least three sealed letters of reference attached to the face page of the original application. FIRST Award (R29) applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. The completed original application and five legible copies must be sent or delivered to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) REVIEW CONSIDERATIONS Applications that are complete and responsive to the program announcement will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by an appropriate National Advisory Council or Board. Review Criteria o scientific, technical, or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research; o availability of the resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research; The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other approved applications. The following will be considered in making funding decisions: Quality of the proposed project as determined by peer review, availability of funds, and program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: John A. Sogn, Ph.D. Division of Cancer Biology, Diagnosis, and Centers National Cancer Institute Executive Plaza North, Room 501 6130 Executive Boulevard MSC 7381 Bethesda, MD 20892-7381 Telephone: (301) 496-7815 FAX: (301) 496-8656 Email: js150X@NIH.gov Direct inquiries regarding fiscal matters to: Ms. Sara Stone Grants Management Branch National Cancer Institute Executive Plaza South, Room 243 Bethesda, MD 20892 Telephone: (301) 4976-7800 x266 Email: StoneS@GAB.NCI.NIH.gov AUTHORITY AND REGULATIONS This program is described in the catalog of Federal Domestic Assistance No. 93.396. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routing education, library, day care, health care or early childhood development services are provided to children. This is consistent with the phs mission to protect and advance the physical and mental health of the american people. .
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