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 301/435-0714.  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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