Subject: NIH GUIDE - RFA CA-91-28 - V20(33) 09/06/91
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Mon, 09 Sep 91 09:44 EST

Hi Paul,
This is #7 of 11.  Please post this one to the NIH Listserver
as  RFACA-91-28.910906.
More to follow. Thank,  M. G. Broaddus
 ---------------------------- Text of forwarded message -----------------------
 
$$XID RFA CA9128 CA-91-28 P1O1 *****************************************
 
REQUEST FOR APPLICATIONS
 
RFA:  CA-91-28
 
VACCINES FOR HUMAN CANCERS OF VIRAL ETIOLOGY
 
P.T. 34; K.W. 0740075, 0715035, 1002045, 0785140
 
National Cancer Institute
 
Letter of Intent Receipt Date:  October 11, 1991
Application Receipt Date:  December 11, 1991
 
INTRODUCTION
 
Cancer continues to be a leading cause of death, and it has been
estimated that approximately 500,000 people will die of cancer in the
United States in 1991.  Vaccines, which could either prevent the initial
development of cancer or function therapeutically to prevent the spread
or recurrence of a tumor that has been treated, should have a
significant impact in reducing cancer morbidity and mortality.
 
Cancer is a diverse set of diseases, the etiology of which is unknown in
most cases.  There is a traditional attitude in medicine that cancer
vaccines for either primary or secondary prevention pose insurmountable
problems.  However, both Jenner and Pasteur were able to develop
appropriate and effective vaccines for smallpox and rabies,
respectively, at a time when neither of the etiological agents had been
isolated or described in detail.  In addition, the existence of what
promises to be an effective vaccine for primary hepatocellular carcinoma
(PHC) associated with chronic infection of hepatitis B virus argues that
other cancer vaccines may also be possible, even for the majority of
cancers for which the etiology is unknown.
 
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 Request for
Applications (RFA), Vaccines for Human Cancers of Viral Etiology, 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 "Healthy People 2000" (Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, D.C. 20402-9325 (telephone 202-783-3238).
 
The present RFA is for a single competition with a deadline of December
11, 1991, for receipt of applications and October 11, 1991, for receipt
of optional letters of intent.  Applications must be prepared and
submitted in accordance with the aims and requirements described in the
RFA.
 
BACKGROUND INFORMATION
 
The possibility of developing cancer vaccines is complicated by the fact
that cancer is a diverse set of diseases, some of which are associated
with specific etiological agents, such as viruses, and others of still
unknown etiology.  The conventional vaccine approach depends on the
ability to identify specific antigens associated with a particular
disease entity or neoplasia and to elicit an appropriate protective host
immune response to those antigens.  Thus, for those cancers in which a
viral disease plays a major role, a conventional vaccine approach may be
feasible.  Such a vaccine must be designed to prevent initial virus
infection, and could additionally prevent the cancers associated later
in life with that virus.  Alternatively, a therapeutic vaccine approach
may be used in which tumor antigens and/or modified cellular substances
appearing during the neoplastic process are reintroduced into the
patient to stimulate anti-tumor activity and prevent the spread or
recurrence of the tumor.
 
Before any cancer vaccine studies can be carried out, a number of basic
issues need to be addressed, including identification of relevant viral
and/or tumor antigens; determination of the parameters needed for these
antigens to achieve effective immunogenicity; and determination of the
immunological effector mechanism(s) responsible for induction by a
vaccine of strong resistance against growth and metastasis of tumors.
In response to an expression of Congressional interest on the topic of
cancer vaccines, advances in the scientific state-of-the-art, and the
need to address these issues in a systematic and timely way, a National
Cancer Institute Workshop on Cancer Vaccines was held in Bethesda, MD,
on October 29-30, 1990.  The purpose of the workshop was to address the
issues relevant to the development of cancer vaccines and to provide the
NCI with suggestions about directions for future research and
development efforts.
 
From remarks and discussions of participants at the consensus
conference, as well as post-conference communications to NCI staff, it
was apparent that a sufficient base of knowledge and technical skill
exists to mandate a vigorous and broadly based cancer vaccine program at
the NCI.  The participants recommended that the NCI undertake the
following additional or expanded scientific activities in biological
carcinogenesis.  Increased emphasis must be placed on basic and applied
studies on the identification of viral or viral-induced antigens that
elicit protective immunity and that form the basis for vaccine
preparation.  Animal models need to be developed to determine immune
response to viral-induced tumors and to test the safety and efficacy of
proposed vaccines.  Research must also be supported to develop prototype
therapeutic vaccines for viruses whose malignant sequelae occur as the
result of chronic infection.  In addition, selected studies must be
carried out on newly discovered agents that have a strong potential for
being involved in the etiology of viral-induced malignancies.  Research
is needed for studies on the human papillomaviruses (HPVs), which are
associated with human cervical cancer, for studies on Epstein-Barr
viruses (EBV), which have been associated with Hodgkin's and
non-Hodgkin's lymphomas, particularly in immunosuppressed individuals,
and for the newly identified hepatitis C virus (HCV) and the
consideration of its role in the etiology of liver cancer.
 
RESEARCH GOALS AND SCOPE
 
The overall thrust of this RFA is to stimulate basic and applied
research leading to the development of vaccines for human cancers of
known, or strongly suspected, viral etiology, including cancers
associated with HPVs, EBV, and HCV.  Identification of protective viral
or viral-induced antigens that form the basis for vaccine preparation,
development of animal models to determine host immune response to
viral-induced tumors and to test the safety and efficacy of proposed
vaccines, and the development of prototype therapeutic vaccines for
viruses for which malignant sequelae occur as the result of chronic
infection are all encouraged.  Applications will not be accepted that
propose research on the hepatitis B virus, the human T-cell lymphotropic
viruses (HTLV-1, HTLV-2), human immunodeficiency virus (HIV-1, HIV-2),
and animal models for any of these latter agents.
 
Development of a vaccine for HPVs is made more difficult by the fact
that there are no simple infectivity assays, no clear indication of the
presence of a neutralizing antibody for HPV-associated carcinoma in
humans, and no suitable animal model or tissue culture system for viral
propagation.  Examples of research on HPVs would include:  (1)
determining whether polyvalent vaccines are required for prevention of
cancer induction by multiple HPV types; (2) identification of the
relevant immunological determinants for cancer vaccines and defining if
they are virion proteins, (3) developing other ways of expressing viral
proteins since in vitro replication of the virus is presently
impossible; (4) determination of the importance of the immune response
to nonstructural viral proteins in either mediating resistance to
progression to cancer or in mediating regression of pre-cancerous
lesions; (5) development of animal models of infection and oncogenesis
and development of bioassays for infectious virus; (6) development of
immune correlates for resistance to progression of papillomavirus
infection to cervical cancer.  The Program Director for these
applications will be Dr. Tom Nightingale, telephone (301) 496-1953.
 
EBV has been associated with Burkitt's lymphoma, nasopharyngeal
carcinoma, B-cell lymphoproliferative diseases in immunodeficient
individuals, and several other malignancies, as well as with infectious
mononucleosis.  B-cell lymphomas in immunocompromised individuals may
represent the result of latent infection, a stage where few EBV genes
are expressed but lymphocytes are altered and can proliferate
indefinitely.  EBV appears to play a variable role in a number of
malignancies.  Examples of research objectives for EBV may include the
following:  (1) studies of the pathogenesis of EBV-induced lymphomas in
the severe combined immunodeficiency (SCID) mouse, and the use of immune
reconstitution by selected human lymphocyte populations to control the
lymphomas; (2) development and assessment of EB viral mutants and their
use as inactivated vaccines for cancer; (3) development and assessment
of glycoprotein cancer vaccines as purified components or incorporated
into replicating viruses; (4) studies of the association of EBV with
various malignancies, particularly the incidence and importance of
B-cell malignancy in immunodeficient patients and the relationship
between EBV and Hodgkin's lymphoma; and (5) studies of the immune
mechanisms that control the proliferation of transformed B-cells in
EBV-infected individuals.  The Program Director for these applications
will be Dr. Gretchen Hascall, telephone (301) 496-4533.
 
The term "non-A, non-B hepatitis virus" (NANBH) describes viral
hepatitis that occurs in the absence of serologic markers for known
hepatotropic agents such as hepatitis A virus (HAV) or hepatitis B virus
(HBV).  A major cause of NANBH has recently been designated HCV.  HCV
causes an acute hepatitis that is somewhat milder than HBV-induced
disease; however, it has been estimated that at least half of the NANBH
infections result in chronic hepatitis, which in turn results in
cirrhosis in approximately 20 percent of these cases.  Chronicity and
cirrhosis carry increased risk of PHC.  HCV is of particular
significance in this country since up to 10 percent of transfusions in
the U. S. are thought to result in hepatitis and more than 90 percent of
the transfusion-associated hepatitis in the United States is associated
with HCV.  Examples of research objectives for HCV may include:  (1)
development and/or use of sensitive and specific assays for blood-borne
HCV to determine the etiologic role of this agent in PHC; (2) studies of
pathogenesis of HCV infections and determinants of oncogenesis; (3)
development of animal models for HCV infection/oncogenesis; (4)
identification of protective HCV epitopes that could lead to development
of vaccines; (5) determination, in transgenic animals, of the oncogenic
potential of specific viral gene products; and (6) determination of the
possible role of cellular oncogenes or anti-oncogenes in HCV-induced
PHC.  The Program Director for these applications will be Dr. John S.
Cole, III, telephone (301) 496-1718.
 
SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS
 
NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical
research grants and cooperative agreements will be required to include
minorities and women in study populations so that research findings can
be of benefit to all persons at risk of the disease, disorder or
condition under study; special emphasis should be placed on the need for
inclusion of minorities and women in studies of diseases, disorders and
conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale should be provided.
 
The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues should be addressed in developing a research design
and sample size appropriate for the scientific objectives of the study.
This information should be included in the form PHS 398 in Section 2,
A-D of the Research Plan AND summarized in Section 2, E, Human Subjects.
Applicants/offerors are urged to assess carefully the feasibility of
including the broadest possible representation of minority groups.
However, NIH recognizes that it may not be feasible or appropriate in
all research projects to include representation of the full array of
United States racial/ethnic minority populations (i.e., Native Americans
(including American Indians or Alaskan Natives), Asian/Pacific
Islanders, Blacks, Hispanics).
 
The rationale for studies on single minority population groups should be
provided.
 
For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology, prevention
(and preventive strategies), diagnosis, or treatment of diseases,
disorders or conditions, including but limited to clinical trials.
 
The usual NIH policies concerning research on human subjects also apply.
Basic research or clinical studies in which human tissues cannot be
identified or linked to individuals are excluded.  However, every effort
should be made to include human tissues from women and racial/ethnic
minorities when it is important to apply the results of the study
broadly, and this should be addressed by applicants.
 
For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.
 
If the required information is not contained within the application, the
application will be returned.
 
Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the selected
study population is inadequate, it will be considered a scientific
weakness or deficiency in the study design and will be reflected in
assigning the priority score to the application.
 
All applications for clinical research submitted to NIH are required to
address these policies.  NIH funding components will not award grants or
cooperative agreements that do not comply with these policies.
 
MECHANISM OF SUPPORT
 
Support of this program will be through the National Institutes of
Health (NIH) grant-in-aid (RO1).  Applicants will be responsible for the
planning, direction, and execution of the proposed project.  Except as
otherwise stated in this RFA, awards will be administered under PHS
grants policy as stated in the Public Health Service Grants Policy
Statement, DHHS Publication No. (OASH) 90-50,000, revised October 1,
1990.
 
This RFA is a one-time solicitation.  Generally, future unsolicited
competitive continuation applications will compete with all
investigator-initiated applications and be reviewed by the Division of
Research Grants (DRG).  However, should the NCI determine that there is
a sufficient continuing program need, a request for competitive
continuation applications will be announced.  Only recipients of awards
under this RFA would be eligible to apply.
 
Approximately $2,000,000 in total costs per year for four years will be
committed to specifically fund applications submitted in response to
this RFA.  It is anticipated that eight to ten awards will be made.
This funding level is dependent on the receipt of a sufficient number of
applications of high scientific merit.  The total project period for
applications submitted in response to the present RFA may not exceed
four years.  The earliest feasible start date for the initial awards
will be July 1992.  Although this program is provided for in the
financial plans of the National Cancer Institute (NCI), the award of
grants pursuant to this RFA is also contingent upon the availability of
funds for this purpose.
 
SPECIAL REQUIREMENTS
None
 
ELIGIBILITY REQUIREMENTS
 
Non-profit and for-profit organizations and institutions, governments
and their agencies are eligible to apply.  Foreign institutions are also
eligible.
 
REVIEW PROCEDURES AND CRITERIA
 
REVIEW PROCEDURES
 
Upon receipt, applications will initially be reviewed by the DRG for
completeness.  Incomplete applications will be returned to the applicant
without further consideration.  Evaluation for responsiveness to the RFA
is an NCI program staff function.  Applications will be judged to
determine how well they meet the goals and objectives of the program as
described in the RFA.  Applications judged non-responsive will be
returned but may be submitted as investigator-initiated research grants
at the next receipt date.  Questions concerning the relevance of
proposed research to the RFA are to be directed to program staff as
described in the INQUIRIES section.
 
If the number of applications submitted is large compared to the number
of awards to be made, the NCI may conduct a preliminary scientific peer
review to eliminate those applications that are clearly not competitive.
The NCI will withdraw from further competition those applications judged
to be noncompetitive and notify the applicant and institutional business
official.
 
Those applications judged to be both competitive and responsive will be
further evaluated according to the review criteria stated below for
scientific and technical merit by an appropriate peer review group
convened by the Division of Extramural Activities, NCI.  The second
level of review by the National Cancer Advisory Board considers the
special needs of the Institute and the priorities of the National Cancer
Program.
 
REVIEW CRITERIA
 
Applications responsive to this competitive solicitation will be
reviewed in accordance with the criteria stated below.
 
o Appropriateness and adequacy of the experimental approach and
methodology proposed to carry out research activities to (a) identify
protective viral or viral-induced antigens that form the basis for
vaccine preparation, (b) develop animal models to determine host immune
response to viral-induced tumors and to test the safety and efficacy of
proposed vaccines, and (c) develop prototype therapeutic vaccines for
viruses for which malignant sequelae occur as the result of chronic
infection.
 
o The scientific merit, technical, and medical significance of the
proposed research, including the adequacy and quality of the research
design.  Familiarity with the proposed techniques must be demonstrated,
e.g., by the presentation of preliminary data.
 
o The expertise and qualifications of the Principal Investigator and
proposed staff and/or collaborators to perform the proposed experiments.
 
o Documentation of the adequacy of the facilities and resources.
 
o Appropriateness of the proposed budget and duration in relation to the
proposed research.
 
METHOD OF APPLYING
 
The most recent revision of the research grant application form PHS 389
(rev. 10/88) must be used in applying for these grants.  These forms
are available at most institutional business offices; from the Office of
Grants Inquiries, Division of Research Grants, National Institutes of
Health, Room 449, Westwood Building, 5333 Westbard Avenue, Bethesda, MD
20892, telephone (301) 496-7441; and from the NCI Program Director named
below.
 
The RFA label available in the 10/88 revision of application form PHS
398 must be affixed to the bottom of the face page.  Failure to use this
label could result in delayed processing of the application such that it
may not reach the review committee before the scheduled review date.  In
addition, the RFA number and title must be typed on line 2 of the face
page of the application form.
 
Submit a signed, typewritten original of the application, including the
Checklist, and four signed, exact photocopies, in one package to the
address below.  The photocopies must be clear and single sided.
 
DIVISION OF RESEARCH GRANTS
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**
 
At time of submission, send two additional copies of the application to:
 
REFERRAL OFFICER
Division of Extramural Activities
National Cancer Institute
Room 838, Westwood Building
5333 Westbard Avenue
Bethesda, MD  20892
 
If the applicant has an approved assurance covering the research
(multiple project assurance for animal subjects), the applicant must
provide, with the application, certification of institutional review
board (IRB) approval if human subjects are involved, and verification of
the institutional animal care and use committee (IACUC) approval if
animals are involved.  These reviews and approvals must occur PRIOR TO
SUBMISSION OF the applications for award and the certifications and
verifications must be SUBMITTED WITH the grant applications.  Failure to
provide require certifications and verifications within the application
may result in deferral or rejection.  If animals or humans will be
subjects of the research at PERFORMANCE SITES OTHER THAN THE APPLICANT
ORGANIZATION, the applicants must identify, within the application, the
assurance status of each participant.  Failure to provide this
information within applications may result in deferral or rejection.
 
Applications must be received by December 11, 1991.  If an application
is received after that date, it will be returned.  If the application
submitted in response to this RFA is substantially similar to a research
grant application already submitted to the NIH for review, but has not
yet been reviewed, the applicant will be asked to withdraw either the
pending application or the new one.  Simultaneous submission of
identical applications will not be allowed, nor will essentially
identical applications be reviewed by different review committees.
Therefore, an application cannot be submitted in response to this RFA
that is essentially identical to one that has already been reviewed.
This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an
introduction addressing the previous critique.
 
LETTER OF INTENT
 
Prospective applicants are asked to submit, by October 11, 1991, a
letter of intent that includes a descriptive title of the proposed
research, the name and address of the Principal Investigator, the names
of other key personnel, the participating institutions, and the number
and title of the RFA in response to which the application is being
submitted.
 
Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, it is requested in
order to provide an indication of the number and scope of applications
to be reviewed.
 
The letter of intent is to be sent to:
 
Dr. Jack Gruber
Chief, Biological Carcinogenesis Branch
Division of Cancer Etiology
National Cancer Institute
Executive Plaza North, Room 540
Bethesda, MD  20892
Telephone:  (301) 496-9740
 
INQUIRIES
 
Written and telephone inquiries concerning the objectives and scope of
this RFA and inquiries about whether or not specific proposed research
would be responsive are encouraged and are to be directed to Dr. Gruber
at the above address.  Telephone communications specifically relating to
proposed studies of the hepatitis C virus are to be directed to:
 
Dr. John S. Cole, III
Telephone:  (301) 496-1718
 
Inquiries about investigations of human papillomaviruses are to be
directed to:
 
Dr. Tom Nightingale
Telephone:  (301) 496-1953
 
Questions on Epstein-Barr virus studies are to be directed to:
 
Dr. Gretchen Hascall
Telephone:  (301) 496-4533
 
The Program Directors welcome the opportunity to clarify any issues or
questions from potential applicants.
 
Direct inquiries regarding fiscal matters to:
 
Ms. Sara Stone
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Suite 243
Bethesda, MD  20892
Telephone:  (301) 496-7800, extension 66
 
This program is described in the Catalog of Federal Domestic Assistance
Number 93.393, Cancer Cause and Prevention Research.  Awards are made
under the authorization of the Public Health Service Act, 301 (c) and
410, Public Law 78-410, as amended, 42 U.S.C. 241; Small Business
Innovation Development Act of 1982, as amended, Public Law 97-219;
Public Law 99-158, 42 U.S.C. 285, Public Law 99-500, and Report 99-711
to accompany H.R. 5233 and administered under PHS grants policies and
Federal Regulations 42 CFR Part 52 and 45 CFR Part 74.  This program is
not subject to the intergovernmental review requirements of Executive
Order 12372 or Health Systems Agency review.