Full Text CA-92-13
RFA:  CA-92-13
P.T. 34

  Gene Therapy+ 
  Clinical Trial 
  Biomedical Research, Multidiscipl 

National Cancer Institute
Letter of Intent Receipt Date:  April 3, 1992
Application Receipt Date:  May 15, 1992
The Division of Cancer Treatment (DCT) of the National Cancer
Institute (NCI) invites program project grant applications (P01) from
interested investigators to establish interactive Gene Therapy
Programs (GTP) with the goal of conducting gene therapy clinical
trials for cancer treatment.  The purpose of this RFA is to promote
the design and implementation of clinical trials of gene therapy, to
support the requisite preclinical studies establishing the scientific
and technical basis for human studies, and to foster the development
of interactions between basic scientists and clinical researchers
necessary for bringing gene therapy to patient trials.  The program
project grant mechanism will support the establishment of broadly
based, multi-disciplinary and multi-institutional research programs
centered around this goal.
The present Request for Applications (RFA) announcement is for a
single competition with a specified application deadline of May 15,
1992.  These awards are envisioned to serve as "implementation"
grants for the initiation and development of new programs in gene
therapy.  Applications must be prepared and submitted in accordance
with the aims and requirements described in the following sections.
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 RFA,
Implementation Grants for Gene Therapy Programs in Cancer Treatment,
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, DC 20402-9325 (telephone 202/783-3238).
Applications may be submitted by domestic non-profit and for-profit
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State or local governments, and
eligible agencies of the Federal government.  Applications may be
submitted from a single institution or may include arrangements with
one or more additional institutions, if appropriate.  Applications
from minority individuals and women are encouraged.
Support of the program will be through the National Institutes of
Health (NIH) program project research grant (P01).  Responsibilities
for the planning, direction, and execution of the proposed project
will be solely that of the applicant.  The total project period for
applications submitted in response to the present RFA may not exceed
four years.  Investigators must follow the "Guidelines for Program
Project Grant of the National Cancer Institute" in preparing an
application.  However, any specific instructions included in this RFA
precedence over the general program project guidelines.  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,
Program project (P01) grants are awarded to an institution on behalf
of a Principal Investigator for the support of a broadly based,
multi-disciplinary, long-term research program with a specific major
goal or basic theme.  A program project generally involves the
organized efforts of groups of investigators who conduct research
projects related to the overall program goal.  The grant may provide
support for the projects and for certain common resources shared by
individuals in the program project if sharing facilitates the total
research effort.  Each project supported under a program project
grant is expected to contribute to and be directly related to the
common theme of the program.  The projects, under the direction of a
project leader, must demonstrate an essential element of unity and
interdependence.  Each GTP application must have a minimum of three
projects with at least one project focused on clinical studies.  In
addition, an administrative core will be needed to coordinate
research activities and to obtain approvals through the regulatory
The application must clearly explain how the projected
multi-disciplinary integrated program would accomplish the stated
goal more efficiently and effectively than would a series of
independent, individual grant-supported studies.  Designation of a
Principal Investigator as program director must be based upon
accomplishment and experience as a scientist, the ability to assume
both the leadership of the research group and the responsibility for
scientific, professional, and administrative functions, and the
commitment of a significant amount of his/her time to the project.
Under current program project guidelines, each project in the program
must have a designated project leader with a demonstrable record of
accomplishment in clinical investigation or one of the basic science
disciplines relevant to the particular subject of investigation.
However, the participation of one junior, but independent,
investigator whose project is an integral part of the overall program
and whose work would be closely related to that of the senior
scientist project leaders of the other projects is encouraged by the
This RFA is a one-time solicitation.  If the NCI determines that
there is a sufficient continuing program need, the NCI will invite
recipients of awards under this RFA to submit competitive
continuation applications for review according to the procedures
described below in APPLICATION PROCEDURES.
Approximately $5,000,000 in total costs per year for four years will
be committed to fund applications submitted in response to this RFA.
It is anticipated that six to eight awards will be made.  First year
budget requests should average $500,000 to $600,000 direct costs.
Direct costs may be utilized to support the research activities of
scientific and professional personnel, consultation services,
equipment, supplies, travel, and publication costs.  Support for
research-related costs of obtaining regulatory approvals may be
authorized.  The initial set aside is not expected to completely fund
the clinical trials; however, sufficient funds should be available
for pilot clinical studies or for preclinical studies necessary for
development of the clinical product and/or procedure and for
regulatory approvals.  Submission of competitive supplements for
additional support is expected when the GTPs are ready to initiate or
expand clinical trials.
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.  Although this program is provided for in the
financial plans of the NCI, the award of grants pursuant to this RFA
is also contingent upon the continuing availability of funds for this
purpose.  The anticipated award date is September 30, 1992.
For the purposes of this RFA, gene therapy will be defined as the
transfer of a functioning gene(s) into somatic cells to treat
disease.  For patients with cancer, genetically altering the
characteristics of tumor cells or host normal cells ex vivo may
enhance the effectiveness of certain forms of immunotherapy and
chemotherapy.  Ultimately, genes may be directly introduced into
tumor cells in vivo to alter the malignant phenotype and halt tumor
Some of the initial applications of gene transfection techniques have
been in the field of cancer immunotherapy. Several groups have
successfully introduced cytokine genes (Interleukin-4 (IL-4),
Interleukin-2 (IL-2), Tumor Necrosis Factor (TNF), interferon-gamma,
and others) into murine tumor cells.  Local production of these
cytokines by the tumor cells not only prevents the outgrowth of the
tumor, but in certain models also induces long-lasting systemic
immunity to a subsequent tumor challenge.  In some cases,
immunization with gene-transfected tumor cells has resulted in the
regression of a non-transfected, established tumor located at a
distant site.  Similar approaches in humans could lead to the
development of enhanced in vivo T cell immune responses against
tumors, that could be expanded by systemic administration of other
cytokines or could be used to generate more potent and specific
cytotoxic T cells (CTL) for adoptive immunotherapy.  Evidence has
also been presented that production of cytokines by adoptively
transferred CTL may be necessary for producing an effective
inflammatory response within the tumor.  Clinical trials of both
cytokine-transfected tumor-infiltrating lymphocytes and tumor cells
transfected with the genes for TNF or IL-2 have recently been
Gene therapy may prove useful in the field of cancer chemotherapy.
For example, one of the major barriers to increasing chemotherapy
dose intensity continues to be bone marrow toxicity despite advances
in marrow transplant technology and the use of hematopoietic growth
factors.  Long-term transfection of genes into marrow hematopoietic
stem cells has been demonstrated in murine models.  Thus it may be
possible to introduce genes for increased drug-resistance
specifically into human stem cells, and through repopulation of the
host with these cells, allow chemotherapy of increased intensity.
Preclinical data suggest gene therapy could also be used directly to
treat some tumors.  The metastatic phenotype is often characterized
by deletion of suppressor genes and/or activation of specific
oncogenes.  Introduction of the retinoblastoma (RB) tumor suppressor
gene into RB-negative tumor cells, or incorporation of a specific
anti-sense message in cells with activated oncogenes, has been shown
to alter the neoplastic phenotype.  The development and application
of these technologies for patients with cancer could represent a
major therapeutic advance.
Although practical and theoretical limitations currently exist for
the application of gene therapy in cancer patients, clinical trials
have already been initiated.  In research centers throughout the
country substantial preclinical data have been obtained that could
serve as the basis of additional clinical trials either immediately
or within the near future.  The purpose of this RFA is to promote the
design and implementation of clinical trials of gene therapy, to
support the requisite preclinical studies establishing the scientific
and technical basis for human studies, and to foster the development
of interactions between basic scientists and clinical researchers
necessary for bringing gene therapy to patient trials.  The program
project grant mechanism will support the establishment of
broadly-based, multi-disciplinary and multi-institutional research
programs centered around this goal.
The Cancer Therapy Evaluation Program is seeking applications for
research program project grants (P01) to establish interactive Gene
Therapy Programs (GTP) with the goal of conducting gene therapy
clinical trials for cancer treatment.  The applications should be
focused on a specific clinical therapeutic approach.  These awards
are envisioned to serve as "implementation grants" for the
development of a collaborative effort between a multi-disciplinary
and, possibly, multi-institutional group of investigators to rapidly
move forward new approaches in gene therapy of cancer into the
clinic.  Funds should be used to conduct the necessary preclinical
studies to prepare a clinical product or procedure for human trials
and to gain regulatory approval to conduct such trials.  The Cancer
Therapy Evaluation Program will provide assistance in gaining
regulatory approvals. NCI is encouraging investigators to forge new
collaborations with other research institutions and industry to
obtain the necessary expertise in all aspects of the research
Initial approaches to gene therapy would involve the alteration and
administration of human somatic cells.  Future techniques may include
approaches such as the direct administration of genetic material to
patients.  Examples of gene therapy for the treatment of cancer
o  implantation of tumor cells transfected with functioning cytokine
genes to elicit an immune response;
o  insertion of genes into host effector cells that will enhance
their ability to recognize and bind tumor specifically and/or will
potentiate the inflammatory response of the host at the site of
o  insertion of genes into normal cells of the host, such as bone
marrow stem cells, that will increase their resistance to the toxic
effects of chemotherapy;
o  in vivo introduction of genes into cancer cells that will restore
suppressor gene function or neutralize the function of activated
oncogenes that maintain the neoplastic phenotype.
Investigators are not limited to the above studies; however, all
studies must be therapeutic in intent and not solely diagnostic.
It is anticipated that each GTP will have multiple subprojects and
shared common resources.  Examples of areas of research for
subprojects would include development of the appropriate high
efficiency retroviral vectors, helper viruses, or producer cell
lines; establishment of animal models for efficacy studies;
preclinical toxicology in cell culture systems and animal models; and
the initial clinical studies.  The time table for the conduct of
clinical studies should be reflected in the individual budgets with a
larger proportion of funds for preclinical studies, if necessary, in
years 1 and 2.  Budgets should average $500,000 to $600,000 direct
costs per year as the initial awards are for the initiation and
implementation of new interactive Gene Therapy Programs.  Grantees
can request up to four years of support.
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
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 not 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
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
Prospective applicants are asked to submit by April 3, 1992, a letter
of intent that includes a descriptive title of the proposed research,
the name, address, and telephone number of the Principal
Investigator, the identities of other key personnel and 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, the information
is helpful in planning for the review of applications.  It allows NCI
staff to estimate the potential review workload and to avoid conflict
of interest in the review.
The letter of intent is be sent to:
Ms. Diane Bronzert
Program Director, Cancer Therapy Evaluation Program
Division of Cancer Treatment
National Cancer Institute
Executive Plaza North, Room 734
Bethesda, MD  20892
Telephone:  (301) 496-8866
FAX:  (301) 480-4663
Applicants who use express mail or a courier service are advised to
follow the carrier's requirements for showing a street address.  The
address for the Executive Plaza North is:
Executive Plaza North, Room 734
6130 Executive Blvd.
Rockville, MD  20852
The research grant application form PHS 398 (revised 10/88 or 9/91)
must be used in applying for these grants.  These forms are available
at most institutional business offices; from the Office of Grant
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.  Copies of the "Guidelines for the Program Project Grant
of the National Cancer Institute" (revised 1987) for the development
of a program project grant application are available from the Program
Director and from the NCI Referral Officer, Division of Extramural
Activities, NCI, Room 848, Westwood Building, 5333 Westbard Avenue,
Bethesda, MD 20892.
In addition to following the format instructions contained in the
Guidelines, include the expanded material listed below:
o  A brief overview of the intended program project and its
o  A description of laboratory and clinical facilities available for
use by the proposed project;
o  Ongoing relevant research studies identifying existing projects
and sources of support;
o  Past research by members of the proposed investigative group
relevant to the application;
o  Specific information on the institution's present patient load and
projections for patient involvement in clinical investigations;
o  The academic positions and major research interests of the program
director and his/her professional staff who will be involved in the
work of the program project;
o  Time line indicating plans for obtaining regulatory approvals and
initiating clinical studies;
o  Collaborative arrangements with other laboratories and
investigators and delineation of the role and anticipated manner of
participation and interaction of the project leader(s), consultants,
and collaborators;
o  Justification for the use of the PO1 mechanism instead of the R012
(individual research grant) mechanism.
The RFA label available in the 10/88 and 9/91 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 in time
for review.  In addition, the RFA number and title "Implementation
Grants for Gene Therapy Programs in Cancer Treatment" must be typed
on line 2 of the face page of the application form and the YES box
must be marked.
Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  In such a case, a letter of agreement from
either the GCRC program director or the Principal Investigator of the
GCRC must be included with the application.
Submit a signed, typewritten original of the application, including
the Checklist, and four signed, exact photocopies, in one package to
the Division of Research Grants at 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 the time of submission, two additional copies of the application
must also be sent to:
Referral Officer
Review Logistics Branch
Division of Extramural Activities
National Cancer Institute
Westwood Building, Room 848
5333 Westbard Avenue
Bethesda, MD  20892
Applications MUST be received by May 15, 1992.  If an application is
received after that date, it will be returned.  The Division of
Research Grants (DRG) will not accept any application in response to
this announcement that is essentially the same as one currently
pending initial review, unless the applicant withdraws the pending
application.  The DRG will not accept any application that is
essentially the same as one already 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.
Review Procedures
Upon receipt, applications will be reviewed by the DRG for
completeness.  Incomplete applications will be returned to the
applicant without further consideration. If the application is not
responsive to the RFA, NCI staff will contact the applicant to
determine whether to return the application to the applicant or
submit it for review in competition with unsolicited applications for
the next review cycle. Questions concerning the relevance of proposed
research to the RFA may be directed to program staff as described in
the INQUIRIES section.
Applications may be triaged by an NCI peer review group on the basis
of relative competitiveness.  The NCI will withdraw from further
competition those applications judged to be noncompetitive for award
and notify the applicant and institutional business official.
Those applications judged to be both competitive and responsive will
be further evaluated, using the review criteria stated below, for
scientific and technical merit by an appropriate peer review group
convened by the Division of Extramural Activities, NCI.  Applications
must be sufficiently complete for review without a site visit.  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.
Reveiw Criteria
The factors considered in evaluating the scientific merit of each
response to this RFA will be:
o  Significance and originality of the research from a scientific and
technical viewpoint.
o  Feasibility of proposed research.
o  Clinical and basic research experience, training, time
availability, and research competence of the investigators involved.
o  Adequacy and appropriateness of the methodology and protocol
o  Potential for accomplishing specific aims and initiating clinical
trials within the time frame proposed.
o  Adequacy of available resources and environment (facilities,
equipment, statistical collaboration, patient population, and
o  Documentation of support from collaborators and consultants
through letters of commitment.
o  Adequacy of plan for the inclusion of women and minorities.
o  Appropriateness of the proposed budget and duration in relation to
the proposed research.
Review criteria for program project grants as stated in the
"Guidelines for the Program Project Grant of the National Cancer
Institute" will also apply.
The anticipated date of award is September 30, 1992.  In addition to
the technical merit of the application, NCI will consider how well
the GTPs meet the goals and objectives of the program as described in
the RFA.  Applications with requested budgets greatly exceeding the
suggested budget of $500,000 to $600,000 direct costs per year may be
at a disadvantage with respect to final NCI funding decisions.
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 strongly encouraged and should be
directed to program staff listed below.  The program staff welcome
the opportunity to clarify any issues or questions from potential
Direct inquiries regarding programmatic issues to:
Ms. Diane Bronzert
Program Director, Cancer Therapy Evaluation Program
Division of Cancer Treatment
National Cancer Institute
Executive Plaza North, Room 734
Bethesda, MD  20892
Telephone:  (301) 496-8866
FAX:  (301) 480-4663
Mario Sznol, M.D.
Senior Investigator, Investigational Drug Branch
Cancer Therapy Evaluation Program
Division of Cancer Treatment
National Cancer Institute
Executive Plaza North, Room 715
Bethesda, MD  20892
Telephone:  (301) 496-8798
FAX:  (301) 402-0428
Direct inquiries regarding fiscal matters to:
Ms. Marian Focke
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 242
Bethesda, MD  20892
Telephone:  (301) 496-7800, extension 46
FAX:  (301) 496-8601
This program is described in the Catalog of Federal Domestic
Assistance No 93.395, Cancer Treatment Research.  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 at 42 CFR 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.

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