Full Text CA-96-009
 
IMMUNOBIOLOGY OF AIDS LYMPHOMA
 
NIH GUIDE, Volume 25, Number 8, March 15, 1996
 
RFA:  CA-96-009
 
P.T. 34

Keywords: 
  Immunology 
  Cancer/Carcinogenesis 
  AIDS 

 
National Cancer Institute
 
Letter of Intent Receipt Date:  April 25, 1996
Application Receipt Date:  May 24, 1996
 
PURPOSE
 
The intent of this initiative is to stimulate research on biologic
and immunologic mechanisms involved in the development of lymphomas
in AIDS patients.  Specifically, this initiative will encourage
development and testing of hypotheses about the mechanisms of
lymphomagenesis in the unique immune environment induced by HIV
infection.  This environment is characterized by defects in immune
regulation, loss of specific immune cell subsets, presence of
abnormal cytokine levels, changes in the architecture of germinal
centers and other lymphoid tissues and an apparent loss of immune
surveillance.  Any or all of these factors may play a role in the
high incidence and distinctive characteristics of AIDS-associated
lymphoma. This dysregulation may lead to an increase in the rate of
generation of transformed lymphocytes and/or to enhanced capacity of
these cells to escape surveillance and cause disease.  Before
effective therapies can be designed, it is necessary to understand
the basic mechanism of lymphomagenesis in AIDS.
 
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), Immunobiology of AIDS Lymphoma, 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. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington,
DC 20402-9325 (telephone 202-512-1800).
 
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.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as principal investigators.
 
MECHANISM OF SUPPORT
 
Support of this program will be through the National Institutes of
Health (NIH) research project grant (R01).  Applicants will be
responsible for the planning, direction, and execution of the
proposed project.  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 April 1, 1994.  This
RFA is a one-time solicitation.  Generally, future unsolicited
competing renewal applications will compete with all
investigator-initiated R01 applications and be reviewed according to
the customary peer review procedures by the Division of Research
Grants (DRG).  However, should the NCI determine that there is a
sufficient continuing program need, a request for renewal
applications will be announced.
 
FUNDS AVAILABLE
 
Approximately $1,000,000 in total costs per year for four years will
be committed to fund applications that are submitted in response to
this RFA.  It is estimated that the average amount of the direct
costs for each award will be $150,000.  It is anticipated that
approximately six individual R01 grant awards will be made.  This
level of support is dependent on the receipt of a sufficient number
of applications of high scientific merit.  Because the nature and
scope of the research proposed in response to this RFA may vary, it
is anticipated that the size of an award may vary also.  The earliest
start date for the initial award will be September 24, 1996.
Although this program is provided for in the financial plans of the
NCI, awards pursuant to this RFA are contingent upon the availability
of funds for this purpose.
 
RESEARCH OBJECTIVES
 
Background
 
The incidence of Non-Hodgkin's Lymphoma (NHL) has increased steadily
during the past decade, with the most dramatic increase occurring in
the AIDS associated B-cell lymphomas.  As AIDS patients are living
longer, NHL has emerged as a major clinical problem in AIDS.  The
causes of this are poorly understood.  Yet, during the same decade,
tremendous progress was made in elucidating mechanisms of B and T
lymphocyte regulation in both normal and immunodeficient patients.
Initially, the emphasis was focused on elucidating the cellular and
molecular mechanisms that govern the function of the immune system in
normal individuals.  Comparisons have been made between immune
mechanisms in non-immunodeficient and immunodeficient individuals.
It is obvious that deficiencies in the functioning components of the
immune system, e.g., B or T cells, could readily account for the lack
of resistance to infectious diseases in immunodeficient animals and
patients.
 
But no such explanation is readily available to explain the etiology
and pathogenesis of AIDS-associated lymphomas.  Studies have shown
that similar immune abnormalities exist among congenitally
immunodeficient, iatrogenically suppressed and AIDS patients.  For
example, low numbers of CD4+ T cells can be found in the peripheral
circulation of all three groups of patients.  Similarly, abnormal
cytokine levels are detected in both non-AIDS and AIDS patients.
This is best exemplified by high levels of interleukin 6 (IL-6)
detected in the common-variable immunodeficiency (CVI) syndrome and
AIDS patients.  This apparently reflects lack of normal B cell
function in both groups of patients.  However, other studies have
shown distinct differences between AIDS patients and patients with
other immunodeficiencies.  For example, Epstein-Barr Virus (EBV) was
reported to induce essentially all of the B lymphomas in
post-transplant recipients whereas EBV appears to play a lesser role
in some AIDS-associated lymphomas. Other studies indicated that HIV
and other retroviruses do not play a direct role in inducing AIDS
lymphomas.
 
The NCI-sponsored workshop entitled "Biology of AIDS Lymphoma," held
in Bethesda in May 1992, provided a forum for discussing the current
state of research into the biologic and immunologic mechanisms that
underlie the development of AIDS lymphoma.  There was general
agreement that while AIDS lymphoma is a heterogeneous collection of
diseases, there are unique features that distinguish AIDS lymphomas
from lymphomas in other immunodeficiency states and lymphomas in the
general population.  Participants identified numerous factors that
might contribute to the unique pattern of lymphomagenesis, but no
consensus was possible at the current state of knowledge on a
mechanistic model for AIDS lymphoma development.
 
On one level, the factors that lead to lymphomagenesis in AIDS are
understandable, but the data that support this understanding are
largely correlative and details are lacking.  Factors that have been
suggested to play a role in AIDS lymphomagenesis include, but are not
limited to, loss of immune surveillance, infection by EBV and other
viruses, chronic antigenic stimulation, high levels of stimulatory
cytokines (such as IL-6), low levels of inhibitory cytokines,
oncogene activation, other increases in DNA damage and alterations in
DNA repair mechanisms. For every factor, important questions remain
unanswered and will remain so until incisive, mechanistic studies are
undertaken.
 
Special Requirements
 
Applicants should understand that the focus of this initiative is on
the basic mechanisms leading to lymphomagenesis in AIDS patients.
Thus, studies designed to test new forms of immunotherapy or other
treatment modalities for AIDS lymphoma are outside the scope of this
initiative.  Thus, applications with a primary focus on designing new
treatments for AIDS lymphoma will not be considered responsive to
this initiative and will be returned to the applicant.
 
It is anticipated that the majority of applications submitted in
response to this RFA will propose experiments requiring access to
cells and/or tissues from AIDS patients.  Because such patient
material is not readily available, applicants who propose such
experiments must document that they have adequate access to these
resources to carry out the proposed studies.  Applicants who do not
demonstrate this access will have their applications returned without
review.
 
The intent of this RFA is to elucidate the mechanisms underlying
lymphomagenesis in AIDS patients.  While the most direct route to
understanding these mechanisms is to study AIDS patients or
patient-derived material, it is recognized that studies of animal
models of AIDS lymphoma or studies involving comparison to
lymphomagenesis in other human immunodeficiency states may yield
important insights into relevant mechanisms.  Such studies might be
designed to shed light on factors such as abnormal cytokine
production in immunodeficient individuals, CD4+ T cell depletion and
subsequent effects on B cell lymphomagenesis, the overall immune
dysfunction in B and T cells and effects on dendritic cells, B cell
lymphomagenesis in immunodeficient individuals, post-transplant
lymphoproliferative disease (PTLD) and lymphomagenesis, immune
surveillance and malignant B cell proliferation, the role of
HIV-infected follicular dendritic cells within germinal centers, the
germinal center microenvironment and immunoregulatory effects on B
cells and the role of chronic polyclonal B-cell stimulation in
lymphoma development.
 
Studies primarily involving animal models of AIDS or humans with
immunodeficiency states other than AIDS will be considered responsive
only if the intent is to derive a testable hypothesis concerning
lymphomagenesis in AIDS patients and if the application contains a
clear and compelling plan to apply the results obtained in a direct
study of AIDS lymphoma.
 
It is clear that the Epstein-Barr virus (EBV) plays a predominant
role in lymphomagenesis in post-transplant recipients and a somewhat
lesser, but still major, role in AIDS lymphomagenesis.  However, the
direct involvement of EBV and/or retroviruses in AIDS lymphomagenesis
was the subject of a previous NCI RFA (RFA CA 90-15).  Therefore,
applications where the sole focus is on EBV-induced or
retrovirus-induced lymphomagenesis in iatrogenically immunosuppressed
individuals (animals or humans) will not be considered responsive to
this initiative and these applications will be returned.  However,
studies that include, but are not limited to, retroviral-oncogene
activation of immune cells or retroviral models of AIDS employing
naturally occurring immunodeficient individuals where the intent is
to derive a testable hypothesis of lymphomagenesis with application
to the human disease will be considered responsive to the initiative.
 
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.
 
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.
 
LETTER OF INTENT
 
Prospective applicants are asked to submit, by April 25, 1996 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 that it contains
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 to be sent to:
 
Dr. John F. Finerty
Division of Cancer Biology, Diagnosis, and Centers
National Cancer Institute
Executive Plaza North, Room 501
6130 Executive Boulevard
Rockville, MD  20892-9904
Telephone:  (301) 496-7815
FAX:  (301) 496-8656
Email:  fin@nih.gov
 
APPLICATION PROCEDURES
 
The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants.  Applications kits are available at
most institutional offices of sponsored research and may be obtained
from the Grants Information Office, Office of Extramural Outreach and
Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267,
email:  girg@drgpo.drg.nih.gov.
 
The RFA label available in the PHS 398 (rev.5/95) application form
must be affixed to the bottom of the face page of the application.
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 title and number must be typed on
line 2 of the face page of the application form and the YES box must
be marked.
 
Submit a signed, typewritten original of the application, including
the Checklist, and three signed, single-sided photocopies, in one
package with the appendices 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)
 
At the time of submission, two additional copies of the application
must also be sent to:
 
Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Suite 636
6130 Executive Boulevard-MSC 7405
Bethesda, MD  20892-7405 (if using U.S. Postal Service)
Rockville, MD  20852 (if hand delivered or delivery service)
 
Applications must be received by May 24, 1996.  If an application is
received after that date, it will be returned to the applicant
without review.  The Division of Research Grants (DRG) will not
accept any application in response to this RFA 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 CONSIDERATIONS
 
Upon receipt, applications will be reviewed for completeness by DRG
and responsiveness by the NCI.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, NCI staff may contact the
applicant to determine whether to return the application to the
applicant or submit it for review in competition with unsolicited
applications at the next review cycle.  Applications that are
complete and responsive to the RFA will be evaluated for scientific
and technical merit by an appropriate peer review group convened by
the NCI in accordance with the review criteria stated below.
 
As part of the initial 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 of review by
the National Cancer Advisory 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  where applicable, appropriateness of the model system chosen for
the experiments proposed and potential relevance of the model system
to AIDS lymphoma;
 
o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;
 
o  demonstration of availability and access to appropriate human
tissue necessary to perform the proposed research;
 
o  where applicable, availability of clinical information associated
with human samples;
 
o  availability of the resources necessary to perform the research;
 
o  appropriateness of the proposed budget and duration in relation to
the proposed research;
 
o Adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be
evaluated.
 
The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment, the safety of the research environment, and
conformance with the NIH guidelines for the Inclusion of Women and
Minorities as Subjects in Clinical Research.
 
AWARD CRITERIA
 
The earliest anticipated date of award is September 24, 1996.  Awards
will be made on the basis of priority score and funds available.  In
addition to technical merit of the application, the NCI will consider
how well the proposed research meets the goals and objectives of the
program as described in the RFA, as well as the level of total cost
requested.  Only highly-rated projects will be funded.
 
INQUIRIES
 
Inquiries concerning this RFA are encouraged.  The opportunity to
clarify any issue or questions from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues to:
 
Dr. John F. Finerty
Division of Cancer Biology
National Cancer Institute
Executive Plaza North, Room 501
6130 Executive Boulevard
Rockville, MD  20892-9904
Telephone:  (301) 496-7815
FAX:  (301) 496-8656
Email:  fin@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 recipients to provide a
smoke-free workplace and promote the nonuse 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 routine 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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