Full Text CA-93-040

IMMUNOBIOLOGY OF AIDS LYMPHOMA

NIH GUIDE, Volume 22, Number 33, September 17, 1993

RFA:  CA-93-040

P.T. 34

Keywords: 
  AIDS 
  Cancer/Carcinogenesis 
  Immunology 


National Cancer Institute

Letter of Intent Receipt Date:  November 15, 1993
Application Receipt Date:  January 7, 1994

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.  The 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
"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).

ELIGIBILITY REQUIREMENTS

Research grant applications may be submitted by domestic and foreign
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.
Applications from minority individuals and women are encouraged.

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.  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
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, if the NCI determines that there is a
sufficient continuing program need, a request for renewal
applications will be announced.  Only recipients of awards under this
RFA will be eligible to apply.

FUNDS AVAILABLE

Approximately $1,500,000 in total costs per year for four years will
be committed to fund applications that are submitted in response to
this RFA.  It is anticipated that at least six to eight 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 July 1, 1994.  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

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 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 (especially 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.

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 and applications with a primary focus on designing new
treatments for AIDS lymphoma will not be considered responsive to
this initiative and these applications will be returned.

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.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are 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 must 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 must 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 must be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study.  This information must be included in the form PHS 398 in
the Research Plan, parts 1-4, AND summarized in part 5, Human
Subjects.  Applicants 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 is defined as 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
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 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.

LETTER OF INTENT

Prospective applicants are asked to submit, by November 15, 1993, 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 and participating institutions, and the
number and title of the RFA in response to which the application may
be 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 at the
address listed under INQUIRIES.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research and from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone 301/710-0267.

The RFA label available in the PHS 398 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 2a 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
Westwood Building, Room 240
Bethesda, MD  20892**

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, Room 636
6130 Executive Boulevard
Bethesda, MD  20892

Applications must be received by January 7, 1994.  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 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 CONSIDERATIONS

Upon receipt, applications will be reviewed by NIH staff for
completeness and responsiveness.  Incomplete applications will be
returned to the applicant without further consideration.  Evaluation
for responsiveness to the program requirements and criteria stated in
the RFA is an NCI program staff function.  Applications that are
judged non-responsive to this RFA will be returned to the applicant
by the NCI.  An application judged to be non-responsive to this RFA
may be submitted as a traditional research project grant (R01), or as
a component of a program project grant (P01), with modification in
accordance with either the R01 or P01 guidelines.  The application
would then not be considered a response to an RFA.

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 (triage) to eliminate those that are clearly
not competitive.  The NCI will remove from further competition those
applications judged to be non-competitive for award and notify the
applicant Principal Investigator and institutional official.

Those applications judged to be both responsive and competitive 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 will be by the National Cancer Advisory Board.

Review criteria for this RFA will be:

o  extent to which the proposed research addresses the goals of the
RFA

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  demonstrated expertise in both the appropriate basic and clinical
sciences of the PI and key personnel, 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  adequacy of provision for the protection of human subjects and the
humane treatment of animals

o  adequacy of the plans for inclusion of females and minorities

o  adequacy of available facilities

The reviewers will also judge the appropriateness of the proposed
budget and duration in relation to the proposed research.

AWARD CRITERIA

The earliest anticipated date of award is July 1, 1994.  In addition
to technical merit of the application, the NCI will consider the
level of total cost requested.  Only highly-rated projects will be
funded.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
NCI program staff welcome the opportunity to clarify any issues or
questions from potential applicants.

Direct inquiries regarding programmatic issues and address the letter
of intent to:

Dr. John F. Finerty
Division of Cancer Biology, Diagnosis, and Centers
National Cancer Institute
Executive Plaza North, Room 501
6130 Executive Boulevard
Bethesda, MD  20892-9904
Telephone:  (301) 496-7815
FAX:  (301) 496-8656

Direct inquiries regarding fiscal matters to:

Mr. Robert Hawkins
Grants Management Branch
National Cancer Institute
Executive Plaza South, Room 243
Bethesda, MD  20892
Telephone:  (301) 496-7800, ext. 13

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 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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