[Federal Register Volume 64, Number 89 (Monday, May 10, 1999)]
[Notices]
[Pages 25050-25052]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-11658]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
National Cancer Institute: Opportunity for a Cooperative Research
and Development Agreement (CRADA) for the Research, Purification, and
Further Development of Immunosuppressive Factor(s) Released From Human
Glioblastoma Cells in Culture
The National Cancer Institute's Experimental Immunology Branch has
identified and characterized the activity of a soluble factor(s)
produced by human glioblastoma tumor cells that suppresses T cell
responses in health donor blood samples.
AGENCY: National Institutes of Health, PHS, DHHS.
ACTION: Notice.
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SUMMARY: The National Cancer Institute (NCI) seeks a Cooperative
Research and Development Agreement (CRADA) Collaborator to aid NCI in
the further characterization and commercial development of the immune-
suppressive factor(s) generated from glioblastoma tumor cells. The
glioblastoma-generated factor(s) appear to act by causing antigen-
presenting cells (APCs), such as monocytes, to undergo a change in
cytokine production which induces apotosis or antigen-specific
unresponsiveness (``anergy'') in T cells. NCI has partially purified
and characterized the immunosuppressive factor(s). Several applications
for this technology have been identified. They include (1) therapy for
graft-host rejection in transplantation surgeries; (2) treatment of
autoimmune diseases; and (3) suppression of severe allergic responses.
NCI is looking for a CRADA Collaborator with a demonstrated record of
success in protein purification and immunosuppressive therapeutics for
the eventual use of this factor(s) in the clinical treatment of
patients. The proposed term of the CRADA can be up to five (5) years.
DATES: Interested parties should notify this office in writing of their
interest in filing a formal proposal no later than July 9, 1999.
Potential CRADA Collaborators will then have an additional thirty (30)
days to submit a formal proposal.
[[Page 25051]]
ADDRESSES: Inquiries and proposals regarding this opportunity should be
addressed to Holly S. Symonds, Ph.D., Technology Development Specialist
(Tel. #301-496-0477, FAX #301-402-2117), Technology Development and
Commercialization Branch, National Cancer Institute, 6120 Executive
Blvd., Suite 450, Rockville, MD 20852. Inquiries directed to obtaining
patent license(s) needed for participation in the CRADA opportunity
should be addressed to Marlene Shinn, M.S., J.D., Technology Licensing
Specialist, Office of Technology Transfer, National Institutes of
Health, 6011 Executive Blvd., Suite 325, Rockville, MD 20852, (Tel.
301-496-7056, ext. 285; FAX 301-402-0220).
SUPPLEMENTARY INFORMATION: A Cooperative Research and Development
Agreement (CRADA) is the anticipated joint agreement to be entered into
with NCI pursuant to the Federal Technology Transfer Act of 1986 and
Executive Order 12591 of April 10, 1987 as amended by the National
Technology Transfer Advancement Act of 1995. NCI is looking for a CRADA
partner to aide NCI in characterization and commercial development of
the tumor cell-derived immune-suppressive factor(s). The expected
duration of the CRADA would be from one (1) to five (5) years.
Cancer patients frequently demonstrate an impaired in vitro and in
vitro T cell immune activity. This deficiency is often reflected in
animal models and affects both tumor antigens and non-tumor antigens.
Cytokine dysfunction appears to contribute to tumor-associated immune
dysregulation, with decreases of IL-2 and/or IFN-gamma production and
increases in IL-4, IL-5, IL-6, and/or IL-10 production. Human gliomas
are frequently very immunosuppressive and provide an interesting
example of tumor-associated immune dysfunction. T cells from glioma
patients are impaired in their ability to respond in vitro to antigens
and to T cell mitogens by proliferation and IL-2 production. In vitro
and clinical findings suggest that one or more factors released into
the glioma culture supernatant (GCS) elicit immunoregulatory effects on
systematic cellular immunity.
To test this hypothesis, NCI scientist investigated whether GCS
would affect monocyte-generated cytokines and T cells from healthy
donors of human peripheral blood mononuclear cells (PBMCs). Incubation
of PBMC with GCS decreased production of IL-12, IFN-gamma, and TNF-
alpha, and increased production of IL-6 and IL-10. The GCS-induced
underproduction of IL-12 and overproduction of IL-10 in monocytes was
correlated with a decrease in IL-12 p40 and an increase in IL-10 mRNA
expression. Incubation with GCS also resulted in reduced expression of
MHC class II and CD80/86 costimulatory molecules on monocytes.
Experiments using exogenous IL-6, TGF-beta-1, TGF-beta-2, or CDGP,
either singly or in combination, did not elicit the changes in with IL-
12 or IL-10 production.
NCI scientists have shown that the immunosuppressive effects found
in GCS are due to a factor(s) that is resistant to extremes in pH,
differentially susceptible to temperature, susceptible to trypsin, and
has a minimum molecular mass of 40 kDa. NCI scientists have also
demonstrated that the glioblastoma factor(s) alter the cytokine
profiles of monocytic APC(s) that, in turn, inhibit T cell function.
Thus, the scientists have shown that monocytes can serve as an
intermediate between tumor-generated immune-suppressive factors and the
T cell responses that are suppressed in glomas. NCI scientists are
currently exploring the possibility that T cells that recognize
antigens presented on treated monocytes will undergo apoptosis or
anergy, while T cells that do not recognize those antigens will retain
their normal activities.
NCI predicts that the therapeutic use of the glioblastoma-generated
immunosuppressive factor(s), once fully characterized and purified,
will be applicable to a wide variety of fields. For example, there is a
great need for immunosuppressive therapy following transplantation
surgeries. A major challenge of tissue transplantation is to
selectively deplete the immune system of responses against antigens
found on the surface of grafted foreign tissue without concomitantly
compromising immunity to antigens of infectious agents or tumors. At
present, the standard approach is to continuously treat the transplant
recipient with immunosuppressive drugs that are non-specific rendering
the patient susceptible to opportunistic infections and/or cancer. By
treating transplant recipients with donor antigen-presenting cells
(APCs) that have been incubated ex vivo with glioblastoma culture
supernatant (GCS), the recipient may be able to be depleted of all
donor-specific T lymphocytes that are responsible for initiating graft
rejection while at the same time maintaining immune integrity.
Immunnosuppressive drugs are also used to treat autoimmune diseases
in which the autoantigen is known. Thus, it may be possible to delete
autoimmune-specific T cells by treating the patient with autologous
antigen-presenting cells that have been incubated with GCS and pulsed
with the antoantigen ex vivo. Such an approach may eliminate the need
for, or reduce the use of, immunosuppressive drugs in both tissue
transplantation and autoimmune diseases.
The described methods are the subject of a U.S. provisional patent
application filed on March 24, 1999 by the Public Health Service on
behalf of the Federal Government. Furthermore, the initial report and
characterization of the invention is described in: Zou et al, Journal
of Immunology, vol. 162: 4882-4892 (1999).
Under the present proposal, the goal of the CRADA will be to
enhance the development of the GCS-generated immunosuppressive
factor(s) in the following areas:
1. Further purification and characterization of the factor(s).
2. Examination of the ability of the purified immunosuppressive
factor to induce apoptosis or anergy in T cells through a monocyte
intermediate using in vitro and in vivo models.
Party Contributions
The role of the NCI in the CRADA may include, but not be limited
to:
1. Providing intellectual, scientific, and technical expertise and
experience to the research project.
2. Providing the CRADA Collaborator with information and data
relating to the glioblastoma-generated immunosuppressive factor(s).
3. Planning research studies and interpreting research results.
4. Carrying out research to validate the immunosuppressive
activities of the GCS-generated factor(s).
5. Publishing research results.
6. Developing additional potential applications of the factor(s).
The role of the CRADA Collaborator may include, but not limited to:
1. Providing significant intellectual, scientific, and technical
expertise or experience to the research project.
2. Planning research studies and interpreting research results.
3. Providing technical and/or financial support to facilitate
scientific goals and for further design of applications of the
technology outlined in the agreement.
4. Publishing research results.
Selecting criteria for choosing the CRADA Collaborator may include,
but not be limited to:
1. A demonstrated record of success in the areas of protein
purification, characterization and therapeutic development.
2. A demonstrated background and expertise in immunological
sciences.
[[Page 25052]]
3. The ability to collaborate with NCI on further research and
development of this technology. This ability will be demonstrated
through expertise and expertise in this or related areas of technology
indicating the ability to contribute intellectually to ongoing research
and development.
4. The demonstration of adequate resources to perform the research
and development of this technology (e.g., facilities, personnel and
expertise) and to accomplish objectives according to an appropriate
timetable to be outlined in the CRADA Collaborator's proposal.
5. The willingness to commit best effort and demonstrated resources
to the research and development of this technology, as outlined in the
CRADA Collaborator's proposal.
6. The demonstration of expertise in the commercial development and
production of products related to this area of technology.
7. The Level of financial support the CRADA Collaborator will
provide for CRADA-related Government activities.
8. The willingness to cooperate with the National Cancer Institute
in the timely publication of research results.
9. The agreement to be bound by the appropriate DHHS regulations
relating to human subjects, and all PHS policies relating to the use
and care of laboratory animals.
10. The willingness to accept the legal provisions and language of
the CRADA with only minor modifications, if any. These provisions
govern the distribution of future patent rights to CRADA inventions.
Generally, the rights of ownership are retained by the organization
that is the employer of the inventor, with (1) the grant of a license
for research and other Government purposes to the Government when the
CRADA Collaborator's employee is the sole inventor, or (2) the grant of
an option to elect an exclusive or nonexclusive license to the CRADA
Collaborator when the Government employee is the sole inventor.
Dated: April 30, 1999.
Kathleen Sybert,
Chief, Technology Development and Commercialization Branch, National
Cancer Institute, National Institutes of Health.
[FR Doc. 99-11658 Filed 5-7-99; 8:45 am]
BILLING CODE 4140-01-M
