[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]


-----------------------------------------------------------------------

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.

-----------------------------------------------------------------------

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