[Federal Register Volume 74, Number 86 (Wednesday, May 6, 2009)]
[Notices]
[Pages 20961-20962]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-10479]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Public Teleconference Regarding Licensing and Collaborative 
Research Opportunities for: TRICOM--A Synergistic Triad of 
Costimulatory Molecules Used in Cancer Vaccines for the Prevention and 
Treatment of Cancer

AGENCY: National Institutes of Health, Public Health Service, HHS.

ACTION: Notice.

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SUPPLEMENTARY INFORMATION: Note that this teleconference, licensing and 
CRADA opportunity will address the treatment of all cancers excluding 
colorectal, melanoma and prostate cancer.

Technology Summary

    TRICOM is a triad of costimulatory molecules used in vector-based 
cancer vaccines that employ a combination of T-cell costimulatory 
signals together with tumor associated antigens (TAAs) to greatly 
enhance the immune response against a variety of cancers. Already 
several TRICOM-based cancer vaccines incorporating TAAs have shown 
promising results during clinical stage development. Pre-clinical 
development of other TRICOM-based vaccines continues, which makes use 
of newly discovered TAAs and T-cell activating peptides derived from 
TAAs that would allow targeting cancers expressing poorly immunogenic 
TAA. Certainly, this cancer vaccine technology has a high potential for 
leading to a new approach in the prevention and/or treatment of cancer.

Competitive Advantage of Our Technology

     The technology is beyond proof-of concept, supported by 
laboratory and clinical trial results and numerous publications.
     Recent Phase II clinical data are also available (to 
qualified licensees) employing TRICOM based vaccines.
     Further clinical studies are ongoing.
     Given the relatively more advanced stage of development of 
this technology, fewer validation studies are required compared to 
other immunotherapy related technologies.

Technology Description

    Cancer immunotherapy is an approach where tumor associated antigens 
(TAAs), which are primarily expressed in human tumor cells, and not 
expressed or minimally expressed in normal tissues, are employed to 
generate a tumor-specific immune response. Specifically, these antigens 
serve as targets for the host immune system and elicit responses that 
results in tumor destruction. The initiation of an effective T-cell 
immune response to relatively weak antigens requires two signals. The 
first one is antigen-specific via the peptide/major histocompatibility 
complex and the second or ``costimulatory'' signal is required for 
cytokine production, proliferation, and other aspects of T-cell 
activation.
    The TRICOM technology employs avirulent poxviruses to present a 
combination of costimulatory signaling molecules with tumor-associated 
antigens (TAAs) to activate T-cells and break the immune systems 
tolerance towards cancer cells. This is achieved using recombinant 
poxvirus DNA vectors that encode both T-cell costimulatory molecules 
and TAAs. The combination of the three costimulatory molecules B7.1, 
ICAM-1 and LFA-3, hence the name TRICOM, has been shown to have more 
than the additive effect of each costimulatory molecule when used 
individually to optimally activate both CD4+ and CD8+ T cells. The 
result is that when a TRICOM based vaccine expressing TAAs is 
administered it greatly enhances the immune response against the 
malignant cells expressing those TAAs. By changing the TAAs used for 
immunization with TRICOM vaccines immune responses can be generated to 
diverse types of cancers. The versatility of the vector-based TRICOM 
based vaccine is that it allows including several TAAs to help maximize 
the effectiveness. Transgenes reflecting alterations of TAAs can also 
be inserted into TRICOM based vaccines to further enhance 
immunogenicity.
    The addition of the two well-known TAAs, carcinoembryonic antigen 
(CEA) and MUC-1, to the TRICOM vector results in the PANVAC vaccine, 
which is used in a prime and boost vaccine strategy. It is well 
established that the overexpression of these two TAAs is associated 
with the presence of a variety of carcinomas; therefore PANVAC is 
potentially effective against a range of tumor types.
    New TAAs are being continually identified. One such example is 
Brachyury. Although Brachyury has been well known for its role in 
developmental cell biology, it has now been implicated in tumor cell 
invasion and metastasis. Pre-clinical data indicates that Brachyury is 
aberrantly expressed on tumors of lung, intestine, stomach, kidney, 
bladder, uterus, ovary, and testis, and in chronic lymphocytic 
leukemia. Additionally, in combination with costimulatory molecules, it 
can effectively activate T-cells to kill cells that originated from 
these tumors. Therefore, as one example, Brachyury combined with TRICOM 
also has potential as a cancer immunotherapy for the treatment of 
several tumors.

Availability

    The technology is available for exclusive and non-exclusive 
license. Some potential licensing opportunities involving recombinant 
poxviral vectors containing transgenes are as follows:
     TRICOM (alone or with a transgene or transgenes for a 
tumor antigen(s) and/or an immunostimulatory molecule).
     PANVAC (CEA-Muc1-TRICOM), with CEA and Muc1 transgenes 
also containing enhancer agonist epitopes.
     Recombinant fowlpox-GM-CSF.
     Brachyury and/or other TAAs with TRICOM.

Applications and Modality

    Vector-based TRICOM (alone or with a transgene(s) for a tumor 
antigen and/or an immunostimulatory molecule(s)), PANVAC and 
combinations thereof can be a potential novel approach for the 
prevention or treatment of cancer (with the exclusion of prostate 
cancer, prostatic diseases, melanoma, and colorectal cancer) and 
infectious diseases.

Market

    With the identification of molecular targets associated with 
cancer, the focus of drug development has shifted from broadly acting 
cytotoxic drugs to targeted therapeutics in the hope of finding drugs 
that selectively kill cancer cells and do not harm normal cells. 
Historically, because the expertise of pharmaceutical companies has 
been in the domain of small molecule therapeutics, several compounds 
have been developed that inhibit the abnormal biochemical activity of 
cancer cells. This approach has been successful to an extent as 
illustrated by the kinase inhibitors and EGFR inhibitors. However, as 
for chemotherapeutics, cancer cells frequently acquire drug resistance 
to targeted small-molecule therapeutics rendering them ineffective in 
the long run. In addition, these small-molecules produce adverse side 
effects which can prevent the administration of the maximum effective 
dose. An alternative approach to overcome these problems relies on the 
use of biologics such as antibodies and vaccines.
    The biotechnology industry has principally focused on an 
immunotherapy approach using monoclonal antibodies (mAb) to enlist the 
help of the patient's own immune

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system. This approach has successfully led to several FDA approved and 
marketed mAbs. Typically, cancer cells are less susceptible to 
acquiring resistance to antibodies; however, as seen for trastuzumab, 
resistance can occur. Another limitation of mAbs is that they activate 
only part of the immune system and do not produce future immunity 
against the cancer. Currently, monoclonal antibodies are the only 
immunotherapy available for treating cancer. More recently, cancer 
vaccines are being developed as an improvement on the immunotherapy 
approach. It is expected that activating the cells of the immune system 
should be greatly more effective in killing cancer cells with the added 
benefit that it would lead to a sustained surveillance by the patient's 
own body that prevents the tumor from reemerging in the future.
    Vaccines have been very successful in the prevention of infectious 
diseases, and are now being evaluated for the treatment of cancer. The 
development of a cancer vaccine could result in a paradigm shift in the 
treatment and clinical management of cancer. Currently, there are no 
cancer vaccines approved for the U.S. market but this could change with 
the development of the TRICOM-based technology of costimulatory 
vaccines that is designed to magnify the immune response against cancer 
cells and lead to prolonged cancer immunity.
    PANVAC, using TRICOM, has much potential for becoming a 
therapeutically effective cancer vaccine. It has been successful in 
Phase I and II clinical studies demonstrating a high safety profile and 
that it is a good candidate for initiating pivotal efficacy studies. 
Recently, very encouraging results were announced for prostate cancer 
therapy using PROSTVACTM which is a vaccine based on the 
same technology platform as PANVAC, which further validates this 
technology platform. PANVAC is a decidedly mature technology that holds 
promise to transform the treatment of cancer.

Patent Estate

    The portfolio includes the following issued patents and pending 
patent applications:
    1. U.S. Patent No. 6,969,609 issued 29 Nov. 2005 as well as issued 
and pending foreign counterparts [HHS Ref. No. E-256-1998/0];
    2. U.S. Patent Application No. 11/321,868 filed 30 Dec. 2005 [HHS 
Ref. No. E-256-1998/1]; and
    3. U.S. Patent No. 6,756,038 issued 29 Jun. 2004 as well as issued 
and pending foreign counterparts [HHS Ref. No. E-099-1996/0];
    4. U.S. Patent No. 6,001,349 issued 14 Dec. 1999 as well as issued 
and pending foreign counterparts [HHS Ref. No. E-200-1990/3-US-01];
    5. U.S. Patent No. 6,165,460 issued 26 Dec. 2000 as well as issued 
and pending foreign counterparts [HHS Ref. No. E-200-1990/4-US-01];
    6. U.S. Patent No. 7,118,738 issued 10 Oct. 2006 as well as issued 
and pending foreign counterparts [HHS Ref. No. E-154-1998/0-US-07];
    7. PCT Application No. PCT/US97/12203 filed 15 Jul. 1997 [HHS Ref. 
No. E-259-1994/3-PCT-02];
    8. U.S. Patent Nos. 7,410,644 issued 12 Aug. 2008 and U.S. Patent 
Application No. 08/686,280 filed 25 Jul. 1996 [HHS Ref. No. E-259-1994/
3-US-08 and/4-US-01];
    9. U.S. Patent No. 6,946,133 issued 20 Sep. 2005 as well as issued 
and pending foreign counterparts [HHS Ref. No. E-062-1996/0-US-01];
    10. U.S. Patent Application No. 11/606,929 filed 1 Dec. 2006 [HHS 
Ref. No. E-062-1996/0-US-11];
    11. U.S. Patent Nos. 6,893,869, 6,548,068 and 6,045,802 issued 17 
May 2005, 15 Apr. 2003 and 4 Apr. 2000 respectively, as well as issued 
and pending foreign counterparts [HHS Ref. Nos. E-260-1994/1-US-03, US-
02, US-01]; and
    12. U.S. Patent No. 7,368,116 issued 6 May 2008 [HHS Ref. No. E-
260-1994/1-US-04];
    13. U.S. Patent Application No. 12/280,534 filed 21 Feb. 2007, 
which published as US-2009-0035266 on 5 Feb. 2009, as well as pending 
foreign counterparts [HHS Ref. No. E-104-2006/0-US-06];
    14. PCT Application No. PCT/US2008/055185 filed 27 Feb. 2008, which 
published as WO 2008/106551 on 4 Sep. 2008 [HHS Ref. No. E-074-2007/0-
PCT-02].
    Note that some of the patent estate above is available for non-
exclusive licensing only.

Cooperative Research and Development Agreement (CRADA) Opportunities

    A CRADA partner for the further codevelopment of this technology in 
all cancers with the exception of prostate, melanoma and colorectal 
cancer is currently being sought by the Laboratory of Tumor Immunology 
and Biology, Center for Cancer Research, NCI. The CRADA partner will 
(a) generate recombinant poxviruses expressing specific tumor-
associated antigens, cytokines, and/or T-cell costimulatory factors, 
(b) cooperate to analyze the recombinant poxviruses containing these 
genes with respect to appropriate expression of the encoded gene 
product(s), (c) supply adequate amounts of recombinant virus stocks for 
preclinical testing, (d) manufacture selected recombinant vaccines for 
use in human clinical trials (with the exception of trials for 
prostatic diseases, melanoma, and colorectal cancer), (e) submit Drug 
Master Files detailing the development, manufacture, and testing of 
live recombinant vaccines to support the NCI-sponsored IND and/or 
company-sponsored IND, (f) supply adequate amounts of clinical grade 
recombinant poxvirus vaccines for clinical trials conducted at the NCI 
Center for Cancer Research (CCR), and (g) provide adequate amounts of 
vaccines for extramural clinical trials, if agreed upon by the parties, 
and conduct clinical trials under company-sponsored or NCI-sponsored 
INDs. NCI will (a) provide genes of tumor-associated antigens, 
cytokines and other immunostimulatory molecules for incorporation into 
poxvirus vectors, (b) evaluate recombinant vectors in preclinical 
models alone and in combination therapies, and (c) conduct clinical 
trials (with the exception of trials for prostatic diseases, melanoma, 
and colorectal cancer) of recombinant vaccines alone and in combination 
therapies.

Next Step: Teleconference

    There will be a teleconference where the principal investigator, 
Dr. Jeffrey Schlom, will discuss this technology. Licensing and 
collaborative research opportunities will also be discussed. If you are 
interested in participating in this teleconference, please call or e-
mail Sabarni Chatterjee; 301-435-5587; [email protected]. OTT 
will then e-mail you the date, time, and number for the teleconference.

    Dated: April 29, 2009.
Richard U. Rodriguez,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. E9-10479 Filed 5-5-09; 8:45 am]
BILLING CODE 4140-01-P