Notice (B): Government-Owned Inventions; Availability for Licensing

Federal Register: November 12, 2009 (Volume 74, Number 217)        
                  Page 58293-58295

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

ACTION: Notice.

SUMMARY: The inventions listed below are owned by an agency of the U.S. 
Government and are available for licensing in the U.S. in accordance 
with 35 U.S.C. 207 to achieve expeditious commercialization of results 
of federally-funded research and development. Foreign patent 
applications are filed on selected inventions to extend market coverage 
for companies and may also be available for licensing.

ADDRESSES: Licensing information and copies of the U.S. patent 
applications listed below may be obtained by writing to the indicated 
licensing contact at the Office of Technology Transfer, National 
Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, 
Maryland 20852-3804; telephone: 301/496-7057; fax: 301/402-0220. A 
signed Confidential Disclosure Agreement will be required to receive 
copies of the patent applications.

Simpler Is Better: The Production of Young Cell Cultures From Tumor 
Infiltrating Lymphocytes (TIL) Yields More Effective Adoptive Cell 
Transfer (ACT) Immunotherapies

    Description of Technology: Available for licensing is an improved 
method of adoptive cell transfer (ACT) immunotherapy that can be 
utilized to treat a variety of infectious diseases and cancers, most 
notably melanoma.
    At its foundation, ACT involves isolating lymphocytes with high 
affinity for a particular antigen, expanding those cells in vitro to 
produce a greater quantity of reactive cells, and infusing the product 
cells into patients to attack cells expressing the antigen, such as 
tumor cells, bacterial cells, or viral particles. Previously utilized 
ACT procedures have been plagued by technical, regulatory, and 
logistical problems that have prevented consistently successful 
clinical outcomes. Through years of research, scientists at the 
National Institutes of Health (NIH) have made great strides in 
developing ACT into a viable approach to treat cancer patients. Of 
note, the ACT protocols developed by NIH scientists have successfully 
treated patients with refractory metastatic melanoma who started with 
very few effective treatment options. These NIH scientists have found 
that isolating cells from the tumor infiltrating lymphocytes (TIL) of a 
patient tumor sample provides a suitable initial lymphocyte culture for 
further in vitro manipulations. They have also discovered that taking 
the isolated cells through one cycle of rapid expansion (including 
exposure to IL-2), rather than multiple cycles, yields lymphocyte 
cultures with higher affinity and longer persistence in patients. Also, 
they have found that administering nonmyeloablative lymphodepleting 
chemotherapy prior to the reinfusion of lymphocytes creates a more 
favorable environment within patients for the transferred cells to 
execute target cell killing. These scientists envision that, for an ACT 
immunotherapy to gain regulatory approval and successfully treat a wide 
array of patients, it will need to be rapid, reliable, and technically 
simple. One of the most critical factors to this approach is the 
generation of effective lymphocyte cultures that will rapidly and 
repeatedly attack the target cells when infused into patients.
    Scientists at the NIH have developed a method of generating CD8+ 
selected ``young'' lymphocyte cultures for infusion into cancer 
patients. Lymphocytes that spend fewer days in vitro between their 
initial isolation from TIL and their ultimate reinfusion into patients 
compared to lymphocytes cultured by previous ACT protocols are 
considered young lymphocyte cultures. Young lymphocytes, typically 19-
35 days old when reinfused into patients, exhibit improved 
proliferation, survival, and enhanced anti-tumor activity within 
patients to yield greater tumor regression compared to older

[[Page 58294]]

lymphocytes, typically 44+ days old. Furthermore, the generation of 
young lymphocyte cultures is more rapid, reliable, and technically 
easier than previous ACT culturing methods. Young lymphocytes are 
isolated from TIL, directed against a single isolated tumor cell 
suspension, enriched for CD8 expression, and rapidly expanded once 
using autologous feeder cells without testing the culture for antigen 
specificity.
    This approach to ACT offers a potentially significant improvement 
and a valuable new immunotherapeutic tool for attacking tumors many 
types of tumors. For diseases, such as metastatic melanoma, where 
patients may only have weeks or months of life expectancy, this 
technology, which provides for improved cell cultures prepared in less 
time, can make a difference between life and death. In addition, this 
method might be applicable in treating other diseases such as AIDS, 
immunodeficiency, or other autoimmunity for which immune effector cells 
can impact the clinical outcome.
    Applications:
     An improved immunotherapy methodology to treat and/or 
prevent the recurrence of a variety of human cancers, such as melanomas 
and glioblastomas, infectious diseases, and autoimmune diseases by 
transferring young lymphocyte cultures engineered into cancer patients.
     A technically simpler, more rapid, more clinically 
reliable ACT procedure with greater potential to overcome the 
technical, regulatory, and logistical hurdles of past ACT methods. This 
technology could be broadly transferrable to a wide array of 
institutions to treat a wide array of patients.
     The immunotherapy component of a combination therapy 
regimen aimed at targeting the specific tumor-associated antigens 
expressed by the cancer cells of individual patients.
    Advantages:
     Technically simpler than previous ACT methods: Decreased 
number of steps in the procedure and less analysis of the cell cultures 
prior to reinfusion into patients.
     More rapid than previous ACT methods: Adoptively 
transferred lymphocytes spend fewer days undergoing in vitro culturing, 
so they are introduced to patients with potentially short life 
expectancies more quickly.
     Reliable, life-saving technology: This technology is 
anticipated by the inventors to yield greater tumor regression and more 
objective clinical responses in patients compared to previous ACT 
protocols and all previously attempted treatments for metastatic 
melanoma.
    Development Status: This technology is being utilized in a clinical 
protocol for adoptive cell transfer. The technology is a critical 
component of the successful immunotherapy regimen being used by the 
inventors and other clinicians at the NCI. Patients enrolled in ACT 
protocols are expected to show enhanced tumor regression and more 
objective responses compared to results obtained with previous 
protocols.
    Market: Cancer continues to be a medical and financial burden on 
U.S. public health. According to U.S. estimates, cancer is the second 
leading cause of death with over 565,000 deaths reported in 2008 and 
almost 1.5 million new cases were reported (excluding some skin 
cancers) in 2008. In 2007, the NIH estimated that the overall cost of 
cancer was $219.2 billion dollars and $89 billion went to direct 
medical costs. Despite our increasing knowledge of oncology and cancer 
treatment methods, the fight against cancer will continue to benefit 
from the development of new therapeutics aimed at treating individual 
patients.
    Inventors: Mark E. Dudley and Steven A. Rosenberg (NCI).
    Related Publications:
    1. KQ Tran et al. Minimally cultured tumor-infiltrating lymphocytes 
display optimal characteristics for adoptive cell therapy. J 
Immunother. 2008 Oct;31(8):742-751.
    2. SA Rosenberg and ME Dudley. Adoptive cell therapy for the 
treatment of patients with metastatic melanoma. Curr Opin Immunol. 2009 
Apr;21(2):233-240
    Patent Status: HHS Reference No. E-273-2009/0--U.S. Provisional 
Application No. 61/237,889 filed 28 Aug 2009
    Related Technologies: HHS Reference No. E-275-2002/1--U.S. Patent 
Application No. 10/526,697 filed 05 May 2005 (foreign counterparts in 
Europe, Canada, and Australia)
    Licensing Status: Available for licensing.
    Licensing Contact: Samuel E. Bish, Ph.D.; 301-435-5282; 
bishse@mail.nih.gov
    Collaborative Research Opportunity: The Center for Cancer Research, 
Surgery Branch, is seeking statements of capability or interest from 
parties interested in collaborative research to further develop, 
evaluate, or commercialize cell and gene therapy technologies, and 
personalized medicines. Please contact John D. Hewes, Ph.D. at 301-435-
3121 or hewesj@mail.nih.gov for more information.

Treating Cancer With Anti-Angiogenic Chimeric Antigen Receptors

    Description of Technology: Metastasis, the growth and spread of 
cancer from a localized tumor to other sites in the body, is promoted 
by the formation of new blood vessels through angiogenesis to ``feed'' 
the tumor. There is an urgent need to develop new therapeutic 
strategies that combine fewer side-effects and more specific anti-tumor 
activity in order to block cancer metastasis in patients. Adoptive 
immunotherapy is a promising new approach to cancer treatment that 
engineers an individual's innate and adaptive immune system to fight 
against specific diseases, including the spread of cancer.
    Chimeric antigen receptors (CARs) are hybrid proteins consisting of 
the portion of an antibody that recognizes a tumor-associated antigen 
(TAA) fused to protein domains that signal to activate the CAR-
expressing cell. Human cells that express CARs, most notably T cells, 
can recognize specific tumor antigens in an MHC-unrestricted manner 
with high reactivity. CARs are able to mediate an immune response that 
promotes robust tumor killing in targeted cells.
    Scientists at the National Institutes of Health (NIH) have 
developed CARs with high affinity for the vascular endothelial growth 
factor receptor 2 (VEGFR2) (also known as kinase domain region (KDR) in 
humans and fetal liver kinase-1 (Flk-1) in mice) to utilize as an 
antiangiogenic tumor therapy. VEGFR2 is expressed on non-cancerous 
vascular endothelia cells, but is overexpressed on tumor endothelial 
cells in a variety of cancers, especially solid tumors. VEGFR2 
overexpression promotes tumor vasculature, growth, and metastasis. The 
VEGFR2-specific CARs feature the antigen binding domain of the KDR-1121 
or DC101 antibody, which recognize portions of the human and mouse 
VEGFR2, respectively. This antibody component is fused to the 
transmembrane and intracellular signaling domains of a T cell receptor 
(TCR). These CARs combine high affinity recognition of VEGFR2 provided 
by the antibody portion with the target cell killing activity of a cell 
expressing an activated TCR. Infusion of these VEGFR2-specific CARs 
into patients could prove to be a powerful new immunotherapeutic tool 
for blocking angiogenic cancer metastasis by killing VEGFR2+ tumor 
cells.
    Applications:
     Immunotherapeutics to treat and/or prevent the 
reoccurrence of a variety of

[[Page 58295]]

human cancers that overexpress human VEGFR2 by introducing anti-VEGFR2 
CAR expressing T cells into patients with metastatic cancer.
     A possible prophylactic therapy to prevent the spread of 
cancer in patients whose cancer is predicted to metastasize.
     A drug component of a combination immunotherapy regimen 
aimed at targeting the specific tumor-associated antigens expressed by 
cancer cells within individual patients.
    Advantages:
     This discovery is widely applicable to many different 
cancers: VEGFR2 is overexpressed in many metastatic cancers that 
utilize angiogenesis to spread from their initial site of development. 
An immunotherapy protocol using anti-VEGFR2 CAR could treat a variety 
of cancer types.
     Antiangiogenic tumor therapy is anticipated to generate 
fewer side-effects compared to other treatment approaches: These CARs 
can be delivered directly to the bloodstream to gain easy access to the 
targeted tumor vascular endothelial cells with minimal effects to 
normal tissues. Furthermore, destroying tumor blood vessels could 
accelerate tumor cell death so that the therapy can be administered for 
a shorter period of time. A reduced therapeutic timeframe and minimal 
access to normal tissues should contribute to reduced side-effects and 
lowered toxicity for this treatment.
     The technology is anticipated to be highly effective and 
killing metastatic cells: Most angiogenic tumor epithelial cells are 
believed to overexpress VEGFR2 to a similar degree. Administering a 
therapeutically effective amount of anti-VEGFR2 CARs to patients may 
leave no or little tumor cells remaining with an opportunity to 
metastasize. Many current angiogenesis therapies do not kill tumors, 
but rather stabilize the tumor, so they require long periods of 
administration.
    Development Status: This technology could soon be ready for 
clinical development since the inventors plan to initiate clinical 
trials using CAR engineered lymphocytes for adoptive immunotherapy of 
cancer.
    Market: The Food and Drug Administration (FDA) has approved eight 
therapies with antiangiogenic properties, including Avastin[reg], 
Erbitux[reg], Vectibix[reg], Herceptin[reg], Tarceva[reg], 
Nexavar[reg], Sutent[reg], Torisel\TM\, Velcade[reg], and 
Thalomid[reg]. The majority of these drugs produced worldwide sales 
exceeding an estimated $500 million in 2007. The fight against cancer 
and its spread will continue to benefit from the development of new 
therapeutics aimed at treating individual patients.
    Cancer continues to be a medical and financial burden on U.S. 
public health. Statistically, in the U.S. cancer is the second leading 
cause of death with over 565,000 deaths reported in 2008 and almost 1.5 
million new cases were reported (excluding some skin cancers) in 2008, 
many with the potential to metastasize. In 2007, the NIH estimated that 
the overall cost of cancer was $219.2 billion dollars and $89 billion 
went to direct medical costs.
    Inventors: Steven A. Rosenberg et al. (NCI).
    Patent Status: HHS Reference No. E-205-2009/0--U.S. Provisional 
Application No. 61/247,625 filed 01 Oct 2009.
    Related Technologies:
     E-045-2009/0--U.S. Provisional Application No. 61/154,080 
filed 20 Feb 2009
     E-312-2007/1--PCT Application No. PCT/US2008/077333 filed 
23 Sep 2008
     E-059-2007/2--PCT Application No. PCT/US2008/050841 filed 
11 Jan 2008, which published as WO 2008/089053 on 24 Jul 2008
     E-304-2006/0--U.S. Provisional Patent Application No. 60/
847,447 filed 26 Sep 2006; PCT Application No. PCT/US2007/079487 filed 
26 Sep 2007, which published as WO 2008/039818 on 03 Apr 2008
     E-093-1995/0--PCT Application No. PCT/US1996/04143 filed 
27 Mar 1996, which published as WO 1996/30516 on 03 Oct 1996
     E-093-1995/2--U.S. Non-Provisional Application No. 08/
084,994 filed 02 Jul 1993
    Licensing Status: Available for licensing.
    Licensing Contact: Samuel E. Bish, Ph.D.; 301-435-5282; 
bishse@mail.nih.gov.
    Collaborative Research Opportunity: The Center for Cancer Research, 
Surgery Branch, is seeking statements of capability or interest from 
parties interested in collaborative research to further develop, 
evaluate, or commercialize this technology. Please contact John D. 
Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more 
information.

    Dated: November 3, 2009.
Richard U. Rodriguez,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. E9-27199 Filed 11-10-09; 8:45 am]

BILLING CODE 4140-01-P