Cancer immunotherapy is a recent 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 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 present technology describes recombinant poxvirus vectors encoding at least three or more costimulatory molecules and tumor associated antigens (TAAs).  The use of three costimulatory molecules such as B7.1, ICAM-1 and LFA-3 (TRICOM®) has been shown to act in synergy with several tumor antigens and antigen epitopes to activate T cells.  The effects with TRICOM® were significantly greater than with one or two costimulatory molecules.  Laboratory results support the greater effect of TRICOM® to activate both CD4⁺ and CD8⁺ T cells.  The invention also describes the use of at least one target antigen or immunological epitope as an immunogen or vaccine in conjunction with TRICOM®.  The antigens include but are not limited to carcinoembryonic antigen (CEA) and MUC-1.  The combination of CEA, MUC-1, and TRICOM® is referred to as PANVAC®.

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, and melanoma) and infectious diseases.

Advantages

• The technology is beyond proof-of-concept, supported by laboratory results and publications.
• Phase I and Phase II clinical data available (to qualified licensees).
• Fewer validation studies are required compared to other immunotherapy related technologies.

Development Status: 

Phase I and Phase II results available (to qualified licensees) for poxvirus recombinants containing transgenes for TRICOM®, CEA-TRICOM®, and PANVAC®.  Further clinical studies are ongoing.

Publications:

1. Kudo-Saito C, Wansley EK, Gruys ME, Wiltrout R, Schlom J, Hodge J. Combination therapy of an orthotopic renal cell carcinoma model using intratumoral vector-mediated costimulation and systemic IL-2. Clin Cancer Res. 2007 Mar 15;13(6):1936-1946.  [PubMed abs]
2. Chakraborty M, Schlom J, Hodge JW. The combined activation of positive costimulatory signals with modulation of a negative costimulatory signal for the enhancement of vaccine-mediated T-cell responses. Cancer Immunol Immunother. 2007 Sep;56(9):1471-1484.  [PubMed abs]
3. Kudo-Saito C, Garnett CT, Wansley EK, Schlom J, Hodge JW. Intratumoral delivery of vector mediated IL-2 in combination with vaccine results in enhanced T-cell avidity and anti-tumor activity. Cancer Immunol Immunother. 2007 Dec;56(12):1897-1910.  [PubMed abs]
4. Garnett CT, Schlom J, Hodge JW. Combination of docetaxel and recombinant vaccine enhances T-cell responses and antitumor activity: effects of docetaxel on immune enhancement. Clin Cancer Res. 2008 Jun 1;14(11):3536-3544.  [PubMed abs]
5. Chakraborty M, Gelbard A, Carrasquillo JA, Yu S, Mamede M, Paik CH, Camphausen K, Schlom J, Hodge JW. Use of radiolabeled monoclonal antibody to enhance vaccine-mediated antitumor effects. Cancer Immunol Immunother. 2008 Aug;57(8):1173-1183.  [PubMed abs]
6. Litzinger MT, Fernando R, Curiel TJ, Grosenbach DW, Schlom J, Palena C. IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity. Blood 2007 Nov 1;110(9):3192-3201.  [PubMed abs]
7. Gelbard A, Garnett CT, Abrams SI, Patel V, Gutkind JS, Palena C, Tsang KY, Schlom J, Hodge JW. Combination chemotherapy and radiation of human squamous cell carcinoma of the head and neck augments CTL-mediated lysis. Clin Cancer Res. 2006 Mar 15;12(6):1897-1905.  [PubMed abs]
8. Kaufman HL, Cohen S, Cheung K, DeRaffele, Mitcham J, Moroziewicz D, Schlom J, Hesdorffer C. Local delivery of vaccinia virus expressing multiple costimulatory molecules for the treatment of established tumors. Hum Gene Ther. 2006 Feb;17(2):239-244.  [PubMed abs]
9. Marshall J, Gulley JL, Arlen PM, Beetham PK, Tsang KY, Slack R, Hodge JW, Doren S, Grosenbach DW, Hwang J, Fox E, Odogwa L, Park S, Panicali D, Schlom J. Phase I study of sequential vaccinations with fowlpox-CEA(6D)-TRICOM (B7-1/ICAM-1/LFA-3) alone and sequentially with vaccinia-CEA(6D)-TRICOM, with and without GM-CSF, in patients with CEA-expressing carcinomas. J Clin Oncol. 2005 Feb 1;23(4):720-731.  [PubMed abs]
10. Palena C, Foon KA, Panicali D, Yafal AG, Chinsangaram J, Hodge JW, Schlom J, Tsang KY. Potential approach to immunotherapy of chronic lymphocytic leukemia (CLL): enhanced immunogenicity of CLL cells via infection with vectors encoding for multiple costimulatory molecules. Blood. 2005 Nov 15;106(10):3515-3523.  [PubMed abs]
11. Yang S, Hodge JW, Grosenbach DW, Schlom J. Vaccines with enhanced costimulation maintain high avidity memory CTL. J. Immunol. 2005 Sep 15;175(6):3715-3723.  [PubMed abs]
12. Yang S, Tsang KY, Schlom J. Induction of higher avidity human CTL by vector-mediated enhanced costimulation of antigen-presenting cells. Clin Cancer Res. 2005 Aug 1;11(15):5603-5615.  [PubMed abs]
13. Hodge JW, Chakraborty M, Kudo-Saito C, Garnett CT, Schlom J. Multiple costimulatory modalities enhance CTL avidity. J Immunol. 2005 May 15;174(10):5994-6004.  [PubMed abs]
14. Tsang K-Y, Palena C, Yokokawa J, Arlen PM, Gulley JL, Mazzara GP, Gritz L, Gómez Yafal A, Ogueta S, Greenhalgh P, Manson K, Panicali D, Schlom J. Analyses of recombinant vaccinia and fowlpox vaccine vectors expressing transgenes for two human tumor antigens and three human costimulatory molecules. Clin Cancer Res. 2005 Feb 15;11(4):1597-1607.  [PubMed abs]
15. Chakraborty M, Abrams SI, Coleman CN, Camphausen K, Schlom J, Hodge JW. External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing. Cancer Res. 2004 Jun 15;64(12):4328-4337.  [PubMed abs]
16. Zeytin HE, Patel AC, Rogers CJ, Canter D, Hursting SD, Schlom J, Greiner JW. Combination of a poxvirus-based vaccine with a cyclooxygenase-2 inhibitor (celecoxib) elicits antitumor immunity and long-term survival in CEA.Tg/MIN mice. Cancer Res. 2004 May 15;64(10):3668-3678.  [PubMed abs]
17. Palena C, Zhu M-Z, Schlom J, Tsang K-Y. Human B cells that hyperexpress a triad of costimulatory molecules via avipox-vector infection: an alternative source of efficient antigen-presenting cells. Blood. 2004 Jul 1;104(1):192-199.  [PubMed abs]
18. Kudo-Saito C, Schlom J, Hodge JW. Intratumoral vaccination and diversified subcutaneous/intratumoral vaccination with recombinant poxviruses encoding a tumor antigen and multiple costimulatory molecules. 2004 Feb 1;10(3):1090-1099.  [PubMed abs]
19. Hodge JW, Poole DJ, Aarts WM, Gomez Yafal A, Gritz L, Schlom J. Modified vaccinia virus ankara recombinants are as potent as vaccinia recombinants in diversified prime and boost vaccine regimens to elicit therapeutic antitumor responses. Cancer Res. 2003 Nov 15;63(22):7942-7949.  [PubMed abs]
20. Hodge JW, Grosenbach DW, Aarts Wm, Poole DJ, Schlom J. Vaccine therapy of established tumors in the absence of autoimmunity. Clin Cancer Res. 2003 May;9(5):1837-1849.  [PubMed abs]
21. Aarts WM, Schlom J, Hodge JW. Vector-based vaccine/cytokine combination therapy to enhance induction of immune responses to a self-antigen and anti-tumor activity. Cancer Res. 2002 Oct 15;62(20):5770-5777.  [PubMed abs]
22. Hodge JW, Sabzevari H, Yafal AG, Gritz L, Lorenz MG, Schlom J.  A triad of costimulatory molecules synergize to amplify T-cell activation. Cancer Res. 1999 Nov 15;59(22):5800-5807.  [PubMed abs]

• U.S. Patent No. 6,969,609 issued November 29, 2005 as well as issued and pending foreign counterparts [HHS Ref. No. E-256-1998/0];
• U.S. Patent Application No. 11/321,868 filed December 30, 2005 [HHS Ref. No. E-256-1998/1]; and
• U.S. Patent No. 6,756,038 issued June 29, 2004 as well as issued and pending foreign counterparts [HHS Ref. No. E-099-1996/0];
• U.S. Patent No. 6,001,349 issued December 14, 1999 as well as issued and pending foreign counterparts [HHS Ref. No. E-200-1990/3-US-01];
• U.S. Patent No.6,165,460 issued December 26, 2000 as well as issued and pending foreign counterparts [HHS Ref. No. E-200-1990/4-US-01];
• U.S. Patent No. 7,118,738 issued October 10, 2006 as well as issued and pending foreign counterparts [HHS Ref. No. E-154-1998/0-US-07];
• PCT Application No. PCT/US97/12203 filed July 15, 1997 [HHS Ref. No E-259-1994/3-PCT-02];
• U.S. Patent Application Nos. 10/197,127.and 08/686,280 filed July 17, 2002 and July 25, 1996 [HHS Ref. No E-259-1994/3-US-08 and /4-US-01];
• U.S. Patent No. 6,946,133 issued September 20, 2005 as well as issued and pending foreign counterparts [HHS Ref. No. E-062-1996/0-US-01];
• U.S. Patent Application No. 11/606,929 filed December 1, 2006 [E-062-1996/0-US-11];
• U.S. Patent Nos. 6,893,869, 6,548,068 and 6,045,802 issued May 17, 2005, April 15, 2003 and April 4, 2000 respectively, as well as issued and pending foreign counterparts [HHS Ref. Nos. E-260-1994/1-US-03, US-02, US-01]; and
• U.S. Patent Application No. 11/090,686 filed March 8, 2005 [HHS Ref. No E-260-1994/1-US-04].

Inventors: 

Jeffrey Schlom (NCI) et al.

Licensees Sought: 

The technology is available for exclusive and non-exclusive license in combinations and fields of use.  Some potential licensing opportunities involving recombinant poxviral vectors containing transgenes are as follows:

1. TRICOM® (alone or with a transgene for a tumor antigen and/or an immunostimulatory molecule);
2. The antigens only, including but not limited to CEA and MUC-1;
3. PANVAC®; and
4. Recombinant fowlpox-GM-CSF.

Collaborative Research Opportunity:  

A Cooperative Research and Development Agreement (CRADA) partner for the further co-development of this technology is currently being sought by the Laboratory of Tumor Immunology and Biology, Center for Cancer Research, NCI.

The CRADA partner will:

1. generate and characterize recombinant poxviruses expressing specific tumor-associated antigens, cytokines, and/or T-cell costimulatory factors,
2. analyze the recombinant poxviruses containing these genes with respect to appropriate expression of the encoded gene product(s),
3. supply adequate amounts of recombinant virus stocks for preclinical testing,
4. manufacture and test selected recombinant viruses for use in human clinical trials (with the exception of trials for prostatic diseases and melanoma),
5. 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,
6. supply adequate amounts of clinical grade recombinant poxvirus vaccines for clinical trials conducted at the NCI Center for Cancer Research (CCR), and
7. 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:

1. provide genes of tumor-associated antigens, cytokines and other immunostimulatory molecules for incorporation into poxvirus vectors,
2. evaluate recombinant vectors in preclinical models alone and in combination therapies, and
3. conduct clinical trials (with the exception of trials for prostatic diseases and melanoma) of recombinant vaccines alone and in combination therapies.

If interested in a Cooperative Research and Development Agreement (CRADA) Opportunity, please submit a statement of interest and capability to Kevin Brand, J.D., in the NCI Technology Transfer Center, telephone: 301/451-4566; email: kb229t@nih.gov.