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Enhanced T-cell Activation by Costimulation: An Effective Immunotherapy for Cancer and Infectious Diseases

Posted Jun 09 2010 5:00pm

Description of Invention:
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 result 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 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), prostate-specific antigen (PSA), and MUC-1.

The combination of CEA, MUC-1, and TRICOM® is referred to as PANVAC® and the combination of PSA and TRICOM® is referred to as PROSTVAC®.

Vector-based TRICOM® (alone or with a transgene for a tumor antigen and/or an immunostimulatory molecule), PANVAC® and PROSTVAC® and combinations thereof can be a potential novel immunotherapeutic approach for the treatment of cancer and infectious diseases.

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

Development Status:
Phase I and Phase II results available for poxvirus recombinants containing transgenes for TRICOM®, CEA-TRICOM®, PANVAC®, and PROSTVAC®. Further clinical studies are ongoing for other combinations.

Jeffrey Schlom (NCI)

Patent Status:
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Relevant Publication:
  1. HL Kaufman, S Cohen, K Cheung, G DeRaffele, J Mitcham, D Moroziewicz, J Schlom, C Hesdorffer. 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 ]
  2. PW Kantoff, LM Glode, SI Tannenbaum, DL Bilhartz, WG Pittman, TJ Schuetz. Randomized, double-blind, vector-controlled study of targeted immunotherapy in patients (pts) with hormone-refractory prostate cancer (HRPC). J Clin Oncol., 2006 ASCO Annual Meeting Proceedings, Part I, Vol 24, No 18S (June 20 Supplement), Abstract No. 2501 . [ Abstract No. 2501 ]
  3. JL Marshall, JL Gulley, PM Arlen, PK Beetham, KY Tsang, R Slack, JW Hodge, S Doren, DW Grosenbach, J Hwang, E Fox, L Odogwu, S Park, D Panicali, J Schlom. Phase I study of sequential vaccinations with fowlpox-CEA(6D)-TRICOM alone and sequentially with vaccinia-CEA(6D)-TRICOM, with and without granulocyte-macrophage colony-stimulating factor, in patients with carcinoembryonic antigen-expressing carcinomas. J Clin Oncol. 2005 Feb 1;23(4):720-731. [ PubMed abs ]
  4. C Palena, KA Foon, D Panicali, AG Yafal, J Chinsangaram, JW Hodge, J Schlom, KY Tsang. 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 ]
  5. J Gulley, N Todd, W Dahut, J Schlom, P Arlen. A phase II study of PROSTVAC-VF vaccine, and the role of GM-CSF, in patients (pts) with metastatic androgen insensitive prostate cancer (AIPC). J Clin Oncol., 2005 ASCO Annual Meeting Proceedings, Vol 23, No 16S (June 1 Supplement), Abstract No. 2504 . [ Abstract No. 2504 ]
  6. S Yang, JW Hodge, DW Grosenbach, J Schlom. Vaccines with enhanced costimulation maintain high avidity memory CTL. J. Immunol. 2005 Sep 15;175(6):3715-3723. [ PubMed abs ]
  7. S Yang, KY Tsang, J Schlom. Induction of higher avidity human CTLs by vector-mediated enhanced costimulation of antigen-presenting cells. Clin Cancer Res. 2005 Aug 1;11(15):5603-5615. [ PubMed abs ]
  8. JW Hodge, M Chakraborty, C Kudo-Saito, CT Garnett, J Schlom. Multiple costimulatory modalities enhance CTL avidity. J Immunol. 2005 May 15;174(10):5994-6004. [ PubMed abs ]
  9. KY Tsang, C Palena, J Yokokawa, PM Arlen, JL Gulley, GP Mazzara, L Gritz, A Gómez Yafal, S Ogueta, P Greenhalgh, K Manson, D Panicali, J Schlom. 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 ]
  10. M Chakraborty, SI Abrams, CN Coleman, K Camphausen, J Schlom, JW Hodge. 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 ]
  11. HE Zeytin, AC Patel, CJ Rogers, D Canter, SD Hursting, J Schlom, JW Greiner. 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 ]
  12. C Palena, MZ Zhu, J Schlom, KY Tsang. 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 ]
  13. C Kudo-Saito, J Schlom, JW Hodge. Intratumoral vaccination and diversified subcutaneous/intratumoral vaccination with recombinant poxviruses encoding a tumor antigen and multiple costimulatory molecules. Clin Cancer Res. 2004 Feb 1;10(3):1090-1099. [ PubMed abs ]
  14. JW Hodge, DJ Poole, WM Aarts, A Gómez Yafal, L Gritz, J Schlom. 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 Nov15;63(22):7942-7949. [ PubMed abs ]
  15. JW Hodge, DW Grosenbach, WM Aarts, DJ Poole, J Schlom. Vaccine therapy of established tumors in the absence of autoimmunity. Clin Cancer Res. 2003 May;9(5):1837-1849. [ PubMed abs ]
  16. WM Aarts, J Schlom, JW Hodge. 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 ]
  17. JW Hodge, H Sabzevari, A Gómez Yafal, L Gritz, MG Lorenz, J Schlom. A triad of costimulatory molecules synergize to amplify T-cell activation. Cancer Res. 1999 Nov 15;59(22):5800-5807. [ PubMed abs ]

Licensing Status:
The technology is available for exclusive and non-exclusive licensing in combinations and for different fields of use. Some potential licensing opportunities are as follows:
  • TRICOM® (alone or with a transgene for a tumor antigen and/or an immunostimulatory molecule);
  • The antigens only, including but not limited to CEA, PSA, and MUC-1;
  • PANVAC® and/or PROSTVAC®; and
  • Recombinant fowlpox-GM-CSF.

Collaborative Research Opportunity:
A 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,
  5. Submit Drug Master Files detailing the development, manufacture, and testing of live recombinant vaccines to support the NCI-sponsored INDs,
  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 through a clinical agreement with the Division of Cancer Treatment and Diagnosis, NCI.
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,
  3. Conduct clinical trials of recombinant vaccines alone and in combination therapies, and
  4. Provide Drug Master Files currently supporting the clinical use of the recombinant poxvirus vaccines.
If interested in the above-described CRADA, please submit a statement of interest and capability to Kevin Brand, J.D. in the NCI Technology Transfer Center at or 301-451-4566.

Cancer - Diagnostics
Cancer - Therapeutics
In-vitro Data

For Additional Information Please Contact:
Sabarni Chatterjee Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Phone: 301-435-5587
Fax: 301-402-0220 Samuel Bish Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Phone: 301-435-5282
Fax: 301-402-0220

Ref No: 1551

Updated: 06/2010

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