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Adoptive Immunotherapy with T Lymphocytes Engineered for Enhanced Survival

Posted Aug 03 2010 5:00pm

Description of Invention:
Available for licensing is a composition, comprising genetically engineered lymphocytes, transduced to express elevated levels of cytokine proteins. This technology is useful for improving cellular adoptive immunotherapies to treat a range of infectious diseases and cancers.

Adoptive immunotherapy has repeatedly been shown to be useful in the treatment of patients with metastatic melanoma. However, clinical efficacy of this treatment is limited by the short-lived survival of the transferred, autologous, antigen-specific T cells. It would be desirable to genetically modify effector cells to provide not only enhanced effector cell survival, but also desired antigen specificity, and improved function, and safety. The current technology provides a method address this desire, by genetically modifying lymphocytes using retroviral vectors.

Specifically, isolated autologous T lymphocytes can be transformed with polynucleotides encoding endogenous cytokines, for example IL-7 or IL-15. IL-15-transduced lymphocyte cultures demonstrate prolonged in vitro persistence. In addition, T cells can be transduced to express not only cytokines but also T cell receptors to confer specificity for certain antigens. Recent data showed that human T lymphocytes engineered to express a murine anti-human p53 T cell receptor can recognize tumor cell lines, as well as fresh human tumors, and are able to kill p53-expressing human tumor cells.

Also provided in the invention are methods for treating patients with transformed lymphocytes as part of adoptive immunotherapy. Applications of this technology beyond cancer include the potential use of cytokine expressing cells in treating infectious and autoimmune diseases and vaccination.

Steven A Rosenberg (NCI)

Patent Status:
HHS, Reference No. E-340-2004/2
US, Application No. 11/576,621 filed 04 Apr 2007

Relevant Publication:
  1. L Gattinoni, SE Finkelstein, CA Klebanoff, PA Antony, DC Palmer, PJ Spiess, LN Hwang, Z Yu, C Wrzesinski, DM Heimann, CD Surh, SA Rosenberg, NP Restifo. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med. 2005 Oct 3;202(7):907-912. [ PubMed: 16203864 ]
  2. LX Wang, R Li, G Yang, M Lim, A O'Hara, Y Chu, BA Fox, NP Restifo, WJ Urba, HM Hu. Interleukin-7-dependent expansion and persistence of melanoma-specific T cells in lymphodepleted mice lead to tumor regression and editing. Cancer Res. 2005 Nov 15;65(22):10569-10577. [ PubMed: 16288050 ]
  3. L Gattinoni, DJ Powell Jr, SA Rosenberg, NP Restifo. Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol. 2006 May;6(5):383-393. [ PubMed: 16622476 ]
  4. CJ Cohen, Z Zheng, R Bray, Y Zhao, LA Sherman, SA Rosenberg, RA Morgan. Recognition of fresh human tumor by human peripheral blood lymphocytes transduced with a bicistronic retroviral vector encoding a murine anti-p53 TCR. J Immunol. 2005 Nov 1;175(9):5799-5808. [ PubMed: 16237072 ]
  5. C Hsu, MS Hughes, Z Zheng, RB Bray, SA Rosenberg, RA Morgan. Primary human T lymphocytes engineered with a codon-optimized IL-15 gene resist cytokine withdrawal-induced apoptosis and persist long-term in the absence of exogenous cytokine. J Immunol. 2005 Dec 1;175(11):7226-7234. [ PubMed: 16301627 ]
  6. SA Rosenberg and ME Dudley. Cancer regression in patients with metastatic melanoma after the transfer of autologous antitumor lymphocytes. Proc Natl Acad Sci USA 2004 Oct 5;101 Suppl 2:14639-14645. [ PubMed: 15381769 ]
  7. CA Klebanoff, SE Finkelstein, DR Surman, MK Lichtman, L Gattinoni, MR Theoret, N Grewal, PJ Spiess, PA Antony, DC Palmer, Y Tagaya, SA Rosenberg, TA Waldmann, NP Restifo. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells. Proc Natl Acad Sci USA 2004 Feb 17;101(7):1969-1974. [ PubMed: 14762166 ]
  8. K Liu and SA Rosenberg. Interleukin-2-independent proliferation of human melanoma-reactive T lymphocytes transduced with an exogenous IL-2 gene is stimulation dependent. J Immunother. 2003 May-Jun;26(3):190-201. [ PubMed: 12806273 ]
  9. K Liu and SA Rosenberg. Transduction of an IL-2 gene into human melanoma-reactive lymphocytes results in their continued growth in the absence of exogenous IL-2 and maintenance of specific antitumor activity. J Immunol. 2001 Dec1;167(11):6356-6365. [ PubMed: 11714800 ]

Licensing Status:
Available for licensing.

Collaborative Research Opportunity:
The NCI Surgery Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the clinical applications of T cell receptor technology. Please contact Steven A. Rosenberg, M.D., Ph.D. at 301-496-4164 for more information.

Cancer - Therapeutics

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

Ref No: 1313

Updated: 08/2010

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