A method of transfecting isolated autologous T-Lymphocytes with endogenous cytokines, for example IL-7 and IL-15, to sustain an adoptive T-lymphocyte response without systemic toxicity.

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.

Publications:

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 abs]

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 abs]

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 abs]

4. CJ Cohen, et al. 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 abs]

5. C Hsu, et al. 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 abs]

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 abs]

7. CA Klebanoff, et al. 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 abs]

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 abs]

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 abs]

U.S. Provisional Application No. 60/617,340 filed 08 Oct 2004 (HHS Reference No. E-340-2004/0-US-01)

PCT Application No. PCT/US05/3640 filed 07 Oct 2005, which published as WO 2007/037780 on 05 Apr 2007 (HHS Reference No. E- 340-2004/2-PCT-01)

U.S. Patent Application No. 11/576,621 filed 04 Apr 2007 (HHS Reference No. E-340-2004/2-US-02)

Inventors:
Steven A. Rosenberg et al. (NCI)

Licensees Sought:
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.