Pediatrics & Medicine
Immunotherapy to Treat EBV-Associated Cancers
Drs. Heslop and Cliona Rooney received the award for their research using immunotherapy with antigen specific T cells to treat EBV associated malignancies. They have previously shown this immunotherapy approach is highly effective in treating EBV associated lymphoma arising in patients who are immunosuppressed after bone marrow transplant and have now extended this approach to the EBV associated cancers Hodgkin’s disease and nasopharyngeal cancer in immunocompetent individuals. In a clinical trial in Hodgkin's Disease published in Journal of Experimental Medicine in 2004 they showed that the infused CTLs could expand, traffic to tumor sites and induce clinical responses in some patients. In a second study in nasopharyngeal cancer two patients with advanced disease had complete sustained responses and two others had partial responses. In follow up studies they are aiming to improve these results by genetically modifying T-cells so they are resistant to tumor evasion mechanisms. Due to concerns with the risk of insertional mutagenesis with this strategy they have devised a novel suicide gene based on a modified human caspase 9 fused to a human FK506 binding protein (FKBP) to allow conditional dimerization using a small molecule pharmaceutical. This system has several advantages over currently available suicide genes because it consists of human gene products with low potential immunogenicity and it maintains function in T cells overexpressing antiapoptotic molecules.
Drs. Heslop and Rooney’s nomination was based on the following publications:
Bollard CM, Aguilar L, Straathof KC, Gahn B, Huls MH, Rousseau A, Sixbey J, Gresik MV, Carrum G, Hudson M, Dilloo D, Gee A, Brenner MK, Rooney CM, Heslop HE. Cytotoxic T lymphocyte therapy for Epstein-Barr virus+ Hodgkin's disease. J Exp Med. 2004 Dec 20;200(12):1623-33.
Straathof KC, Bollard CM, Popat U, Huls MH, Lopez T, Morriss MC, Gresik MV, Gee AP, Russell HV, Brenner MK, Rooney CM, Heslop HE. Treatment of nasopharyngeal carcinoma with Epstein-Barr virus--specific T lymphocytes. Blood. 2005 Mar 1;105(5):1898-904.
Straathof KC, Pule MA, Yotnda P, Dotti G, Vanin EF, Brenner MK, Heslop HE, Spencer DM, Rooney CM. An inducible caspase 9 safety switch for T-cell therapy. Blood. 2005 Jun 1;105(11):4247-54.