HIGH-CAPACITY ADENOVIRAL VECTORS EXPRESSING HSV1-TK ELICIT TUMOR REGRESSION IN A SYNGENEIC INTRACRANIAL GLIOMA MODEL EVEN IN THE PRESENCE OF SYSTEMIC IMMUNITY AGAINST ADENOVIRUSES AS WOULD BE ENCOUNTERED IN CLINICAL TRIALS

KING; MUHAMMAD; KROEGER; PUNTEL; LAROCQUE; LIU; PALMER; NG; LOWENSTEIN; CASTRO

Dallas, Texas, USA

Congreso; Society for Neuro-Oncology; 2007

IM-09. HIGH-CAPACITY ADENOVIRAL VECTORSEXPRESSING HSV1-TK ELICIT TUMOR REGRESSION INA SYNGENEIC INTRACRANIAL GLIOMA MODEL EVENIN THE PRESENCE OF SYSTEMIC IMMUNITY AGAINSTADENOVIRUSES AS WOULD BE ENCOUNTERED INCLINICAL TRIALSGwendalyn King,1 Akm Muhammad,1 Kurt Kroeger,1 Mariana Puntel,1Daniel Larocque,1 Chunyan Liu,1 Donna Palmer,2 Phillip Ng,2 PedroLowenstein,1 and Maria Castro1; 1Gene Therapeutics Research Institute,Cedars Sinai Medical Center, Los Angeles, CA, USA; 2Department ofMolecular and Human Genetics, Baylor College of Medicine, Houston,TX, USAMalignant glioma (GBM) is the most common subtype of primarybrain tumor. In preclinical models, replication deficient adenoviruses (Ad)expressing herpes simplex virus type 1-hymidine kinase (Ad-TK) combinedwith prodrug ganciclovir (GCV) are highly efficient in causing tumorregression. Further, Ad-TK is currently been tested in phase III clinical trialsand the results of a small phase II trial are encouraging (Ali S et al.,Molecular Therapy, 2004 10:1071). The majority of humans have beeninfected with adenovirus over the course of their lives and develop longtermimmunological memory that could eliminate therapeutic transgeneexpression when using first generation Ad vectors, therefore hamperingefficacy in clinical applications (Thomas CE et al., PNAS, 1997 97:7482).To overcome this pitfall, we developed high-capacity replication deficientviral vectors expressing HSV1-TK (HC-AdTK) under the control of themurine CMV promoter. Because these vectors are devoid of all Ad codingregions, they become invisible to the host’s immune system and can sustainvery long-term transgene expression even in the presence of anti-Ad circulatingantibodies as could be encountered in human patients undergoingclinical trials for GBM. We assessed HC-Ad mediated HVS1-TK expressionin the presence of a strong systemic immune response to Ads as could beencountered in the clinic. As expected, animals peripherally immunizedwith Ad vectors developed systemic immunity to adenovirus (as detectedby neutralizing antibody and IFN elispot assays). Thirty days after HC-Adinjection in brain, comparable expression of TK was observed in all animalsregardless of systemic immunity. Meanwhile, TK expression from thefirst generation AdTK was completely abolished in the animals with preexistingimmunity to adenovirus. We next wished to determine whethertreatment with HC-AdTK would elicit tumor regression and long-termsurvival even in the presence of a systemic immune response against Ads.To do so, Lewis rats were peripherally immunized by injection of either Advector or saline (non-immunized controls). Fourteen days later only animalsperipherally immunized with Ad vectors had developed systemic immunityto adenovirus (as detected by neutralizing antibody and IFN elispot assays).5000 CNS-1 rat glioma cells were unilaterally implanted in the striatumand treatment was administered seven days later by intratumoral injectionof HC-AdTK (with peripheral GCV). Regardless of adenoviral peripheralimmune status, treatment with HC-AdTK resulted in tumor regression andlong-term survival in ~60% of the tumor bearing animals. Utilizing anidentical experimental paradigm, treatment with first generation AdTK,resulted in the death of Ad immunized animals. In conclusion, even in thepresence of anti-adenoviral immunity, HC-Ad-TK vectors induced gliomaregression and long-term survival indicating this treatment could be highlyeffective in human GBM patients regardless of previous exposure to adenovirus.Supported by NIH/NINDS Grant 1R01 NS44556.01, MinoritySupplement NS445561; 1R21-NSO54143.01; 1UO1 NS052465.01 toM.G.C.; NIH/NINDS Grants 1 RO1 NS 054193.01; RO1 NS 42893.01;U54 NS045309-01, and 1R21 NS047298–01 to P.R.L. G.D.K. is supportedby NINDS F32 NS0503034-01.