IS5-1IMMUNE AND GENE THERAPY AS AN EMERGING CANCER TREATMENT

Abstract Although there have been much progress in cancer treatment, there still are many patients who suffered from advanced or metastatic cancers which are refractory to current standard anticancer treatments. We have been involved in two new approaches, namely immunotherapy at clinical level and oncolytic virotherapy at preclinical level, to develop new therapy targeting such disastrous condition. Our first approach is the immunotherapy. We have recently concluded the Phase I clinical trial of multiplex vaccinations with HLA-A*2402 restricted tumor-associated antigens peptides (TAA), preceded by the administration of low-dose cyclophosphamide (CPM) in order to eliminate Tregs and confirmed the safety and efficacy of this new immune therapy. Furthermore, we have been conducting a Phase I clinical trial of immune cell therapy in order to confirm the safety and efficacy of CTL, in solid tumor patients preconditioned by CPM and followed by the dendritic cells and interleukin-2. This study targeted the novel HLA-A*0201 or HLA-A*2402-restricted TAA, RING finger protein 43, and was designed to administrate CTL at two dose levels. Both of our two clinical trials so far showed no severe adverse events, greater than Grade 3, in our patients. Clinical responses of stable disease (SD) and mixed response were observed. In conclusion, these trials are tolerable and may be clinically efficient for patients suffered from advanced solid tumor. Further immunological assessment should be conducted to explore the valid biomarkers in order to predict clinical efficacy before treatment. Our second approach is the oncolytic virotherapy. We previously demonstrated that intratumoral injection of coxsackievirus B3 (CVB3) induced not only a potent oncolytic activity followed by systemic antitumor immune stimulation, but also myocarditis and pancreatitis in syngeneic non-small cell lung cancer (NSCLC) -loaded mice. To improve the safety profile of CVB3, we successfully constructed a novel recombinant CVB3 by inserting two normal tissue-specific microRNA target sequences complementary to miR-1 and miR-217 into the CVB3 genome (CVB3-miRT) . CVB3-miRT showed more abundant viral replication than the parental CVB3 in NSCLC cells with low expression levels of miR-1 and miR-217. On the other hand, both of miR1-transduced NSCLC cells as well as normal lung fibroblast cells were dramatically resistant to the oncolysis by CVB3-miRT infection. Of note, serial administrations of CVB3-miRT, but not parental CVB3, into human NSCLC xenograft tumors in nude mice, elicited attenuated histological findings of both pancreatitis and myocarditis without weight loss, and decreased serum amylase level without losing its original significant antitumor activity. Collectively, our novel genetically attenuated strain of CVB3 could be a promising antitumor modality for the treatment of NSCLC patients. In this symposium, our recent data on these two new approaches will be presented.