Genetic induction of antigens and receptors as targets for cancer radiotherapy

Limitations to radioimmunotherapy include bone marrow suppression due to the long serum half-life of radiolabeled monoclonal antibodies (mAbs) and poor tumor penetration of the large molecular weight mAb. In addition, low or variable expression of tumor-associated target antigens or receptors may lead to poor tumor localization of radiolabeled mAbs. Attempts to overcome these problems have included the use of radiolabeled peptides to improve tumor penetration and reduce bone marrow suppression and the use of biological response modifiers to increase target antigen expression. This report discusses a novel approach toward radiotherapy which combines gene transfer techniques, to induce high level tumor antigen or receptor expression, with radioligands that target the induced antigen or receptor. Major emphasis will be on the use of radiolabeled peptides for targeting induced receptors because the small molecular weight peptides may overcome tumor penetration and bone marrow suppression problems. Replication-deficient adenoviral vectors were constructed encoding the cDNA for carcinoembryonic antigen (CEA), thyrotropin-releasing hormone receptor (TRHr), epidermal growth factor receptor (EGFr), murine interleukin-4 receptor (mIL-4r), gastrin-releasing peptide receptor (GRPr), and the somatostatin receptor subtype (SSTr2). In vitro binding and in vivo tumor localization was observed with radiolabeled anti-CEA mAbs, thyrotropin-releasing hormone, epidermal growth factor, IL-4 fusion toxin, bombesin analogues, and octreotide analogues to cells infected with adenoviral vectors encoding the genes for CEA, TRHr, EGFr, mlL-4r, GRPr, and SSTr2, respectively. Also, methods to develop increased antigen or receptor expression using a replication enabling system will be discussed. Approaches to restrict antigen or receptor expression to the tumor through specific targeting of adenoviral vectors to the tumor or limiting the expression of protein to the tumor will be discussed. These methods should be useful for increasing the therapeutic efficacy of targeted radiotherapy.