Treatment of experimental pancreatic cancer with 213-Bismuth-labeled chimeric antibody to single-strand DNA

Pancreatic cancer (PCa) is one of the deadliest cancers, carrying a very poor prognosis. Pancreatic ductal adenocarcinoma, synonymous to pancreatic cancer, is the 4th leading cause of cancer deaths. The “silent killer” is characterized by its metastatic behavior even before the primary tumor can be detected (1), resulting in a five-year survival rate of only 4%. Gemcitabine and erlotinib, FDA-approved drugs for pancreatic cancer treatment, improve median survival by less than six months in advanced stage patients (2-4), underscoring the need for alternative approaches. Radioimmunotherapy (RIT) relies on antigen-antibody binding to deliver cytotoxic doses of alpha- or beta radiation to tumor cells (5, 6). RIT has been successfully used to treat refractory and recurrent lymphomas, with two radiolabeled monoclonal antibodies (mAb) targeted against CD20 (Zevalin® and Bexxar®) (7). More recently FDA has approved Zevalin as a first-line therapy for newly diagnosed patients with non-Hodgkin’s lymphoma (NHL). The power of RIT in comparison with many other therapeutic modalities is its cytocidal nature, when particulate radiation emanating from the mAbs causes physical destruction of the cell. This is very different from trying to abrogate a single step in a multistep pathway as cancer cells often find alternative ways to thrive. In addition, RIT has an excellent safety record, having many fewer side effects than conventional chemotherapy, and its efficacy is not subject to multidrug resistance mechanisms. The antigens that have been traditionally targeted in PCa are surface proteins such as MUC1 or CEA (carcinoembriogenic antigen) (8, 9) which are also expressed on healthy tissues, thus limiting the dose which can be safely delivered to the tumor. Targeting of intracellular antigens that become available for mAb binding in aggressively growing tumors as a result of fast cellular turnover was first suggested two decades ago as an alternative to targeting surface antigens in RIT (10). The advantage of this approach is that mAbs to intracellular antigens have very low cross-reactivity with irrelevant surface antigens on healthy tissues, allowing high specificity and low toxicity of treatment. It is important to emphasize that when treating cancers by targeting intracellular antigens – only a limited number of cells in the tumor need to be non-viable to allow radiolabeled mAb targeting. Ionizing radiation is emitted in a 360o sphere and as alpha- and beta-particles have a range in tissue which covers at least several cells’ diameters, even distant cancer cells will be killed via the so called “cross-fire” effect (Fig. 1). In this regard a human-mouse chimeric mAb chTNT3 to single-strand DNA (ssDNA) and RNA (11) has been already used in its radiolabeled form in patients with advanced lung cancer with encouraging results (12). We hypothesized that in aggressively growing pancreatic tumors there will be a sufficient number of non-viable cells for the radiolabeled chTNT3 mAb to get access to its antigen and to deliver cytocidal radiation to the rest of the tumor. We also hypothesized that preceding RIT with administration of a chemotherapeutic agent would kill some of tumor cells thus providing more target for the radiolabeled mAb to bind, resulting in a higher radiation dose to the tumor. Here we describe our results on combining RIT with chTNT3 mAb radiolabeled with powerful alpha-emitting radionuclide 213-Bismuth (213Bi) with chemotherapy with gemcitabine or cisplatin for treatment of experimental PCa.

BRYAN R. A.;  JIANG Z.;  JANDL T;  STRAUSS J;  KOBA W;  ONYEDIKA C;  MORGENSTERN Alfred;  BRUCHERTSEIFER Frank;  EPSTEIN A;  DADACHOVA E.; 

2014-12-09

EXPERT REVIEWS

JRC73781

1473-7140,   

http://informahealthcare.com/doi/abs/10.1586/14737140.2014.952285,    https://publications.jrc.ec.europa.eu/repository/handle/JRC73781,   

10.1586/14737140.2014.952285,