Evaluation of Platinum Chemotherapy in Combination with HER2-Targeted α-Particle Radiation

Abstract

The studies described herein assess the potential of combining platinum-based chemotherapy with high-linear energy transfer (LET) α-particle-targeted radiation therapy using trastuzumab as the delivery vehicle. An initial study explored the combination of cisplatin with ²¹³Bi-trastuzumab in the LS-174T i.p. xenograft model. This initial study determined the administration sequence of cisplatin and ²¹³Bi-trastuzumab. Cisplatin coinjected with ²¹³Bi-trastuzumab increased the median survival (MS) to 90 days versus 65 days for ²¹³Bi-trastuzumab alone. Toxicity was observed with a weight loss of 17.6% in some of the combined treatment groups. Carboplatin proved to be better tolerated. Maximal therapeutic benefit, that is, a 5.1-fold increase in MS, was obtained in the group injected with ²¹³Bi-trastuzumab, followed by carboplatin 24 hours later. This was further improved by administration of multiple weekly doses of carboplatin. The MS achieved with administration of 3 doses of carboplatin was 180 days versus 60 days with ²¹³Bi-trastuzumab alone. The combination of carboplatin with ²¹²Pb radioimmunotherapy was also evaluated. The therapeutic efficacy of ²¹²Pb-trastuzumab (58-day MS) increased when the mice were pretreated with carboplatin 24 hours prior (157-day MS). These results again demonstrate the necessity of empirically determining the administration sequence when combining therapeutic modalities.