Effect of combination radioimmunotherapy (RAIT) and chemoimmunotherapy on therapeutic response and toxicity in xenograft models of human pancreatic carcinoma: First experimental studies.

Abstract

206 Background: Preclinical and early clinical data with RAIT involving a 90Y-labeled antibody to a pancreatic mucin antigen (hPAM4, clivatuzumab tetraxetan) have shown promising therapeutic activity in combination with gemcitabine. Selective targeting of therapeutic drugs using antibody-drug conjugates (ADC) might be useful in pancreatic cancer therapy. Methods: ADCs composed of SN-38 coupled to an internalizing anti-TROP-2 antibody, an antigen found on many epithelial cancers, or to the non-internalizing anti-mucin humanized IgG, were prepared (6 SN-38/IgG). Nude mice bearing s.c. Capan-1 or BxPC3 xenografts (∼0.35 cm3) were given multiple ADC doses (twice weekly, 4 weeks) or appropriate controls of a non-targeting IgG-SN-38 conjugate or irinotecan. Other groups of animals were treated with the ADC conjugates and RAIT, using RAIT at 60% and 100% of its MTD. The endpoint was time to progress to 3.0 cm3 (TTP), with animals monitored up to 22 weeks. Results: ADCs alone were each able to inhibit tumor growth significantly compared to untreated animals. The specificity of the effect was a dose-dependent and related to antigen saturation at higher doses. When ADC was combined with RAIT, TTP improved significantly and more animals were tumor-free. An effective ADC dose could be combined even with RAIT given at its MTD, achieving enhanced efficacy with minimal additional toxicity. ADC + RAIT treatments were best when RAIT was given 1-2 weeks before, the same day, or within 1 week after the ADC treatment, but delaying RAIT for 2 weeks after ADC treatment reduced efficacy. The same anti-pancreatic mucin antibody, hPAM4, could be used in the combination treatment both as RAIT and as an ADC without losing effectiveness. Conclusions: These studies show the feasibility of using ADC for the treatment of pancreatic cancer, and for combining antibody drug- and radionuclide-targeted therapeutics for improved efficacy with minimal toxicity. Supported in part from NCI grant R01 CA115755. [Table: see text]