Combination radioimmunotherapy and chemoimmunotherapy involving different or the same targets improves therapy of human pancreatic carcinoma xenograft models

摘要

Chemoimmunotherapy with antibody-drug conjugates (ADC) is emerging as a promising therapy for solid tumors, while radioimmunotherapy (RAIT) of solid tumors has been relatively ineffective because of their resistance to radiation. We developed antibody-SN-38 conjugates that have significant anti-tumor activity in xenograft models at non-toxic doses. The goal of this study was to determine if an ADC could be combined with RAIT to enhance efficacy without a commensurate increase in host toxicity. Nude mice bearing human pancreatic cancer xenografts (Capan-1 and BxPC-3) were treated with a single dose of ⁹⁰Y-labeled anti-mucin antibody (hPAM4; clivatuzumab tetraxetan) alone or in combination with an anti-Trop-2-SN-38 conjugate, typically administered twice weekly over 4 weeks. The combination, even at RAIT’s maximum tolerated dose, controlled tumor progression and cured established xenografts significantly better than the individual treatments, without appreciable toxicity. The ADC could be started 1 week after or up to 2 weeks before RAIT with similar enhanced responses, but delaying RAIT for 2 weeks after the ADC was less effective. A non-specific ADC provided additional benefit over using free drug (irinotecan), but the response was enhanced with the specific ADC. When targeting Capan-1 with ample mucin, hPAM4 could be used as the RAIT and the ADC agent without losing effectiveness, but in BxPC-3 with less mucin, targeting of different antigens was preferred. These studies show the feasibility of combining ADC and RAIT for improved efficacy without increased toxicity.