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

Abstract

Chemoimmunotherapy with antibody-drug conjugates (ADC) is emerging as a promising therapy for solid tumors, whereas radioimmunotherapy (RAIT) of solid tumors has been relatively ineffective because of their resistance to radiation. We developed antibody-SN-38 conjugates that have significant antitumor activity in xenograft models at nontoxic 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 antimucin 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 nonspecific 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.

Figure 1. Enhanced therapeutic response by combining RAIT and ADC without substantial toxicity

Nude mice (9–10 animals/group) bearing s.c. Capan-1 tumors averaging ~0.3 cm³ were given twice weekly injections of 0.5 mg (8 μg of SN-38) of the hRS7-SN-38 conjugate for 4 weeks starting on Day 0, or a single injection of ⁹⁰Y-hPAM4 IgG at 75 μCi or 130 μCi (50 μg of hPAM4 IgG). Other groups of animals received the ADC treatment 2 h before the 2 RAIT treatments. Individual animal tumor growth curves are shown as well as a survival curve based on the time to progression (TTP) to 3.0 cm³. The median survival times and number of animals having no evidence of tumor at the conclusion of the study (21 weeks) are indicated.

Figure 2. Selective targeting by the ADC improves the combination response

Nude mice bearing Capan-1 tumors (all groups starting with 10 animals) were given a single treatment of ⁹⁰Y-hPAM4 IgG (50 μCi) on the same day treatment was initiated with irinotecan (13 μg, 7.5 μg SN-38 equivalents, twice weekly for 4 weeks), the specific (hRS7-SN-38; 0.5 mg/dose) or irrelevant (anti-CD20-SN-38; 0.5 mg/dose) conjugates given twice weekly for 4 weeks.

Figure 3. RAIT, ADC, and GEM combination therapy

Nude mice bearing Capan-1 tumors (all groups started with 10 animals) were given a single treatment of ⁹⁰Y-hPAM4 IgG (75 μCi/50 μg) with GEM at the doses indicated once weekly for 3 weeks starting 2 days after the ⁹⁰Y-hPAM4 treatment or with GEM plus the hRS7-SN-38 IgG conjugate (0.5 mg/dose, twice weekly for 4 weeks) that was initiated 2 h prior to the RAIT treatment.

Figure 4. RAIT and ADC combination therapy targeting the same antigen

Nude mice bearing Capan-1 tumors were treated with ⁹⁰Y-hPAM4 IgG alone (75 μCi/50 μg), hPAM4-SN-38 IgG (0.5 mg/dose, twice weekly for 4 weeks) alone, or they were given both treatments either on the same day (ADC given 2 h before RAIT) or delaying ADC treatment initiation for 1 week after RAIT.

Figure 5. Combination therapy in nude mice bearing the BxPC-3 human pancreatic cancer cell line

Animals were given treatments of ⁹⁰Y-hPAM4 IgG or the ⁹⁰Y-labeled irrelevant anti-CD20 IgG alone (75 μCi/50 μg) or in combination with irinotecan (13 μg, twice weekly for 4 weeks), the specific hRS7-SN-38 IgG or the irrelevant anti-CD20-SN-38 conjugate (ADC given twice weekly for 4 weeks, 0.5 mg/dose).