Journal Article

694 Potent combination activity of B7-H4 TOP1i ADC puxitatug samrotecan with the monovalent bispecific anti-PD-1/TIGIT antibody rilvegostomig and PARP1 inhibitor saruparib in experimental cancer models

Omar, Bilal A, Gonzalez, Juan Alvarez, Chariou, Paul L, Flynn, Matthew, Johnson, Yoshimi, Cazes, Alex, Chesebrough Jon, Rothstein, Raymond, Paucarmayta Ana, Albertella, Mark, Hammond, Scott A

2025

Overview

BackgroundMultiple clinical trials investigating the combination of immunotherapy (IO) with antibody drug conjugates (ADC), with or without concurrent chemotherapy, are underway and showing promising results. Mechanism-based triple combination therapies utilizing ADC, IO and a third agent offer an opportunity for additional patient benefit. We investigated the antitumor efficacy of the B7-H4 targeting topoisomerase ADC puxitatug samrotecan (Puxi-sam), the PD1/TIGIT targeting, Fc-reduced monovalent bispecific antibody rilvegostomig and the PARP1-selective inhibitor (PARP1i) saruparib in combination in experimental cancer models.MethodsA 3D tumor spheroid model was generated using RL95-2 endometrial cancer cells and tumor reactive T cells primed on HLA-A24 restricted survivin/BIRC5 tumor antigen peptides or RL95-2 whole cell lysates. Syngeneic MC38 tumor cell lines were engineered to stably express human B7-H4. Tumor cells were implanted in wild-type C57BL6 mice and when tumors reached between 100-200 mm3, mice were randomized to receive either monotherapy doublet or triple combination therapy. Puxi-sam was administered as a single i.v. dose at 7 mg/kg, saruparib was administered orally daily for 21 days at 0.1 mg/kg and the murine surrogate of rilvegostomig was administered twice weekly i.p. at 10 mg/kg. A subset of mice had tumors harvested at 11 days post onset of dosing for pharmacodynamic evaluation by flow cytometry.ResultsIn vitro treatment of endometrial spheroid-T cell co-cultures with ADC-IO, ADC-PARPi and triplet combination induced additive tumor spheroid growth inhibition. In the fully immunocompetent syngeneic mouse model, the combination of Puxi-sam and rilvegostomig induced significant tumor growth inhibition (p<0.0001) and improved survival compared to monotherapies. The addition of saruparib further enhanced the anti-tumor activity and resulted in a majority of animals having complete and durable tumor regression. A follow up pharmacodynamic study assessed a cohort of tumors collected 11 days post treatment initiation. Flow cytometry of the dissociated tumors revealed a greater than 2-fold increase in intratumoral CD3 positive T cells, including a greater than 3-fold increase in cytotoxic effector CD8 positive T cells after triplet therapy compared to untreated mouse tumors. Further, there were decreased intratumoral myeloid derived suppressor cells (MDSCs) and increased macrophages expressing the co-stimulatory molecule CD86 in the triplet therapy group compared to the untreated group.ConclusionsRobust anti-tumor activity and tumor immune microenvironment modulation can be achieved with the combination of patuxitug-samrotecan, saruparib and rilvegostomig.Ethics ApprovalThe studies described were approved by the Institutional Animal Care and Use Committee of Astrazeneca under protocol AUP22-25.

• Publisher: BMJ Publishing Group LTD
• Subject: Antibodies / Cancer therapies / Cohort analysis / Flow cytometry / Lymphocytes / Pharmacodynamics / Tumors