Abstract 5847: Development of a selective haem oxygenase-1 inhibitor for the immunotherapy treatment of cancer

Abstract Immunotherapy has been hailed as a breakthrough for cancer therapy, however, only a fraction of patients respond in the clinic. The tumour microenvironment (TME) represents a major obstacle to the success of these treatments in solid tumours, of which, tumour-associated macrophages (TAMs) play a major role. A sub-population of perivascular TAMs express an enzyme called haem oxygenase-1 (HO-1), through which they have been demonstrated to subvert the anti-tumour response by immune suppression and exclusion of CD8+ T cells. HO-1+ TAM-containing tumours can therefore negate the immune-stimulating effects of chemotherapy to become treatment-resistant. Inhibiting HO-1 has been demonstrated to reverse this effect and re-sensitise tumours to immune-dependent cell death. However, there are no clinically available HO-1 inhibitors, and the current landscape of candidates suffer from undesirable pharmacokinetics and exhibit isoform promiscuity; blocking the activity of both HO-1 and the HO-2 isoform which maintains redox homeostasis in healthy tissues.This study has developed several novel, selective HO-1 inhibitors using a synthetic chemistry approach and validated activity with an in vitro microsomal system. We identified two lead compounds based on selectivity and potency for HO-1. A preliminary safety screen took place in vitro using non-malignant cells and confirmed a lack of general toxicity. Anti-tumour efficacy was evaluated in vivo using a murine model of fibrosarcoma, where administration of either lead HO-1 inhibitor synergised with standard-of-care chemotherapy to deliver durable tumour control and was associated with a re-invigorated lymphoid compartment. We utilised in silico modelling to predict lead compound pharmacokinetics, which are expected to be orally bioavailable. Unexpectedly, one of these candidates effectively penetrates the blood brain barrier, which is now under investigation for therapeutic utility in glioblastoma. Citation Format: Emre Demirel, Alessia Marrocu, Meriem Bahri, Mark Laws, James N. Arnold, Khondaker Miraz Rahman. Development of a selective haem oxygenase-1 inhibitor for the immunotherapy treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5847.