Despite all the advances in immuno-oncology over the past 10 years, the treatment of cancer remains a significant challenge. In particular, even though close to half of all cancer patients are eligible for T cell based IO therapies, only about 12% of eligible patients derive benefit from T cell checkpoint inhibitors. Recent research has led experts in the field to turn their attention to the role of macrophages in immunosuppression and tumour promotion. Macrophages are one of the most abundant immune cells in the tumour microenvironment and are found in over 75% of cancer patients. Because macrophages play a key role in suppressing the immune system, they have long been associated with poor patient prognosis.
Potential therapeutic strategies to target tumour-associated macrophages are the new frontier in solid tumour treatment. Juho Jalkanen, Chief Development Officer of Faron Pharmaceuticals, describes the growing interest in macrophages as “a poorly understood, but promising area of immuno-oncology”. The need for better solid tumour treatment is in many ways due to the restrictions of other leading immunotherapy techniques. “For select tumours, there have been significant advances with T cell checkpoint inhibitors, specifically PD-1 inhibitors”, says Igor Feldman, Co-founder and Chief Analytics Officer at Verseau Therapeutics. “However, less than 6% of cancer patients benefit from CPI treatments, so there is a clear need for better medications for the vast majority currently not being served.”
The New Frontier: 3 Industry Case-Studies
So how is the industry addressing the need for therapeutic strategies targeting macrophages? From polarisation and infiltration to conditioning, the possibilities are numerous. We sat down with 3 leading pharmaceutical companies on the cusp of macrophage treatment to find out more.
1.) Verseau Therapeutics
Founded in 2017, Verseau Therapeutics’ discovery engine has identified and validated over 20 druggable macrophage targets from human tumour tissue analysis. Currently, the company is prioritising two main targets for clinical development. These programs are based on encouraging ex vivo human studies and preclinical data in humanised and syngeneic murine models. The first program is expected to initiate clinical trials in early 2022 with a second program to reach the clinic about a year later.
Verseau’s ‘Macrophage Repolarisation Target Discovery Engine’ implements a patient-focused discovery process leveraging human biology to respond to unmet clinical needs. The engine involves the identification of the macrophage modulating targets from cancer patient tumour data and is followed by validation of those targets whose knockdown most potently repolarises human macrophages. Lead selection for the two prioritised, first-in-class targets identified the most promising monoclonal antibodies across a range of functional characteristics and preclinical studies, including repolarisation of pro-tumorigenic human macrophages, ex vivo assessment of human TME remodelling, and in vivo assessment of antitumour biology. Clinical testing of both novel and differentiated programs will be underway within the next 18 months. According to Feldman, Verseau’s two programs “are monoclonal antibodies that have the potential to reduce tumour growth by transforming the tumor microenvironment from an immunosuppressive state to an immune-activating state where the macrophages can unleash an immune attack on tumour cells.”
2.) Pathios Therapeutics
Also founded in 2017, Pathios Therapeutics is a cutting-edge biotech company that solely pursue small molecule inhibitors of the pH sensing GPR65 for applications in cancer immunotherapy. The activation of GPR65 in immune cells by the acidic tumour microenvironment and its resultant immunosuppression may be one of the principal reasons many cancers do not respond to current T Cell checkpoint therapies. With its recent research into the validation of GPR65, Pathios found that GPR65 is a critical innate immune checkpoint in human cancers. GPR65 activation by an acidic microenvironment is a key causative factor in creating a ‘cold’ tumour, which explains the lack of patient response to treatment. To address this, Pathios propose their ‘Macrophage Conditioning’ approach, which holds significant promise as a strategy for targeting the innate immune systems in cancers and, as such, holds substantial clinical promise.
The active drug discovery programme has resulted in the discovery of PTT-3196, a selective small-molecule inhibitor that can inhibit GPR65 in multiple contexts such as human PBMCs. Most significantly, this molecule can dose-dependently counteract low pH-induced suppression of anti-tumour, immunostimulatory pathways and decrease expression of pro-tumourigenic immunosuppressive and tissue repair pathways. “It robustly activates the innate immune system in vivo by inhibiting proximal signalling and rescues the suppression of key chemokines”, explains Chief Executive Officer Stuart Hughes.
3.) Faron Pharmaceuticals
Founded in 2003, Faron Pharmaceuticals is a Finnish clinical-stage biopharmaceutical company developing novel treatments in immuno-oncology. Currently, Faron is focusing on targeting macrophage scavenger receptors. Juho Jalkanen, Chief Development Officer, summarises Faron’s approach as “aiming to work with and reprogram macrophages instead of depleting them”. Scavenger receptors are classical M2 markers associated with cancer growth and metastases. Reprogramming macrophages by targeting scavenger receptors in TAMs enhances innate and adaptive antitumour immune response.
Faron proposes a precision immunotherapy called Bexmarilimab, which is an anti-CLEVER-1 mAb. Jalkanen terms CLEVER-1 (also called Stabilin1) as “the biggest, baddest scavenger receptor of them all” and is closely associated with survival, therapeutics response, and T-cell dysfunction. Bexmarilimab reprograms the CLEVER-1 by converting immunosuppressive M2 macrophages to immune-stimulating M1 macrophages in the tumour microenvironment. The therapeutic is currently in phase I/II clinical development for patients with untreatable solid tumours, and data shows that Bexmarilimab can be the first-ever macrophage immune checkpoint therapy.
The future of macrophage treatment has the potential to revolutionise the treatment of cancer. The pioneering efforts of industry leaders such as Verseau Therapeutics, Pathios Therapeutics, and Faron Pharmaceuticals attests to the promise of macrophage targeting. At Oxford Global, we believe that this is the field of immuno-oncology to watch, and we have our eyes firmly peeled.