Angiotensin Receptor Antagonist-Beta Blocker Drug Combination: Novel Cancer Immunotherapeutic
Figure 1. Pre-treatment (right) vs Post-treatment (left). Brain tumor response to treatment with ARB/BRB combination with tumor vaccine. A dog with malignant glioma (left panel, evaluated at the FACC at CSU, was treated with daily oral dosing of losartan and propranolol, in combination with an allogeneic cancer vaccine (no additional treatment administered). Significant tumor regression was noted on day 30 post-treatment MRI images (right panel).
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At A Glance
- Recent studies from CSU have revealed that angiotensin-receptor antagonists (ARBs) have potent immune modulatory activity, exerted by depleting macrophages from tumors through inhibition of CCR2 signaling
- These studies have also demonstrated an additive or synergistic interaction between ARBs and beta receptor blockers (BRB) for induction of anti-tumor activity, meditated by reversing the immune suppressive tumor microenvironment (TME)
- The two-drug combination can be used alone for immunotherapy, or combined with cancer vaccines or checkpoint inhibitors to increase anti-tumor activity
- Proof-of-concept and safety studies have been conducted in rodent models and in a dog spontaneous brain cancer model
As cancers evolve and enlarge, the TME becomes progressively more hostile to T cells and other immune effector cells as it becomes infiltrated with immune suppressive cells such as macrophages and regulatory T cells. Thus, even effective cancer immunotherapies such as vaccines and checkpoint inhibitors and CART cells are prevented from their full activity by the immune suppressive TME. Combining modification of the TME with T cell targeted immunotherapies can significantly improve tumor control, without increasing toxicity. The challenge is to find new drugs that can be used to effectively and safely modify the TME.
To address the need for effective TME modifying agents, researchers at the Flint Animal Cancer Center at CSU have screened and identified novel MOAs for two existing drugs that exert previously unrecognized immunological activity. One drug (losartan, an ARB) has been shown in a recent publication (below) to act as a CCR2 antagonist to block monocyte migration, which when sustained leads to tumor macrophage depletion. The second drug (propranolol, a beta receptor antagonist), also functions as a monocyte migration inhibitor and as a TME modifying drug. The activity of both drugs has been demonstrated in rodent cancer models, which documented the impact of the combination therapy on T cell infiltration into tumor tissues. In addition, the activity of the ARB/BRB treatment combined with a cancer vaccine was demonstrated in rodent models, and in ongoing trials in dogs with spontaneous brain cancers.
- MOA demonstrated for ARBs and BRBs as novel repurposed cancer immunotherapeutic
- Two drug combination administered in fixed combination dosing schedule
- Both ARBs and BRBs have long safety records, thus de-risking the drug combination
- Two drug combination compatible with multiple different cancer therapy modalities, including radiation therapy, cytotoxic therapy, targeted therapeutics, and immunotherapy
Regan, Daniel P, et al. “The Angiotensin Receptor Blocker Losartan Suppresses Growth of Pulmonary Metastases via AT1R-Independent Inhibition of CCR2 Signaling and Monocyte Recruitment.” Journal of Immunology (Baltimore, Md. : 1950), U.S. National Library of Medicine, 15 May 2019, www.ncbi.nlm.nih.gov/pubmed/30971441.
Last updated: January 2020
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