Enhancing immuno-oncology efficacy with H1-antihistamine in cancer therapy: a review of current research and findings

Cancer remains a major global cause of death, posing significant treatment challenges. The interactions between tumor cells and the tumor microenvironment (TME) are crucial in influencing tumor initiation, progression, metastasis, and treatment response. There has been significant research and clinical interest in targeting the TME as a therapeutic approach in cancer, with advancements being made through drug development. Histamine binds to HRH1 receptors on the TME, which inhibit CD8+ T cell activity, promote tumor growth, and contribute to resistance against immunotherapy. By inhibiting CD8+ T cells, the effectiveness of immunotherapies targeting these cells is reduced. By blocking the HRH1 pathway, H1-antihistamines can mitigate this suppression and enhance the response to immunotherapies that target CD8+ T cells. Therefore, understanding the role of histamine and its potential impact on T cells and the role of H1-antihistamines in improving immune-oncology (I/O) agents' efficacy ultimately could lead to more effective cancer therapies. The objective of this review is to examine the current literature to investigate the potential role of H1-antihistamines on the effectiveness of I/O drugs and their role in enhancing treatment against cancer. We conducted a comprehensive literature search, which included multiple databases including PubMed, Google Scholar, and EMBASE, as well as a search of oncology congresses. Our literature review initially identified thirty studies. Twenty-three of these were excluded for failing to meet inclusion criteria, which varied from study design to the type of antihistamines and patient populations involved. The clinical studies investigated the effect of different generations of H1-antihistamines in combination with I/O treatments on patients' outcomes. The findings from these studies indicated that patients using H1-antihistamines concomitantly with I/O agents experienced longer median overall survival (mOS), progression-free survival (mPFS), or improved survival compared to those who did not use antihistamines. Additionally, these trials differentiated between cationic and non-cationic H1-antihistamines, revealing that users of cationic antihistamines had overall better outcomes in terms of longer mOS and mPFS. The assessed trials were consistent in their comparisons of quantitative and qualitative, efficacy, and safety outcomes.