Impact of prophylactic TNF blockade in the dual PD-1 and CTLA-4 immunotherapy efficacy and toxicity

Abstract

The TNF blockade therapy is currently a well-established treatment option for a variety of autoimmune diseases such as rheumatoid arthritis (RA), psoriasis or Crohn's disease, given the proinflammatory role of TNF in the course of these diseases. Importantly, TNF neutralization is also used for the treatment of corticosteroid-refractory immune-related adverse events (irAEs) induced by the combined anti-PD-1 and anti-CTLA-4 immunotherapy. The manifestation of these toxicities is an important limiting factor for the successful implementation of the inhibitory checkpoint blockade therapy (ICB), restraining its anti-tumor efficacy. In our recent study (Perez-Ruiz et al., Nature 569(7756): 428-432.), we analyzed the potential impact of prophylactic TNF neutralization therapy in the anti-PD1/CTLA-4 efficacy. Through several mouse models, we demonstrated that TNF neutralization ameliorated ICB-exacerbated colitis in addition to improving ICB-dependent anti-tumor efficacy. Similar results were obtained after prophylactic TNF blockade in graft vs host xenografted mouse models with human immune cells, which showed a reduction in colitis and hepatitis. Importantly, there was a preservation of the immunotherapeutic control of xenografted tumors after ICB treatment. Moreover, TNF and TNF-dependent gene expression is upregulated in the colon mucosa from patients affected by colitis as a side effect of ipilimumab and nivolumab. Our results, thus, provide evidence of the successful combination of prophylactic TNF neutralization with ICB therapy strategy to ameliorate toxicities, while keeping or even ameliorating anti-tumor efficacy. The prophylactic TNF blockade strategy is clinically feasible since excellent TNF inhibitors have been approved for the treatment of autoimmunity and are used for the immune-related serious adverse events in immunotherapy.

Keywords: CTLA-4; PD-1; cancer; colitis; immunotherapy; toxicity; tumor necrosis factor.

Figure 1. FIGURE 1: Reducing the toxicity of cancer immunotherapy.

(A) The presence on activated lymphocytes of the inhibitory receptors PD-1, which binds to PD-L1, and CTLA-4, which binds to the costimulatory molecules CD80 and CD86, causes immune cell dysfunction facilitating tumor evasion. (B) The introduction of inhibitory blockade therapy that prevents PD-1/PD-L1 or CTLA-4/CD86-CD80 interactions by monoclonal antibody therapy has shown to improve CD8 T cell cytotoxic function and thus has been successfully implemented in a variety of tumors such as melanoma, with little toxicity. (C) Dual therapy that combines anti-PD-1 and anti-CTLA-4 has a more effective anti-tumor response when compared to single therapy, but, at the cost of the increase in the frequency of immune-related adverse events, which induces tissue damage, being TNF an important mediator of this effect. (D) The administration of dual ICB therapy in combination with prophylactic TNF neutralization is able to palliate the treatment-related toxicity side effects while becoming more efficacious towards the anti-tumor response by limiting the activation induced cell death (AICD) on the lymphocytes.