Addressing the Elephant in the Immunotherapy Room: Effector T-Cell Priming versus Depletion of Regulatory T-Cells by Anti-CTLA-4 Therapy

Abstract

Cytotoxic T-lymphocyte Associated Protein 4 (CTLA-4) is an immune checkpoint molecule highly expressed on regulatory T-cells (Tregs) that can inhibit the activation of effector T-cells. Anti-CTLA-4 therapy can confer long-lasting clinical benefits in cancer patients as a single agent or in combination with other immunotherapy agents. However, patient response rates to anti-CTLA-4 are relatively low, and a high percentage of patients experience severe immune-related adverse events. Clinical use of anti-CTLA-4 has regained interest in recent years; however, the mechanism(s) of anti-CTLA-4 is not well understood. Although activating T-cells is regarded as the primary anti-tumor mechanism of anti-CTLA-4 therapies, mounting evidence in the literature suggests targeting intra-tumoral Tregs as the primary mechanism of action of these agents. Tregs in the tumor microenvironment can suppress the host anti-tumor immune responses through several cell contact-dependent and -independent mechanisms. Anti-CTLA-4 therapy can enhance the priming of T-cells by blockading CD80/86-CTLA-4 interactions or depleting Tregs through antibody-dependent cellular cytotoxicity and phagocytosis. This review will discuss proposed fundamental mechanisms of anti-CTLA-4 therapy, novel uses of anti-CTLA-4 in cancer treatment and approaches to improve the therapeutic efficacy of anti-CTLA-4.

Standard Versus Modified Ipilimumab, in Combination With Nivolumab, in Advanced Renal Cell Carcinoma: A Randomized Phase II Trial (PRISM)

“…Intriguingly, however, preclinical studies suggest that CTLA-4-targeting agents that favor regulatory T-cell depletion within the tumor microenvironment, while avoiding peripheral T-cell activation, may be associated with a favorable toxicity profile, potentially paving the way for a new generation of safer and more efficacious anti-CTLA-4 antibodies. [15][16][17] In conclusion, the results of the PRISM trial establish the superior safety of IPI dosing once every 12 weeks compared with once every 3 weeks, in combination with NIVO, in patients with aRCC. Although a formal internal efficacy comparison was not possible, no meaningful differences between treatment arms were observed on the basis of informal comparisons.…”

Clinical efficacy and biomarker analysis of dual PD-1/CTLA-4 blockade in recurrent/metastatic EBV-associated nasopharyngeal carcinoma

“…Most of the currently available models suggest that immune checkpoint blockade functions by reinvigoration of existing and recruitment of circulating CD8 populations. In addition, CTLA-4-blockade is also known to downregulate Tregs 34 . Cell type signature analysis from our Nanostring IO360 data showed evidence of these phenomena in our samples, with lower Treg populations, lower proportions of CD8 vs exhausted CD8, more tumor infiltrating lymphocytes, and more CD8 vs Treg proportions in on-treatment samples of partial responders compared with non-responders (Fig.…”

Inducing mismatch repair deficiency sensitizes immune-cold neuroblastoma to anti-CTLA4 and generates broad anti-tumor immune memory

“… 38 In our studies, we observed an increase in CD4 + T cells in idMMR neuroblastoma tumors ( Figure 2 G); therefore, we decided to treat the tumor-bearing animals with an anti-CTLA4, which mainly depends on CD4 + T cells for its effectiveness. 39 , 40 To this end, we treated pMMR and idMMR neuroblastoma tumor-bearing mice with anti-CTLA4 therapy to assess T cell-based anti-tumor immune responses ( Figure 4 A). This treatment effectively inhibited the growth of idMMR neuroblastoma tumors, and it cured ∼70% of idMMR neuroblastoma tumor-bearing mice without inducing any significant toxicity in treated animals ( Figures 4 B, 4C, and S5 B).…”