Regulatory T cells (Tregs) are a subpopulation of T cells that act in an immunosuppressive manner downregulating the activation and proliferation of effector T cells. Generation of an anti-tumour immune response can lead to complete and durable tumour regression across cancer types, with effector T cells being a critical component.
Multiple studies have reported high levels of tumour-infiltrating Tregs to correlate with adverse patient outcomes, making a target for Treg depletion an area of intense research. CD25, which is the high-affinity subunit of the interleukin-2 (IL2) receptor, is highly expressed on Tregs, with much lower expression levels on effector T cells and other immune subsets. Anti-CD25 monoclonal antibodies (mAbs) were developed as a means of targeting Tregs for antibody-dependent cellular cytotoxicity (ADCC), thereby eradicating this immune subset.
While CD25 is expressed on other immune subsets and critical for IL2 signalling, levels are too low to initiate ADCC. Unfortunately, anti-CD25 antibodies were dropped from the oncology pipeline after no clinical benefit was observed. The lack of efficacy was due to the mAbs blocking all interaction between IL2 and the IL2 receptor (IL2R), thereby preventing any IL2 stimulation of effector T cells.
RG6292, a novel anti-CD25 developed by Tusk Therapeutics, binds CD25 without blocking the IL2/IL2R interaction. The mAb was developed using GlymaxX technology41, which enhances ADCC capacity, further promoting Treg targeting. Additionally, research by Solomon and colleagues showed that loss of Tregs in response to RG6292 leads to surplus IL2 circulation, thereby increasing IL2-driven stimulation of effector T cells.
In 2018, Tusk Therapeutics was purchased by Roche in a deal worth up to $759m, with Roche taking over the development of RG6292. There are two ongoing Phase I trials investigating the use of RG6292 in solid tumours, both as a monotherapy and in combination with Roche’s anti-PD-L1 inhibitor Tecentriq (atezolizumab). Patient samples from the trials have already shown RG6292 to deplete Tregs, increase effector T cell activity, proliferation and tumour infiltration, as well as upregulating PD-L1 expression.
A study by Galvez-Cancino and colleagues, shared at this year’s ESMO Congress, is investigating RG6292 as a therapeutic for glioblastoma, a hard-to-treat malignancy with very poor patient outcomes. Using glioblastoma mouse models, the study found RG6292 dramatically altered the tumour microenvironment. In addition to Treg depletion and effector T cell activation, proliferation and migration, there was also upregulation of myeloid cells, which drive ADCC. Many mAbs utilised in the oncology setting work by targeting tumour cells for ADCC, making RG6292 and mAb therapy a rational combination. Indeed, treatment with RG6292 and a mAb targeting mutant epidermal growth factor receptor (EGFR) (expressed in the glioblastoma model) led to complete and durable tumour regression in 100% of mice.
While still in the early stages of development, RG6292 shows great promise as a Treg-depleting immunotherapy, which may be rationally combined with a broad range of immunotherapies and mAb-based therapies across cancer indications. Tregs have been long identified as a cause of therapy failure, but this exciting therapeutic may play a role in overcoming this immunosuppressive barrier and become a significant agent in Roche’s pipeline.