Targeting Tumor-Infiltrating Regulatory T Cells with JTX-1811: A Promising Approach for Overcoming Resistance in Cancer Therapy

Immune checkpoint blockade has been a significant advancement in cancer treatment, but many patients do not respond to PD-1 or CTLA-4 inhibitors. There is an urgent need for new therapies to help non-responders. Jounce has developed specific gene signatures to identify potential targets in large cancer datasets. Regulatory T cells (Tregs), which can resist ICB, are a promising target for new therapies. Tregs are crucial for immune balance and preventing damage, but they are often abundant in tumors where they may hinder anti-tumor responses. The goal is to find treatments that remove tumor-infiltrating Tregs (TITRs) without affecting Tregs in the rest of the body. A strong link has been found between TITRs and CCR8 across various cancer types, with CCR8 being particularly selective for TITRs.

To investigate this, researchers examined CCR8 levels in TITRs from different tumors and compared them to Tregs from normal tissues and blood. Peripheral blood Tregs had almost no CCR8, and those from normal colon tissue had significantly lower CCR8 levels than TITRs. A series of monoclonal antibodies (mAbs) were created to bind specifically to CCR8 and block its signaling. These mAbs were tested for their ability to induce antibody-dependent cell-mediated cytotoxicity (ADCC). No ADCC was observed when target cells had normal tissue Treg levels of CCR8. However, when cells had TITR levels of CCR8, strong ADCC was observed, particularly with afucosylated human IgG1 Fc antibodies. This suggests a therapeutic potential where TITRs can be selectively removed without affecting normal tissue Tregs.

Preclinical studies have shown that an anti-CCR8 antibody with enhanced ADCC activity can inhibit tumor growth alone and in combination with anti-PD-1, even in resistant models. A humanized monoclonal antibody, JTX-1811, is being developed for this purpose, which could be effective in PD-1 resistant cases and potentially restore the effectiveness of PD-1 inhibitors in resistant situations.