CCR8 (C-C Motif Chemokine Receptor 8)

P1, N=99, Terminated, BeiGene | N=263 --> 99 | Trial completion date: Mar 2027 --> Jan 2026 | Active, not recruiting --> Terminated | Trial primary completion date: Mar 2027 --> Jan 2026; This decision was conducted by the sponsor and not driven by safety concerns as no new safety signals have been observed in the CCR8 program.

Our findings establish that the CCR8/CCL1 axis drives the formation of an immunosuppressive niche in the liver by recruiting both Tregs and functionally suppressed CCR8+ T cells, thereby facilitating parasite immune evasion. This study not only elucidates a pivotal mechanism of immune escape in AE but also identifies CCR8 as a promising novel immunotherapeutic target for this neglected tropical disease.

Importantly, therapeutic neutralization of CCL1 using a monoclonal antibody significantly prolonged median survival in both immunocompetent GL261 murine GBM and BNI1-3 patient-derived xenograft (PDX) models, accompanied by reduced TAM infiltration and attenuated FAK/PI3K-AKT signaling. Our findings establish TAM-derived CCL1 as a pivotal regulator of GBM pathogenesis and demonstrate that targeting the CCL1-AMFR axis disrupts both tumor-intrinsic growth and immunosuppressive TME dynamics, representing a promising therapeutic strategy for this lethal malignancy.

Therapeutically, agents targeting chemokine pathways, most notably the CCR4 monoclonal antibody Mogamulizumab, have demonstrated clinical efficacy, while emerging inhibitors of CCR6, CCR5, and CXCR4 offer promising avenues for intervention. We further highlight how recent single-cell and other high-dimensional omics studies refine cell-type-specific chemokine sources and receptor expression, enabling more precise mapping of chemokine-driven intercellular communication programs in CTCL TME remodeling and better prioritization of therapeutic targets and biomarkers.

Additionally, efficacy of combination therapy was CD8 T cell dependent. These findings highlight the potential of combining RT with Treg-targeting therapies to enhance anti-tumor immunity.

P3, N=400, Not yet recruiting, LaNova Medicines Limited

In vivo efficacy studies were conducted using the EMT6 syngeneic breast tumor model, characterized by an immunosuppressive tumor microenvironment, assessing the antitumor effects of a CCR8-targeted small molecule (IPG7236) as monotherapy or in combination with anti-PD-L1 treatment...This study identifies Treg-enriched and immunosuppressive breast cancer subtype through integrative multi-omics analysis and demonstrates, through both in-silico and in-vivo approaches, the therapeutic potential of combining Treg-targeted and PD-L1 blockade therapies. These findings highlight Treg-mediated immunosuppression as a key determinant of therapeutic responsiveness, providing a biological rationale for patient stratification and guiding the development of personalized combination strategies for clinical translation.

Our results indicate that asthma-induced T cell reprogramming inhibits tumor growth by promoting the release of decorin and a subsequent suppression of CCR8 and the intercellular binding kinetics in microglia, followed by blocking of CCL5 production in TME via suppression of NFκB. We developed anti-cancer strategies by leveraging this asthma-induced immune regulation.

Treatment of tumor bearing human CCR8 knock-in (huCCR8KI) mice with CHS-114 resulted in significant tumor growth inhibition (62.6%) accompanied by remodeling of the tumor immune microenvironment and enhanced differentiation of a subset of cytotoxic CD8+ T cells. Based on the promising preclinical data, we are evaluating CHS-114 in clinical trials as an investigational agent for the treatment of solid tumors with and without the anti-PD-1 antibody toripalimab (NCT05635643, NCT06657144).

We detail the quantitative expression profiles of these molecules on various subsets of leukocytes and provide validation data for these mAbs. The implications of these expression profiles are discussed for the potential therapeutic targeting of immune-mediated diseases and cancer.

Our findings suggest that CCR8⁺ Tregs suppress antitumor immunity in gastric cancer by affecting surrounding CD8⁺ T cells through spatial segregation. Targeting CCR8⁺ Tregs may offer a promising strategy to improve the efficacy of immunotherapy in gastric cancer.

111In-DOTA-Fab also exhibited pronounced kidney uptake which persisted even at 72 h. The kidney clearance and retention of 111In-DOTA-Fab might represent a problem during therapy employing 225Actimium or other long-lived therapeutic radionuclides by potentially causing a dose-limiting kidney toxicity. This imaging/biodistribution evaluation not only determined that full-size anti-CCR8 IgG is the optimal antibody format for pre-clinical development but also informed on the timing of immunotherapy administration in future radioimmunotherapy and immunotherapy combination studies.