While cancer immunotherapies have transformed treatment outcomes, most patients fail to respond primarily due to immune resistance mechanisms. Targeting tumor antigens along with suppressive factors may overcome such barriers. Glycoprotein A repetitions predominant (GARP) is a cell surface receptor that anchors latent transforming growth factor beta and contributes to immunosuppression, with its expression mostly to regulatory T cells (Tregs), cancer cells, and platelets. This study examines the therapeutic impact of engaging effector T cells to target GARP-expressing tumor cells along with Tregs, utilizing our unique anti-GARP antibody (PIIO-1) that targets tumors and Tregs but spares platelets.
We developed an anti-human GARP/CD3 bispecific T-cell Engager (BiTCE) with a tandem single-chain variable fragment construct. Human T cells armed with BiTCE were co-cultured with GARP+ tumor cells to assess cytotoxicity. In vivo efficacy and safety were evaluated using both immunocompromised and immunocompetent preclinical models that represent highly refractory diffuse large B-cell lymphoma, acute lymphoblastic leukemia, and glioblastoma. Importantly, we utilized systemic adeno-associated virus-mediated BiTCE delivery in vivo to overcome the pharmacokinetic challenges of short half-life of the typical BiTCE proteins without Fc.
We demonstrate that elevated GARP expression in human tumors correlates with poor survival and higher relapse rates after first-line therapies. Our anti-GARP/CD3 BiTCE shows strong in vitro and in vivo efficacy against both GARP-expressing hematologic and solid tumor models without significant toxicity.
Our study provides a novel BiTCE therapeutic platform that enables us to achieve long-term tumor control and overcome tumor resistance by engaging CD3 on effector T cells to target GARP-expressing cancer and Tregs. The Anti-GARP/CD3 platform therefore holds the promise as a novel therapy of cancer immunotherapy worthy for clinical translation.
NIH R01
Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
Ziyu Wang, Yaa S Amankwah, J. Mandula et al.· Journal of Immunology· 0 citations
Background Dedifferentiated liposarcoma (DDLPS) is characterized by abundant immune cell infiltration yet derives limited benefit from immune checkpoint blockade and stimulator of interferon genes (STING) agonist-based strategies, suggesting tumor-mediated suppression of antitumor immunity. Tumor-associated macrophages are the most abundant immune populations in DDLPS, but the factors regulating their function remain incompletely understood. Methods Extracellular vesicles (EVs) were isolated from two DDLPS cell lines and serum from 16 DDLPS patients and 13 healthy donors. EVs’ impact on cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) -induced macrophage activation was assessed by cytokine secretion, surface markers, functional assays and macrophage-T-cell coculture. Proteomics was performed in EV-treated and EV-untreated macrophages from three donors. Pathway and protein interaction analyses were integrated with The Cancer Genome Atlas (TCGA) DDLPS transcriptomic and survival data. Results We show that EVs released by DDLPS cells suppress macrophage responsiveness to classic STING agonist cGAMP. EVs derived from DDLPS attenuated cGAMP-induced expression of type I interferon-associated cytokines and chemokines, reduced IFN-β secretion, and impaired phosphorylation of STING, TBK1 and IRF3. Functionally, DDLPS EV exposure shifted macrophages toward an immunoregulatory phenotype, restrained phagocytic activity, and attenuated macrophage-dependent T-cell proliferation while promoting T-cell exhaustion. Proteomic profiling revealed extensive macrophage reprogramming characterized by suppression of STING-associated signaling, antigen processing and presentation associated pathways and proteins targeted by miR-16-5p. Consistent with these findings, STING expression was associated with prolonged overall survival in DDLPS, while reduced expression of miR-16-5p target proteins was associated with attenuated STING pathway activity and immunostimulatory macrophage signatures. Conclusions These findings identify EV-mediated suppression of macrophage STING signaling as a mechanism of immune dysfunction in DDLPS and provide a framework for understanding immune resistance in this disease.
Qi Zhang, J. Mandula, Patricia Sarchet et al.· bioRxiv· 0 citations
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