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eSymposia | Advances in Cancer Immunotherapy


CUE-102 Immuno-STATs for selective targeting and expansion of WT1-specific T cells for the treatment of cancer patients expressing WT1


Aug 17, 2020 12:00am ‐ Aug 17, 2020 12:00am

Description

CUE-102 Immuno-STATs for selective targeting and expansion of WT1-specific T cells for the treatment of cancer patients expressing WT1 Histed A., Girgis N., Moreta M., Soriano J., Witt L., Merazga Z., Diaz F., Zhao F., Kemp M., Ruthardt P., Thapa D., Suri A., Quayle S., Ross J., Cemerski S. WT1 has been ranked first amongst 75 tumor associated antigens in an effort by the National Cancer Institute to prioritize cancer antigens for therapeutic targeting. Development of novel modalities to target WT1 provide a significant opportunity to address high unmet medical need in WT1-positive malignancies, including AML, ovarian, endometrial, breast, lung, colorectal and pancreatic cancer. We have developed, in partnership with LG Chem, two novel fusion proteins, termed Immuno-STATs (Selective Targeting and Activation of T cells), that are comprised of HLA-A*02 or HLA-A*24 molecules (human leukocyte antigen) presenting peptide epitopes derived from WT1. Each CUE-102 Immuno-STAT molecule also contains four copies of affinity-attenuated human interleukin-2 (IL-2), and an effector attenuated human immunoglobulin G (IgG1) Fc domain. We present here the biochemical characterization of the CUE-102/A02 Immuno-STAT and its bioactivity across a variety of in vitro and in vivo studies. CUE-102/A02 Immuno-STAT presents the WT137-45 peptide in the context of HLA-A*02, and selectively targets and activates WT137-45-specific CD8+ T cells. Signaling, cell-based assays and cytokine release studies confirmed significant functional attenuation of the IL-2 components of CUE-102. Primary stimulation of unprimed hPBMCs, or re-stimulation of hPBMCs after initial WT1 peptide stimulation, led to robust expansion of WT137-45 -specific CD8+ T cells and demonstrated the ability of the CUE-102/A02 Immuno-STAT to stimulate and expand WT137-45 antigen-specific T cells from both unprimed and pre-primed T cell repertoires. CUE-102/A02 also expanded a population of WT137-45-specific CD8+ T cells upon administration to naïve HLA-A*02 transgenic mice. In both cases the expanded T cells exhibited a polyfunctional response upon challenge with WT137-45-presenting target cells. The repertoire of the expanded cells, their polyfunctionality and ability to recognize and respond to WT1 peptide-presenting target cells suggest that CUE-102 Immuno-STATs have the potential to enhance anti-tumor immunity in patients with WT1-positive malignancies.

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