RT Journal Article
SR Electronic
T1 1323 CUE-102 selectively activates and expands WT1-specific T cells for the treatment of patients with WT1+ malignancies
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP A1374
OP A1374
DO 10.1136/jitc-2022-SITC2022.1323
VO 10
IS Suppl 2
A1 Girgis, Natasha
A1 Christie, Yu
A1 Merazga, Zohra
A1 Hatfield, Steven
A1 Histed, Alex
A1 Zhao, Fan
A1 Moniz, Raymond
A1 Yeung, Kristin
A1 Diaz, Fulvio
A1 Bautista, Wynona
A1 Ross, John
A1 Cemerski, Saso
A1 Suri, Anish
A1 Levisetti, Matteo
A1 Quayle, Steven
YR 2022
UL http://jitc.bmj.com/content/10/Suppl_2/A1374.abstract
AB Background Wilms’ Tumor 1 (WT1) was ranked as the highest priority antigen for therapeutic targeting in an effort by the National Cancer Institute. Development of novel modalities targeting 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. Leveraging the Immuno-STATTM platform of targeted IL-2 therapies, and the ongoing development of CUE-101, CUE-102 is being developed as a novel therapeutic fusion protein to selectively activate tumor antigen-specific T cells to treat WT1-expressing cancers. CUE-102 consists of two human leukocyte antigen (HLA) molecules presenting a WT1 peptide, four affinity-attenuated human interleukin-2 (IL-2) molecules, and an effector attenuated human immunoglobulin G (IgG1) Fc domain.Methods Cellular activity and specificity of CUE-102 were demonstrated in human PBMCs, while the in vivo activity of CUE-102 was assessed in HLA-A2 transgenic mice. HLA-A2/WT1-specific TCRs were validated and expressed in primary human CD8+ T cells. Antigen-specific cells were identified by flow cytometry using tetramer staining, activation markers and cytokine production.Results Multiple in vitro assessments demonstrated that CUE-102 selectively binds, activates, and expands naturally occurring WT137-45-specific CD8+ T cells from PBMCs of healthy and cancer patient donors, consistent with its design. These CD8+ T cells exhibit polyfunctional and cytotoxic responses upon challenge with WT1-presenting target cells. In addition, significant functional attenuation of the IL-2 components of CUE-102 was shown, similar to preclinical results obtained with CUE-101. In vivo studies in HLA-A2 transgenic mice confirmed that CUE-102 elicits and expands polyfunctional WT1-specific CD8+ T cells from naïve and previously immunized mice without significantly altering the frequencies of other immune lineages. The WT1-specific CD8+ T cells expanded in vivo exhibit polyfunctional cytokine responses upon restimulation and selectively kill target cells presenting WT1 peptide in vivo. WT1-specific CD8+ T cells elicited in vivo by CUE-102 were detectable for >180 days following the last CUE-102 treatment, demonstrating the establishment of a long-term memory response to this tumor antigen.Conclusions CUE-102 elicits selective expansion of WT1-specific cytotoxic CD8+ T cells both in vitro and in vivo. These results, together with its similarity to CUE-101, support its anticipated tolerability profile and potential for clinical efficacy in an ongoing Phase 1 clinical trial (NCT05360680).Ethics Approval Studies using animals were conducted in accordance with guidelines established by the Smart Labs Institutional Animal Care and Use Committee under protocol 21SL09-0007.