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720 CUE-102 selectively activates and expands WT1-specific T cells for the treatment of patients with WT1+ malignancies
  1. Christie Zhang1,
  2. Natasha Girgis1,
  3. Zohra Merazga1,
  4. Steven Hatfield1,
  5. Alex Histed1,
  6. Fan Zhao1,
  7. Raymond Moniz1,
  8. Kristin Yeung1,
  9. Fulvio Diaz1,
  10. Jason Brown1,
  11. Mark Haydock1,
  12. Luke Witt1,
  13. Wynona Bautista1,
  14. John Ross1,
  15. Saso Cemerski1,
  16. Anish Suri1,
  17. Kenneth Pienta2,
  18. Matteo Levisetti1 and
  19. Steve Quayle1
  1. 1Cue Biopharma, Cambridge, MA, United States
  2. 2Johns Hopkins School of Medicine, Cambridge, MA, United States


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-STAT 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 Human PBMCs were tested to demonstrate cellular activity and specificity of CUE-102, while 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. Tetramer staining and flow cytometry identified cell populations and activation markers.

Results Multiple in vitro assessments demonstrate that CUE-102 selectively activates and expands WT1-specific CD8+ T cells from PBMC of healthy and cancer bearing donors. These CUE-102-expanded 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 confirm 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 polyfunctionality in response to peptide-loaded target cells, and selectively kill WT1-presenting target cells in vivo.

Conclusions CUE-102 elicits selective expansion of a WT1-specific population of 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 a Phase 1 trial planned to initiate in 2022.

Ethics Approval All animal studies followed guidance from the SmartLabs Institutional Animal Care and Use Committee protocol MIL-100 and were performed in compliance with federal guidelines.

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