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321 Preclinical potency assessment of SynKIR-110, a mesothelin-specific KIR-CAR T cell therapy for mesothelioma
  1. Jun Xu1,
  2. Selene Nunez-Cruz2,
  3. Jacqueline Rivera1,
  4. Michael Milone2 and
  5. Laura Johnson1
  1. 1Verismo Therapeutics, Philadelphia, PA, USA
  2. 2University of Pennsylvania, Philadelphia, PA, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background Mesothelin (MSLN) is an attractive therapeutic target known to have strong expression in a variety of human solid tumors including mesothelioma (MESO), ovarian cancer (OvC), and cholangiocarcinoma (CHOL) with a restricted and weak expression profile on normal mesothelial cells.1 Previously, MSLN-specific CAR T cell therapies exhibited suboptimal persistence and limited efficacy in patients with a manageable safety profile.2–4 To overcome the poor functional persistence of CAR T in the solid tumors, we previously developed a MSLN-specific Killer Immunoglobulin receptor (KIR)-CAR consisting of one antigen binding domain derived from the SS1 anti-MSLN antibody and one T cell activation domain DAP12 on two split chains to mimic natural multichain immunoreceptors.5 To extend our understanding of potency of the first MSLN-specific KIR-CAR T cell therapy (SynKIR-110), we assessed the impact of engineered T cell dose in an NSG mouse xenograft of human mesothelioma comparing SynKIR-110 to the clinically tested MSLN-specific 41BBζ CAR T (MSLN-41BBζ).

Methods NSG mice were first injected subcutaneously with 2x106 MSLN-positive EM-meso tumors. On Day 6, low and high doses of SynKIR-110, MSLN-41BBζ or non-transduced T cells (NTD) were intravenously injected by tail vein. Mouse weights were monitored, and tumor volume was measured by calipers. Multiple organs/tissues at Day 11 and Day 32 after T cell infusion were collected for H&E staining and histopathology evaluation for high dose T cell treatment groups. Sera was also collected for serum chemistries.

Results MSLN-41BBζ or NTD treated mice, showed overt malignant neoplasms at the subcutaneous injection site along with metastatic lesions in the lung, liver, and stomach. Mononuclear infiltrations in multiple organs/tissues consistent with expected xenogeneic graft versus host disease (GVHD) was also observed. High dose MSLN-41BBζ treated mice showed a delay in tumor growth relative to NTD treated mice. In contrast, high dose SynKIR-110 treated mice showed significant reductions of tumor growth, and complete elimination of malignant neoplasm at the primary injection site as well as absence of detectable metastatic lesions or other tissue pathology.

Conclusions The preclinical study demonstrates that the anti-tumor efficacy of SynKIR-110 is dose dependent with greater potency compared to MSLN-41BBζ CAR T cells previously evaluated in the clinic. This enhanced potency was observed both at the primary tumor site and metastatic sites. These data support further clinical development of SynKIR-110 in patients with advanced solid tumors. SynKIR-110 is currently being investigated in a Phase I clinical trial STAR-101 (NCT05568680).


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