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323 Preclinical development of AB-1015, an integrated circuit T cell therapy containing an ALPG/MSLN logic gate and FAS/PTPN2 shRNA-miR, for the treatment of ovarian cancer
  1. Hongruo Yun1,
  2. Jasper Williams1,
  3. Dina Polyak2,
  4. James Zhang1,
  5. Michelle Nguyen1,
  6. Irene Scarfo1,
  7. Jessica Fuhriman1,
  8. Aaron Cooper1,
  9. Jennifer McDevitt1,
  10. Stephen Santoro1 and
  11. Jun Feng1
  1. 1ArsenalBio, South San Francisco, CA, USA
  2. 2ArsenalBio, Palo Alto, CA, 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 CAR T cell activity in solid tumors is limited by off-tumor toxicity, antigen heterogeneity, poor persistence, and functional suppression resulting from the tumor microenvironment (TME). To address these challenges, we have developed AB-1015, an autologous, integrated circuit T (ICT) cell product for the potential treatment of ovarian cancer. The AB-1015 DNA cassette includes two functional modules: an ’AND’ logic gate targeting ALPG/P and MSLN designed to limit off-tumor toxicity through dual tumor antigen recognition, and a dual shRNA-miR targeting FAS and PTPN2 to resist TME suppression and to improve ICT cell function. The AB-1015 DNA cassette is inserted into the T cell genome at a defined genomic site, GS94, via CRISPR integration of transgenes by electroporation (CITE).

Methods The dual-antigen specificity of AB-1015 was evaluated in vivo using a dual flank tumor xenograft model where one tumor expressed both ALPG and MSLN, and the contralateral tumor expressed MSLN alone. To model priming antigen heterogeneity that AB-1015 may encounter in the tumor, we utilized an admixed co-culture system where varying proportions of ALPG+MSLN+ target cells were spiked into cultures that were otherwise MSLN+. In addition, AB-1015 anti-tumor activity and the capability to overcome TME were also assessed in vivo using an intraperitoneal OVCAR3 ovarian xenograft model and a subcutaneous MSTO-FASL xenograft model.

Results AB-1015 demonstrated specific activity against ALPG+MSLN+ tumors but had no effect against MSLN+ tumors in the in vivo dual flank specificity model. In the in vitro heterogeneity assay, AB-1015 was able to eliminate admixed co-cultures where as few as 5% of the target cells expressed ALPG+MSLN+. In the intraperitoneal OVCAR3 ovarian xenograft model, AB-1015 showed potent anti-tumor activity as demonstrated by decrease in bioluminescent signal from the tumors treated with AB-1015. Furthermore, in the subcutaneous MSTO-FASL xenograft model, AB-1015 could resist FASL suppression via shRNA knockdown of FAS. As a result, AB-1015 is capable of completely clearing these otherwise difficult-to-treat tumors in this model.

Conclusions AB-1015 is specific for ALPG/P+MSLN+, demonstrates superior potency compared with logic gated T cells alone, and is resistant to ovarian TME suppression in preclinical studies. Based on these promising preclinical data, AB-1015 is being studied in a phase I clinical trial (NCT05617755).

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