Targeting Tissue Factor for Immunotherapy of Triple-Negative Breast Cancer Using a Second-Generation ICON

Hu, Zhiwei; Shen, Rulong; Campbell, Amanda R.; McMichael, Elizabeth L.; Yu, Lianbo; Ramaswamy, Bhuvaneswari; London, Cheryl A.; Xu, Tian; Carson, William E.

doi:10.1158/2326-6066.cir-17-0343

Cited by 33 publications

(56 citation statements)

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“…VECs (64% of 14 patients with TNBC) 14 . In addition, our laboratory reported that TF is a novel oncotarget for CSCs, which were isolated from human breast, lung and ovarian cancer cell lines including TNBC, tumor xenografts and patients with breast cancer 15 .…”

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confidence: 99%

“…Besides its role as the primary initiator of coagulation, TF is also a modulator of pathological angiogenesis [24][25][26] . We and our collaborators along with other groups have identified TF as an angiogenesis-specific receptor on VEGF-stimulated angiogenic microvascular endothelial models in vitro as well as in vivo in angiogenic VECs (the inner layer) of the pathological neovasculature of endometriosis, age-related macular degeneration (AMD) and solid cancers, including melanoma 27,28 , lung cancer 29 and breast cancer 29 , and from tumor xenografts in mice and breast cancer tissues from patients 14,16 . In cancer, TF is highly expressed on the cancer cells in many types of solid cancers 14,23,[30][31][32] , acute myeloid and lymphoblastic leukemia (AML and ALL) and sarcoma 23,32 as well as in Hodgkin's lymphoma 33 and multiple myeloma (MM, TF detected in 10 out of 18 patients with MM and 3 MM lines) 34 .…”

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confidence: 99%

“…ICON is a chimeric antibody-like homodimer immunoconjugate (210 kDa) 36 that consists of murine or human fVII full-length peptide (406 amino acid residues, aa) fused to the Fc region of IgG1 27,28,35,37 . The procoagulant effects of ICON-encoded zymogen fVII have been significantly eliminated via targeted mutation of the lysine reside at position 341 (K341A) 35 , but was not completely depleted (5% of activated fVII, fVIIa) 14 . Our lab recently improved it to a second-generation ICON (called L-ICON or L-ICON1) by removing the procoagulant heavy chain of fVII from ICON, resulting in a >50% reduction in molecular mass (92.5 kDa), complete depletion of procoagulant activity 14 and higher binding activity and antibody-dependent cell-mediated cytotoxicity (ADCC) to TNBC cells than the original ICON.…”

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confidence: 99%

“…The procoagulant effects of ICON-encoded zymogen fVII have been significantly eliminated via targeted mutation of the lysine reside at position 341 (K341A) 35 , but was not completely depleted (5% of activated fVII, fVIIa) 14 . Our lab recently improved it to a second-generation ICON (called L-ICON or L-ICON1) by removing the procoagulant heavy chain of fVII from ICON, resulting in a >50% reduction in molecular mass (92.5 kDa), complete depletion of procoagulant activity 14 and higher binding activity and antibody-dependent cell-mediated cytotoxicity (ADCC) to TNBC cells than the original ICON. It is well documented that NK cells are crucial as CD16+ ADCC effector cells for the efficacy of antibody immunotherapy using ICON 36 , L-ICON 14 or other therapeutic antibody 38 .…”

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confidence: 99%

“…Our lab recently improved it to a second-generation ICON (called L-ICON or L-ICON1) by removing the procoagulant heavy chain of fVII from ICON, resulting in a >50% reduction in molecular mass (92.5 kDa), complete depletion of procoagulant activity 14 and higher binding activity and antibody-dependent cell-mediated cytotoxicity (ADCC) to TNBC cells than the original ICON. It is well documented that NK cells are crucial as CD16+ ADCC effector cells for the efficacy of antibody immunotherapy using ICON 36 , L-ICON 14 or other therapeutic antibody 38 . However, NK cells are often impaired in cancer patients 38 , including patients with breast cancer 39,40 .…”

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Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer

2020

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Triple-negative breast cancer (TNBC), representing ~15% of globally diagnosed breast cancer, is typically an incurable malignancy due to the lack of targetable surface targets for development of effective therapy. To address the unmet need for TNBC treatment, we recently determined that tissue factor (TF) is a useful surface target in 50-85% of patients with TNBC and developed a secondgeneration TF-targeting antibody-like immunoconjugate (called L-ICON) for preclinical treatment of TNBC. Using the chimeric antigen receptor (CAR) approach, here we develop and test TF-targeting CARengineered natural killer (TF-CAR-NK) cells that co-express CD16, the Fc receptor (FcγIII) to mediate antibody-dependent cellular toxicity (ADCC), for a preclinical assessment of immunotherapy of TNBC using TF-CAR-NK cell as single agent therapy and in combination with L-ICON. Our preclinical results demonstrate that TF-CAR-NK cells alone could kill TNBC cells and its efficacy was enhanced with L-ICON ADCC in vitro. Moreover, TF-CAR-NK cells were effective in vivo for the treatment of tnBc in cell lineand patient's tumor-derived xenograft mouse models. Thus, this study established the proof of concept of targeting TF as a new target in CAR-NK immunotherapy for effective treatment of TNBC and may warrant further preclinical study and potentially future investigation in TNBC patients.The adoptive transfer of chimeric antigen receptor (CAR)-expressing T and natural killer (NK) cells represents a novel cancer immunotherapy approach. The concept of the CAR is based upon the idea of expressing novel receptors on the T or NK cell surface that would enable the T and NK cell to identify corresponding antigens on the surface of a target cell. The basic CAR construct consists of an extracellular antigen-recognition domain, usually single-chain antibody variable fragments (scFv), attached to an extracellular spacer domain, a transmembrane domain of CD28 and a signaling cytoplasmic domain such as 4-1BB (CD137), OX40 (CD134), DAP10, ICOS and CD3zeta chain (CD3ζ). The most advanced application is the use of CAR-T cells targeting CD19, a surface antigen on B cell malignancies, which has demonstrated antitumor efficacy in patients with these cancers 1 . However, early-phase clinical trials of CAR T therapy also showed that this treatment is frequently associated with side effects 1 , some even causing life-threatening toxicity 2 , partly due to the fact that current CAR targets are expressed by both the malignant cells and normal cells, such as CD19, which is also expressed by normal B cells throughout the B cell lineage 1 . Also, one of the major challenges in CAR therapy is the heterogeneity of tumor antigens, for instance, antigen loss or low antigen density on the cancer cells 3 . To overcome these challenges, it would be ideal to develop CAR T or CAR NK cells that could target a surface molecule that is commonly yet selectively expressed by several major tumor compartments, including but not limited to, the cancer cell, cancer stem cell (CSC) and tum...

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Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer

2020

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Conversion of anti-tissue factor antibody sequences to chimeric antigen receptor and bi-specific T-cell engager format

Saunderson,

Halpin,

Tan

et al. 2024

Cancer Immunol Immunother

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Background The efficacy of antibody-targeted therapy of solid cancers is limited by the lack of consistent tumour-associated antigen expression. However, tumour-associated antigens shared with non-malignant cells may still be targeted using conditionally activated-antibodies, or by chimeric antigen receptor (CAR) T cells or CAR NK cells activated either by the tumour microenvironment or following 'unlocking' via multiple antigen-recognition. In this study, we have focused on tissue factor (TF; CD142), a type I membrane protein present on a range of solid tumours as a basis for future development of conditionally-activated BiTE or CAR T cells. TF is frequently upregulated on multiple solid tumours providing a selective advantage for growth, immune evasion and metastasis, as well as contributing to the pathology of thrombosis via the extrinsic coagulation pathway. Methods Two well-characterised anti-TF monoclonal antibodies (mAb) were cloned into expression or transposon vectors to produce single chain (scFv) BiTE for assessment as CAR and CD28-CD3-based CAR or CD3-based BiTE. The affinities of both scFv formats for TF were determined by surface plasmon resonance. Jurkat cell line-based assays were used to confirm the activity of the BiTE or CAR constructs. Results The anti-TF mAb hATR-5 and TF8-5G9 mAb were shown to maintain their nanomolar affinities following conversion into a single chain (scFv) format and could be utilised as CD28-CD3-based CAR or CD3-based BiTE format. Conclusion Because of the broad expression of TF on a range of solid cancers, anti-TF antibody formats provide a useful addition for the development of conditionally activated biologics for antibody and cellular-based therapy.

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Tissue factor: a neglected role in cancer biology

Gao

et al. 2022

J Thromb Thrombolysis

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Targeting Tissue Factor for Immunotherapy of Triple-Negative Breast Cancer Using a Second-Generation ICON

Cited by 33 publications

References 60 publications

Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer

Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer

Conversion of anti-tissue factor antibody sequences to chimeric antigen receptor and bi-specific T-cell engager format

Tissue factor: a neglected role in cancer biology

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