Discriminatory Power of Combinatorial Antigen Recognition in Cancer T Cell Therapies.

Precise discrimination of tumor from normal tissues remains a major roadblock for therapeutic efficacy of chimeric antigen receptor (CAR) T cells. Here, we perform a comprehensive in silico screen to identify multi-antigen signatures that improve tumor discrimination by CAR T cells engineered to integrate multiple antigen inputs via Boolean logic, e.g., AND and NOT. We screen >2.5 million dual antigens and ∼60 million triple antigens across 33 tumor types and 34 normal tissues. We find that dual antigens significantly outperform the best single clinically investigated CAR targets and confirm key predictions experimentally. Further, we identify antigen triplets that are predicted to show close to ideal tumor-versus-normal tissue discrimination for several tumor types. This work demonstrates the potential of 2- to 3-antigen Boolean logic gates for improving tumor discrimination by CAR T cell therapies. Our predictions are available on an interactive web server resource (antigen.princeton.edu).

[1]  Y. Kew,et al.  Combinational Targeting Offsets Antigen Escape and Enhances Effector Functions of Adoptively Transferred T Cells in Glioblastoma , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[2]  Russell M. Gordley,et al.  Engineering Customized Cell Sensing and Response Behaviors Using Synthetic Notch Receptors , 2016, Cell.

[3]  S. Sleijfer,et al.  Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[4]  Shivani Srivastava,et al.  Logic-Gated ROR1 Chimeric Antigen Receptor Expression Rescues T Cell-Mediated Toxicity to Normal Tissues and Enables Selective Tumor Targeting. , 2019, Cancer cell.

[5]  Y. Dang,et al.  Effect of CELSR3 on the Cell Cycle and Apoptosis of Hepatocellular Carcinoma Cells , 2020, Journal of Cancer.

[6]  I. Gill,et al.  Axl receptor tyrosine kinase is a potential therapeutic target in renal cell carcinoma , 2015, British Journal of Cancer.

[7]  T. Yoneda,et al.  Cadherin-6 Mediates the Heterotypic Interactions between the Hemopoietic Osteoclast Cell Lineage and Stromal Cells in a Murine Model of Osteoclast Differentiation , 1998, The Journal of cell biology.

[8]  A. Pierani,et al.  Kremen1-induced cell death is regulated by homo- and heterodimerization , 2019, Cell Death Discovery.

[9]  S. Eccles,et al.  Dual Targeting of ErbB2 and MUC1 in Breast Cancer Using Chimeric Antigen Receptors Engineered to Provide Complementary Signaling , 2012, Journal of Clinical Immunology.

[10]  M. Merino,et al.  T Cells Targeting Carcinoembryonic Antigen Can Mediate Regression of Metastatic Colorectal Cancer but Induce Severe Transient Colitis. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[11]  Xiaohan Qu,et al.  Role of AXL expression in non-small cell lung cancer , 2016, Oncology letters.

[12]  Christian Stolte,et al.  COMPARTMENTS: unification and visualization of protein subcellular localization evidence , 2014, Database J. Biol. Databases Curation.

[13]  Michel Sadelain,et al.  PD-1– and CTLA-4–Based Inhibitory Chimeric Antigen Receptors (iCARs) Divert Off-Target Immunotherapy Responses , 2013, Science Translational Medicine.

[14]  Yu‐quan Wei,et al.  AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications , 2019, Molecular Cancer.

[15]  Bonnie Berger,et al.  Geometric Sketching Compactly Summarizes the Single-Cell Transcriptomic Landscape. , 2019, Cell systems.

[16]  F. Marshall,et al.  Cadherin-6, a cell adhesion molecule specifically expressed in the proximal renal tubule and renal cell carcinoma. , 1997, Cancer research.

[17]  S. Rosenberg,et al.  Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[18]  Kole T. Roybal,et al.  Engineering T Cells with Customized Therapeutic Response Programs Using Synthetic Notch Receptors , 2016, Cell.

[19]  R. Camp,et al.  CD70 expression patterns in renal cell carcinoma. , 2012, Human pathology.

[20]  T. Ismail,et al.  Glutamate dependent NMDA receptor 2D is a novel angiogenic tumour endothelial marker in colorectal cancer , 2016, Oncotarget.

[21]  R. V. van Lier,et al.  CD70 represents the human ligand for CD27. , 1994, International immunology.

[22]  M. Zannini,et al.  Candidate genes and pathways downstream of PAX8 involved in ovarian high-grade serous carcinoma , 2016, Oncotarget.

[23]  Matthew L Baker,et al.  TanCAR: A Novel Bispecific Chimeric Antigen Receptor for Cancer Immunotherapy , 2013, Molecular therapy. Nucleic acids.

[24]  Cheng Li,et al.  Adjusting batch effects in microarray expression data using empirical Bayes methods. , 2007, Biostatistics.

[25]  S. Halford,et al.  The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity , 2017, Cancer Immunology, Immunotherapy.

[26]  S. Rosenberg,et al.  Adoptive cell transfer as personalized immunotherapy for human cancer , 2015, Science.

[27]  R. V. van Lier,et al.  Expression of the Murine CD27 Ligand CD70 In Vitro and In Vivo4 , 2003, The Journal of Immunology.

[28]  Nicola J. Rinaldi,et al.  Genetic effects on gene expression across human tissues , 2017, Nature.

[29]  Michel Sadelain,et al.  Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells , 2012, Nature Biotechnology.

[30]  K. Davis,et al.  Tisagenlecleucel in Children and Young Adults with B‐Cell Lymphoblastic Leukemia , 2018, The New England journal of medicine.

[31]  R. Levy,et al.  Axicabtagene Ciloleucel CAR T‐Cell Therapy in Refractory Large B‐Cell Lymphoma , 2017, The New England journal of medicine.

[32]  J. Yang,et al.  Preclinical Evaluation of Chimeric Antigen Receptors Targeting CD70-Expressing Cancers , 2016, Clinical Cancer Research.

[33]  Kole T. Roybal,et al.  Precision Tumor Recognition by T Cells With Combinatorial Antigen-Sensing Circuits , 2016, Cell.