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Anti-tumor and immune modulating activity of T cell induced tumor-targeting effectors (TITE)

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Abstract

Adoptive transfer of Bispecific antibody Armed activated T cells (BATs) showed promising anti-tumor activity in clinical trials in solid tumors. The cytotoxic activity of BATs occurs upon engagement with tumor cells via the bispecific antibody (BiAb) bridge, which stimulates BATs to release cytotoxic molecules, cytokines, chemokines, and other signaling molecules extracellularly. We hypothesized that the release of BATs Induced Tumor-Targeting Effectors (TITE) by this complex interaction of T cells, bispecific antibody, and tumor cells may serve as a potent anti-tumor and immune-activating immunotherapeutic approach. In a 3D tumorsphere model, TITE showed potent cytotoxic activity against multiple breast cancer cell lines compared to control conditioned media (CM): Tumor-CM (T-CM), BATs-CM (B-CM), BiAb Armed PBMC-CM (BAP-CM) or PBMC-CM (P-CM). Multiplex cytokine analysis showed high levels of Th1 cytokines and chemokines; phospho-protein signaling array data suggest that the prominent JAK1/STAT1 pathway may be responsible for the induction and release of Th1 cytokines/chemokines in TITE. In xenograft breast cancer models, IV injections of 10× concentrated TITE (3×/week for 3 weeks; 150 μl TITE/injection) was able to inhibit tumor growth significantly (ICR/scid, p < 0.003; NSG p < 0.008) compared to the control mice. We tested the key components of the TITE for immune activating and anti-tumor activity individually and in combinations, the combination of IFN-γ, TNF-α and MIP-1β recapitulates the key activities of the TITE. In summary, master mix of active components of BATs–Tumor complex-derived TITE can provide a clinically controllable cell-free platform to target various tumor types regardless of the heterogeneous nature of the tumor cells and mutational tumor.

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References

  1. Lum LG et al (2015) Targeted T-cell therapy in stage IV breast cancer: a phase I clinical trial. Clin Cancer Res 21(10):2305–2314

    Article  CAS  Google Scholar 

  2. Vaishampayan U et al (2015) Phase I study of anti-CD3 × anti-Her2 bispecific antibody in metastatic castrate resistant prostate cancer patients. Prostate Cancer 2015:285193

    Article  Google Scholar 

  3. Thakur A et al (2018) Immune T cells can transfer and boost anti-breast cancer immunity. Oncoimmunology 7(12):e1500672

    Article  Google Scholar 

  4. Thakur A, Lum LG (2016) In Situ immunization by bispecific antibody targeted T cell therapy in breast cancer. Oncoimmunology 5(3):e1055061

    Article  Google Scholar 

  5. Sen M et al (2001) Use of anti-CD3 × anti-HER2/neu bispecific antibody for redirecting cytotoxicity of activated T cells toward HER2/neu+ tumors. J Hematother Stem Cell Res 10(2):247–260

    Article  CAS  Google Scholar 

  6. Thakur A, Norkina O, Lum LG (2011) In vitro synthesis of primary specific anti-breast cancer antibodies by normal human peripheral blood mononuclear cells. Cancer Immunol Immunother 60(12):1707–1720

    Article  CAS  Google Scholar 

  7. Thakur A et al (2012) A Th1 cytokine-enriched microenvironment enhances tumor killing by activated T cells armed with bispecific antibodies and inhibits the development of myeloid-derived suppressor cells. Cancer Immunol Immunother 61(4):497–509

    Article  CAS  Google Scholar 

  8. Hernandez C, Huebener P, Schwabe RF (2016) Damage-associated molecular patterns in cancer: a double-edged sword. Oncogene 35(46):5931–5941

    Article  CAS  Google Scholar 

  9. Thakur A et al (2013) Microenvironment generated during EGFR targeted killing of pancreatic tumor cells by ATC inhibits myeloid-derived suppressor cells through COX2 and PGE2 dependent pathway. J Transl Med 11:35

    Article  CAS  Google Scholar 

  10. Pardo J et al (2004) Apoptotic pathways are selectively activated by granzyme A and/or granzyme B in CTL-mediated target cell lysis. J Cell Biol 167(3):457–468

    Article  CAS  Google Scholar 

  11. Goping IS et al (2003) Granzyme B-induced apoptosis requires both direct caspase activation and relief of caspase inhibition. Immunity 18(3):355–365

    Article  CAS  Google Scholar 

  12. Zhang Y, Liu Z (2017) STAT1 in cancer: friend or foe? Discov Med 24(130):19–29

    PubMed  Google Scholar 

  13. Rauch I, Muller M, Decker T (2013) The regulation of inflammation by interferons and their STATs. JAKSTAT 2(1):e23820

    PubMed  PubMed Central  Google Scholar 

  14. Able AA, Burrell JA, Stephens JM (2017) STAT5-interacting proteins: a synopsis of proteins that regulate STAT5 activity. Biology (Basel) 6(1):20

    Google Scholar 

  15. Dimberg A et al (2003) Ser727/Tyr701-phosphorylated Stat1 is required for the regulation of c-Myc, cyclins, and p27Kip1 associated with ATRA-induced G0/G1 arrest of U-937 cells. Blood 102(1):254–261

    Article  CAS  Google Scholar 

  16. Hoefig KP, Heissmeyer V (2018) Posttranscriptional regulation of T helper cell fate decisions. J Cell Biol 217(8):2615–2631

    Article  CAS  Google Scholar 

  17. Liu W et al (2017) T lymphocyte SHP2-deficiency triggers anti-tumor immunity to inhibit colitis-associated cancer in mice. Oncotarget 8(5):7586–7597

    Article  Google Scholar 

  18. Su YL et al (2018) STAT3 in tumor-associated myeloid cells: multitasking to disrupt immunity. Int J Mol Sci 19(6):1803

    Article  Google Scholar 

  19. Zhao D et al (2014) VEGF drives cancer-initiating stem cells through VEGFR-2/Stat3 signaling to upregulate Myc and Sox2. Oncogene 34:3107

    Article  Google Scholar 

  20. Bogin L, Degani H (2002) Hormonal regulation of VEGF in orthotopic MCF7 human breast cancer. Cancer Res 62(7):1948–1951

    CAS  PubMed  Google Scholar 

  21. Lee TH et al (2003) Vascular endothelial growth factor modulates the transendothelial migration of MDA-MB-231 breast cancer cells through regulation of brain microvascular endothelial cell permeability. J Biol Chem 278(7):5277–5284

    Article  CAS  Google Scholar 

  22. Binnemars-Postma K et al (2018) Targeting the Stat6 pathway in tumor-associated macrophages reduces tumor growth and metastatic niche formation in breast cancer. FASEB J 32(2):969–978

    Article  CAS  Google Scholar 

  23. Torri A et al (2017) Extracellular microRNA signature of human helper T cell subsets in health and autoimmunity. J Biol Chem 292(7):2903–2915

    Article  CAS  Google Scholar 

  24. Podshivalova K, Salomon DR (2013) MicroRNA regulation of T-lymphocyte immunity: modulation of molecular networks responsible for T-cell activation, differentiation, and development. Crit Rev Immunol 33(5):435–476

    Article  CAS  Google Scholar 

  25. Rodriguez-Galan A, Fernandez-Messina L, Sanchez-Madrid F (2018) Control of immunoregulatory molecules by miRNAs in T cell activation. Front Immunol 9:2148

    Article  Google Scholar 

  26. Testa U et al (2017) miR-146 and miR-155: two key modulators of immune response and tumor development. Noncoding RNA 3(3):22

    PubMed Central  Google Scholar 

  27. Liang Y, Pan HF, Ye DQ (2015) microRNAs function in CD8+T cell biology. J Leukoc Biol 97(3):487–497

    Article  CAS  Google Scholar 

  28. Paladini L et al (2016) Targeting microRNAs as key modulators of tumor immune response. J Exp Clin Cancer Res 35:103

    Article  Google Scholar 

  29. Cioffi M et al (2017) The miR-25-93-106b cluster regulates tumor metastasis and immune evasion via modulation of CXCL12 and PD-L1. Oncotarget 8(13):21609–21625

    Article  Google Scholar 

  30. Yu Z et al (2010) microRNA 17/20 inhibits cellular invasion and tumor metastasis in breast cancer by heterotypic signaling. Proc Natl Acad Sci USA 107(18):8231–8236

    Article  CAS  Google Scholar 

  31. Soleimani A et al (2019) Role of TGF-beta signaling regulatory microRNAs in the pathogenesis of colorectal cancer. J Cell Physiol. https://doi.org/10.1002/jcp.28169

    Article  PubMed  Google Scholar 

  32. Porter DL et al (2011) Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365(8):725–733

    Article  CAS  Google Scholar 

  33. Guedan S, Ruella M, June CH (2018) Emerging cellular therapies for cancer. Annu Rev Immunol. https://doi.org/10.1146/annurev-immunol-042718-041407

    Article  PubMed  PubMed Central  Google Scholar 

  34. Watanabe K et al (2018) Expanding the therapeutic window for CAR T cell therapy in solid tumors: the knowns and unknowns of CAR T cell biology. Front Immunol 9:2486

    Article  Google Scholar 

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Acknowledgements

Authors would like to thank Dr. Manley T. Huang for his help with antigen expression on tumor cells. These studies were funded in part by R01 CA 092344 (L.G.L.), R01 CA 140412 (L.G.L), 5P39 CA 022453 from the National Cancer Institute, and startup funds from the Barbara Ann Karmanos Cancer Institute and the University of Virginia.

Funding

This study was primarily supported by funding from in part by DHHS R01 CA 092344, R01 CA 140314, R01 CA 182526, P30CA022453 (Microscopy, Imaging, and Cytometry Resources Core) and startup funds from the University of Virginia Cancer Center.

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Author notes

  1. Archana Thakur and Sri Vidya Kondadasula have shared authorship.

Authors and Affiliations

  1. Bone Marrow Transplant Program, Division of Hematology/Oncology, Department of Medicine, University of Virginia Cancer Center, 1335 Lee Street, West Complex 7191, Charlottesville, VA, 22908, USA

    Archana Thakur, Dana L. Schalk, Edwin Bliemeister, Johnson Ung, Eli Casarez & Lawrence G. Lum

  2. Departments of Oncology and Medicine, Wayne State University and Karmanos Cancer Institute, Detroit, MI, 48201, USA

    Sri Vidya Kondadasula & Amro Aboukameel

  3. Department of Pharmacology, Wayne State University and Karmanos Cancer Institute, Detroit, MI, 48201, USA

    Kyungmin Ji & Bonnie F. Sloane

Authors
  1. Archana Thakur
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  2. Sri Vidya Kondadasula
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  3. Kyungmin Ji
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  4. Dana L. Schalk
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  8. Eli Casarez
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  10. Lawrence G. Lum
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Contributions

AT and LGL conceived and designed the study, performed statistical analysis, and wrote the manuscript. LGL and BFS participated in the design of the study and helped in drafting the manuscript. SVK, KJ, DLS, EB, JU, AA, EC performed the experiments and participated in the data analysis. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Archana Thakur.

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Conflict of interest

AT is co-founder of Nova Immune Platform Inc.; LGL is co-founders of TransTarget, Inc; SVK, KJ, DLS, EB, JU, AA, EC and BFS have no conflict of interest. The data presented in this manuscript are original and have not been published elsewhere except in the form of abstracts and poster presentations at symposia and meetings.

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Thakur, A., Kondadasula, S.V., Ji, K. et al. Anti-tumor and immune modulating activity of T cell induced tumor-targeting effectors (TITE). Cancer Immunol Immunother 70, 633–656 (2021). https://doi.org/10.1007/s00262-020-02692-8

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  • DOI: https://doi.org/10.1007/s00262-020-02692-8

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