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364 Non-clinical development of T-Plex component TSC-200-A0201: a natural HPV16 E7-specific TCR-T cell therapy for the treatment of HPV16-positive solid tumors
  1. Sonal Jangalwe,
  2. Badr Kiaf,
  3. Daniel C Pollacksmith,
  4. Shubhangi Kamalia,
  5. Sveta Padmanabhan,
  6. Hannah Bader,
  7. Tary Traore,
  8. Nivya Sharma,
  9. Victor Ospina,
  10. Debanjan Goswamy,
  11. Alok Das Mahopatra,
  12. Shazad A Khokhar,
  13. Kimberly M Cirelli,
  14. Vivin Karthik,
  15. Kenneth L Jahan,
  16. Nicolas Gaspar,
  17. Livio Dukaj,
  18. Jin He,
  19. Ryan E Kritzer,
  20. Alexander Cristofaro,
  21. Chandan K Pavuluri,
  22. Amy Virbasius,
  23. Elisaveta Todorova,
  24. Tyler M Sinacola,
  25. Savannah G Szemethy,
  26. Kyra N Sur,
  27. Vandana Keskar,
  28. Chris Malcuit,
  29. Qikai Xu,
  30. Yifan Wang,
  31. Danielle Ramsdell,
  32. Kenneth Olivier,
  33. Antoine J Boudot,
  34. Ribhu Nayar and
  35. Gavin MacBeath
  1. TScan Therapeutics, Waltham, MA, 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 T-Plex is an autologous TCR-T cell therapy product comprising customized combinations of 2–3 TCR-T cell components that recognize different tumor antigens presented on specific HLA class I molecules. Each component of T-Plex is engineered using a transposon-based vector encoding the therapeutic TCR, CD8α and CD8β co-receptors, a CD34 epitope tag, a dominant-negative TGFβRII (DN-TGFβRII), and a mutated form of dihydrofolate reductase (DHFRdm). TSC-200-A0201 is intended for the treatment of HPV16+ HLA-A*02:01+ cancers. HPV16 is an oncogenic virus responsible for ~57% of cervical cancers and ~21% of head and neck squamous cell carcinomas. HPV16 E7 oncoprotein drives oncogenic transformation of infected cells and is not expressed by healthy tissues, making it a compelling immunotherapeutic target.

Methods The TSC-200-A0201 TCR is a naturally occurring TCR discovered using TScan’s proprietary ReceptorScan platform. TSC-200-A0201 TCR-T cells engineered using a full-scale representative workflow for the planned manufacturing process were used to investigate the in-vitro pharmacology and toxicology of TSC-200-A0201. TSC-200-A0201 was evaluated for avidity and target-dependent cytotoxicity, proliferation, and cytokine secretion in vitro as well as for anti-tumor efficacy in vivo. The contribution of DN-TGFβRII was assessed by testing the ability of TSC-200-A0201 TCR-T cells to resist the immuno-suppressive effects of TGFβ. Further, TSC-200-A0201 was assessed for risk of alloreactivity and off-target recognition using TScan’s SafetyScan screen. Finally, to assess the risk of off-target/off-tumor activity, TSC-200-A0201 TCR-T cells were tested for their reactivity to an extensive panel of 74 healthy human primary and iPSC-derived cells from tissues that are traditionally assessed in toxicology studies, including those expressing high levels of the putative off-targets of TSC-200-A0201.

Results TSC-200-A0201 displayed high avidity for the cognate peptide (EC50 of ~4.2 pg/mL) and target-dependent secretion of inflammatory cytokines, killing of target cells, and proliferation of both engineered CD4+ and CD8+ T cells. Moreover, TSC-200-A0201 successfully controlled the growth of HLA-A*02:01+ HPV16+ tumors in mice. Target-dependent IFN-γ production and proliferation of TSC-200-A0201 was maintained in the presence of physiological levels of TGFβ. Further, TSC-200-A0201 displayed no alloreactivity to the 110 most common class I HLAs in the US population. Although a few putative off-targets were identified in the SafetyScan screen, TSC-200-A0201 showed no reactivity to normal primary or iPSC-derived cells.

Conclusions TSC-200-A0201 exhibits high specificity and potency. Based on these results, TSC-200-A0201 has been cleared by the U.S. FDA for clinical development and has been incorporated in the T-Plex Phase 1 clinical trial master protocol.

Ethics Approval Animal studies were performed at CR Discovery Services, a facility accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC). This facility complies with the recommendations of the Guide for Care and Use of Laboratory Animals with respect to restraint, husbandry, surgical procedures, feed and fluid regulation, and veterinary care. IACUC number: EB17–010-301.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

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