Article Text

Download PDFPDF

769 Interim clinical and translational data from NTC-001, a phase I study to evaluate the non-engineered neoantigen-specific T cell product BNT221 in patients with advanced or metastatic melanoma
  1. Jessica SW Borgers1,
  2. Divya Lenkala2,
  3. Brian McCarthy2,
  4. Victoria Kohler2,
  5. Sebastian Hymson2,
  6. Emily Jackson2,
  7. Katya Esaulova2,
  8. Joong Hyuk F Sheen2,
  9. Olivia Finney2,
  10. Kristen Balogh2,
  11. Sebastian Klobuch1,
  12. Matthijs D Linssen1,
  13. Cynthia Nijenhuis1,
  14. Richard B Gaynor2,
  15. Mark DeMario2,
  16. John B Haanen1 and
  17. Marit MVan Buuren2
  1. 1Netherlands Cancer Institute, Amsterdam, Netherlands
  2. 2BioNTech US, Cambridge, 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 Neoantigens, tumor-specific antigens derived from the mutanome, elicit antitumor immune responses. The interim results of a phase I study (NCT04625205) evaluating a personalized, non-engineered, neoantigen-specific T-cell product (BNT221) targeting multiple neoantigens are presented.

Methods Nine patients with checkpoint- and, if applicable, BRAFi-resistant metastatic melanoma received BNT221, completing dose-escalation enrollment. Up to sixty immunogenic MHCI- and MHCII-restricted neoantigens were selected with our RECON® bioinformatics platform for use in an ex vivo induction process (NEO-STIM™) to prime, activate and expand memory and de novo T-cell responses from both the CD4+ and the CD8+ T-cell compartment, using PBMCs collected via leukapheresis.

Two BNT221 doses (≥ 1 × 108 cells to ≤ 1 × 109 cells and >2 × 109 cells to ≤ 1 × 1010 cells) were evaluated in a 3+3 escalation design. Endpoints included safety and determination of highest tolerable dose (primary) and efficacy per RECIST 1.1 (secondary). Patients were pretreated with lymphodepleting chemotherapy.

Drug product, peripheral blood and tumor samples were collected for immune analysis and sequencing to monitor the composition, functionality, persistence, and tumor trafficking of the induced neoantigen-specific T-cell responses.

Results BNT221 was well-tolerated. No dose-limiting toxicities were observed, with grade 3–4 toxicities post-infusion limited to hematologic toxicities from lymphodepletion. Seven patients showed stable disease as best overall response (12–36+ weeks). Of those, two patients showed tumor reductions at cutaneous and visceral sites and reported quality of life improvements.

All patients received a polyclonal drug product with neoantigen-specific, polyfunctional CD8+ and CD4+ T-cells of central- and effector-memory phenotype (range: 8–13 responses per product). A subset of clonotypes present in the drug product were detected up to six weeks post-infusion. To date, 106 neoantigen-specific clonotypes recognizing 19 different neoantigens across four patients have been identified. Of all reactive T cell receptors (TCRs) characterized (n = 57), all TCRs but one, exclusively recognized the mutant epitope and the functional avidity ranged from 0.8nM – 8.5µM. Neoantigen-specific clonotypes were detected in post-treatment tumor through TCR sequencing analysis in one patient tested, for whom tumor reduction was observed post BNT221.

Conclusions In this first in human study, BNT221 as a single infusion therapy demonstrated a tolerable safety profile, product persistence, prolonged stable disease, and tumor reductions in patients with checkpoint inhibitor-resistant metastatic melanoma. Translational analysis shows that the generated products contain multiple highly functional tumor-specific T-cell populations against neoantigens. Further clinical investigation of BNT221 in combination with anti-PD-1 is warranted and currently underway.

Acknowledgements We thank all the patients and their families who participated in the study. We are grateful to our collaborators at the NKI for execution of our study and the members of BioNTech for their support and assistance. The study is sponsored by BioNTech.

Ethics Approval This study was approved by the Central Committee on Research Involving Human Subjects (CCMO), NL72301.000.19.

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

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.