Article Text

Download PDFPDF

375 Expansion of HPV-16 specific T cells in patients with HPV-related cancers treated with bintrafusp alfa
  1. Nicole Toney,
  2. Yo-Ting Tsai,
  3. Claire Rumfield,
  4. Samuel Pellom,
  5. Caroline Jochems,
  6. Julius Strauss,
  7. James Gulley,
  8. Jeffrey Schlom and
  9. Renee Donahue
  1. NIH, Bethesda, MD, USA


Background The safety and efficacy of bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β ‘trap’) fused to a human IgG1 mAb blocking PD-L1, have been demonstrated in patients with human papillomavirus (HPV)-related cancers in an open label, multicenter phase 1 trial (NCT02517398), and an open-label, single center phase 2 trial (NCT03427411). The current study aimed to investigate whether HPV-16-specific T cells are expanded with therapy and associate with the clinical response of patients in these trials. We also present pre-clinical evidence from a mouse model of HPV-associated cancer supporting the combination of bintrafusp alfa with an HPV-16 targeted therapeutic vaccine and an immunostimulatory cytokine.

Methods Peripheral blood mononuclear cells (PBMC) were obtained from 33 patients prior to and 2 weeks after 1 and/or 3 cycles of bintrafusp alfa and evaluated for HPV-16 specific CD4+ and CD8+ T cells. PBMCs were stimulated with 15-mer peptide pools of the HPV-16 E6 and E7 oncoproteins, and T cell responses were assessed for the production of cytokines (TNFa, IFNg, IL-2) and positivity for the degranulation marker CD107a. Multifunctional T cells, positive for >2 measures, were also enumerated. For pre-clinical studies, a syngeneic mouse model of TC-1 carcinoma was treated with bintrafusp alfa alone or in combination with a liposomal-based HPV-16 therapeutic vaccine (PDS 0101) and a tumor targeting immunocytokine (NHS-muIL12) and evaluated for anti-tumor activity and immune responses.

Results HPV-16 specific T cells were increased after 1 cycle of bintrafusp alfa in a greater proportion of responders (9/14) than non-responders (4/17) (p=0.03). In addition, the magnitude of HPV-16 specific T cells was greater after 1 (p=0.04) and 3 (p<0.0001) cycles of bintrafusp alfa in responders than non-responders. Multifunctional HPV-16-specific T cells were also increased to a greater extent in responders than non-responders. Preclinical studies demonstrated that the combination of bintrafusp alfa with an HPV-16-targeted therapeutic vaccine along with an immunocytokine resulted in maximal anti-tumor activity and T cell responses.

Conclusions An early increase in HPV-16 specific T cells (after a single administration of bintrafusp alfa, prior to restaging) was associated with clinical activity in patients with HPV-related cancers undergoing bintrafusp alfa therapy. This evidence, and the pre-clinical finding of enhanced antitumor activity observed when combining bintrafusp alfa with an HPV-16 targeted vaccine and an immunostimulatory cytokine have provided the rational for an ongoing study evaluating this combination in patients with advanced HPV-associated malignancies (NCT04287868).

Ethics Approval All patients provided written informed consent for participation in a clinical trial that was approved by the Institutional Review Board at the National Cancer Institute (NCT02517398, NCT03427411)

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. 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.