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Abstract
Background Prognosis is poor for patients with recurrent/metastatic (R/M) human papillomavirus (HPV) 16+ head and neck squamous cell carcinoma (HNSCC) after first-line standard of care therapy. HB-200 is comprised of an alternating sequence of two replicating attenuated arenavirus vectors derived from LCMV (HB-201) and Pichinde virus (HB-202), respectively, expressing the same non-oncogenic HPV16 E7E6 fusion protein.1 In a Phase 1 study, HB-200 monotherapy induced strong and long-lasting HPV16 E6 and E7-specific CD8+ T cell responses and demonstrated a favorable safety profile and antitumor activity in previously treated patients with HPV16+ R/M HNSCC.2 Here, we report long-term circulating tumor specific immune responses and clinical benefit in these patients.
Methods Patients with HPV16+ HNSCC post at least 1 prior systemic R/M anti-cancer therapy were treated with HB-200 monotherapy (alternating intravenous administration of HB-202 and HB-201 every 3 weeks [Q3W] then Q6W) until disease progression or unacceptable toxicity. Four dose levels of HB-200 were explored. HPV16 specific T cell responses were evaluated in peripheral blood mononuclear cells (PBMCs) by both direct IFN-γ ELISpot and intracellular cytokine staining (ICS) performed without prior in vitro expansion. Tumor analyses including sequencing were performed for patients with available baseline and on-treatment biopsies. Antitumor activity was measured by RECIST v1.1 per investigator assessment.
Results As of March 31, 2023, 41 patients with HPV16+ R/M HNSCC (37 oropharynx, 1 larynx, 2 nasopharynx, 1 unknown primary) were treated with HB-200 monotherapy. HB-200 rapidly induced HPV16+ tumor-specific CD8+ T cells in more than 90% of patients analyzed. The E6/E7 T cell responses were maintained for more than 8 months and on-going as of data cut-off. Circulating tumor-specific T cells responses increased up to 1250-fold (median 174, range 93–1250) from baseline, with more than 57% of patients exhibiting ≥1% (maximum 48%) tumor specific CD8+ T cells out of total CD8+ T cells. Furthermore, tumor-specific CD8+ T cells increased in poly-functionality during treatment. Characterization of paired tumor biopsies revealed that HB-200 induced increased CD8+ T cell infiltration in tumors. Across all HB-200 doses, disease control rate was 48.5% in 33 heavily pre-treated patients with imaging evaluation (1 partial response, 15 stable disease), and overall survival is being assessed.
Conclusions HB-200 monotherapy induces promising HPV16+ tumor-specific T cell responses and tumor infiltration in heavily pre-treated patients. This immune response coupled with clinical benefit in monotherapy suggests that HB-200 may enhance and strengthen current immunotherapy approaches by targeting specific tumor antigens.
Acknowledgements The authors would like to thank all the patients participating in this study, their caregivers and study personnel. The study is sponsored by Hookipa Pharma, Inc.
Trial Registration Clinicaltrials.gov NCT04180215
References
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Ethics Approval This study was approved by Ethics and Institutional Review Boards (IRBs) at all study sites. IRB reference numbers:
20–165A(5) (Memorial Sloan Kettering Cancer Center), IRB19–1294 (University of Chicago), 2019–0928 (University of Texas M. D. Anderson Cancer Center), HS# STUDY-19–01049 (Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute), 1275383 (Washington University School of Medicine), 1282128 (University of Alabama at Birmingham Heersink School of Medicine), 1266389 (Banner MD Anderson Cancer Center), H-200–001 (RM 662) (Stephenson Cancer Center at University of Oklahoma Health Sciences Center), STUDY2019000305 (Providence Cancer Institute), Pro00092499 (Greenville Hospital System University Medical Center), 202101073 (University of Iowa), HS-19–00931 (University of Southern California, Norris Cancer Center), PRO00036737 (Medical College of Wisconsin), CODIGO:EC/21/252/6495 (R) (Hospital Universitari Vall d’Hebron, Spain). All participants provided written informed consent.
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