999MO - HARE-40: A phase I/II trial of therapeutic HPV vaccine (BNT113) in patients with HPV16 driven carcinoma

Background

5% of new cancers are caused by human papillomaviruses (HPV). BNT113 is a lipoplex-formulated uridine mRNA vaccine encoding E6 and E7 antigens of HPV-16.

Methods

HARE-40 is an open label, phase I/II trial of BNT113 in 2 UK hospitals. Arm 1A included patients with resected HPV16+ HNSCC, disease free at least 12 months after curative treatment. Arm 1B included patients with HPV16+ cancers treated palliatively. BNT113 was given intravenously q1w x 4 then q2w x 4 with intrapatient dose escalation from 7.2 μg to 29 μg (Arm 1A cohort 1) or to 72.8 μg (Arm 1A cohort 2 and Arm 1B). The phase I primary endpoint was DLT and in phase II disease control rate (DCR – irRECIST) with secondary endpoints including adverse drug reactions [ADRs] and immune responses.

Results

From 05/2017 to 01/2023, 17 patients with HPV16+ HNSCC participated in Arm 1A. 76% were male (n=13) with median age 63. Arm 1B enrolled 13 patients with anal (38%, n=5), HNSCC (23%, n=3), cervical (15%, n=2), other (23%, n=3) after failure of prior therapies; 77% were female (n=10) with median age 58. 19 (63%) received all 8 doses. Although no DLTs were reported, 2 patients in Arm 1A met individual MTDs. Grade≥1 ADRs ≤1wk after any vaccination/Grade≥3 ADRs ≤90d after last vaccination were experienced in 90% (n=26)/24% (n=7) patients among the 29 dosed. Disease control was seen in 5/7 patients (71%, 95% CI 29% – 96%) in Arm 1B with post-treatment tumour scans. Of evaluable patients, 70% mounted cellular immune responses against E6/7 as measured ex vivo by IFNγ ELISpot : 11/13 patients Arm 1A and 3/7 in Arm 1B. Anti-E7 IgG-Ab responses were detected in 8/15 (Arm 1A) and 5/9 (Arm 1B) patients. De novo T cell responses against E7 epitopes were found ex-vivo at a dose of 72.8 μg (Arm 1A Cohort II and Arm 1B); CD4+ and CD8+ E7-reactive T cell clones, were detected after in-vitro stimulation also at 29 μg (5/6 patients, Arm 1A). Vaccine-induced E7/E6-specific T cells reached up to 4.9% of CD8 T cells in circulation and were tracked by multimers in several patients longitudinally. TCR-seq (TIL and blood analysis) and TME characterisation data will be presented.

Conclusions

BNT113 was overall well tolerated. Vaccine-induced immune responses were seen in the majority of patients in the adjuvant setting and in the presence of advanced disease.

Clinical trial identification

EudraCT 2014-002061-30 (Release date 12/05/2014); ISRCTN51789191 (Release date 15/12/2016).

Editorial acknowledgement

Legal entity responsible for the study

University Hospital Southampton NHS Foundation Trust.

Funding

This trial is being funded by a European Grant (IACT) with additional financial support from BioNTech SE, the Experimental Cancer Medicine Centre Initiative (ECMC) and Southampton Clinical Trials Unit Cancer Research UK core funding.

Disclosure

C.H.H. Ottensmeier: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Roche Genentech; Financial Interests, Personal, Other, consulting: Sebastian Bio; Financial Interests, Personal, Other, head of SAB: Neuvogen; Financial Interests, Personal, Stocks/Shares: Neuvogen; Financial Interests, Institutional, Research Grant, trial funding: Verastem, Merck Sharpe and Dohme; Financial Interests, Institutional, Coordinating PI, phase I trial: Transgene; Financial Interests, Institutional, Coordinating PI: Delcath Systems, PsiOxus, Touchlight genetics; Financial Interests, Coordinating PI, Coordinating PI on two clinical trials: Biontech; Financial Interests, Institutional, Research Grant, trial funding to previous employer (HARE40 trial): Biontech. S. Crabb: Financial Interests, Personal, Invited Speaker: AstraZeneca, Astellas, Bayer, Janssen, Pfizer, Merck, Ipsen; Financial Interests, Personal, Advisory Board: Pfizer/Merck, MSD, Roche, MSD, AstraZeneca, Astellas, Novartis, EMD, Bayer, Pfizer, Amphista Therapeutics, Merck, Janssen, Amgen; Financial Interests, Institutional, Funding: AstraZeneca, Astex Pharmaceuticals, Clovis Oncology, Roche, Pfizer; Financial Interests, Personal, Funding: AstraZeneca. I. Karydis: Financial Interests, Institutional, Local PI, Site for Company sponsored study: Genentech, BioNTech AG, Achilles Therapeutics, Replimmune Inc, ModernaTX, Inc, ScanCell Ltd; Financial Interests, Institutional, Local PI, Site PI in a study co-funded by an unrestricted educational grant: Immunocore LTd. D.M. Graham: Financial Interests, Personal, Advisory Board, Consulting role on advisory board: Clinigen; Financial Interests, Institutional, Coordinating PI, Institutional funding from study: MSD; Financial Interests, Institutional, Local PI, Institutional funding from study: Codiak Biosciences, Starpharma, Faron Pharmaceuticals, Synthon, Janssen, Incyte; Financial Interests, Institutional, Other, Sub-I: Institutional funding from studyResearch funding: AstraZeneca; Financial Interests, Institutional, Other, Sub-I: Institutional funding from study: Roche, BerGenBio, GSK, Bayer, Bicycle Pharmaceuticals, Carrick, Taiho Pharmaceuticals, CytomX Therapeutics, RedX Pharma PLC, Eisai Inc, Octimet, Orion Pharma, Kinex Pharmaceuticals, Boehringer Ingelheim, BMS, Turning Point Therapeutics, Immutep, Agalimmune, Kymab, Blueprint, Astellas, Cellcentric, UCB Biopharma USL, Eli Lilly, Seagen, Repare therapeutics, Timepoint Therapeutics, Astex, Stemline, Crescendo Biologics Ltd, ADC Therapeutics, Genentech, Avacta Life Sciences Ltd, Nurix Therapeutics Inc; Financial Interests, Institutional, Other, Sub-I: Institutional finding from study: Chugai Pharmaceuticals; Non-Financial Interests, Institutional, Training, Training and support of research inclusivity seminar: Gilead. J. Dias, R. Das, J. Furlanetto, J. Setzer: Financial Interests, Personal, Financially compensated role: BioNTech SE; Financial Interests, Personal, Full or part-time Employment: BioNTech SE; Financial Interests, Personal, Stocks/Shares: BioNTech SE. E. Johnson: Financial Interests, Personal, Full or part-time Employment: BioNTech SE; Financial Interests, Personal, Financially compensated role: BioNTech SE; Financial Interests, Personal, Stocks/Shares: BioNTech SE. U. Sahin, Ö. Türeci: Financial Interests, Personal, Financially compensated role: BioNTech SE; Financial Interests, Personal, Full or part-time Employment: BioNTech SE; Financial Interests, Personal and Institutional, Leadership Role: BioNTech SE; Financial Interests, Personal, Ownership Interest: BioNTech SE; Financial Interests, Personal, Stocks or ownership: BioNTech SE; Financial Interests, Personal, Stocks/Shares: BioNTech SE. G. Griffiths: Non-Financial Interests, Institutional, Research Funding: Janssen-Cilag, AstraZeneca, Novartis, Astex, Roche, Heartflow, Celldex, Bristol Myers Squibb, BioNTech SE, Cancer Research UK, National Institute for Health Research (NIHR), The British Lung Foundation, Unitaid, GSK; Financial Interests, Personal, Invited Speaker, Delivery of CPD training courses: AstraZeneca, AbbVie; Non-Financial Interests, Institutional, Funding, Funding to run the cancer vaccine platform: NHS England. All other authors have declared no conflicts of interest.