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Abstract
Background When designing tumour vaccines, there are two primary types of antigens to consider: tumour-specific antigens (TSAs) and tumour-associated antigens (TAAs). TSAs, which derive from onco-viral antigens or gene mutation-driven neoantigens, are highly immunogenic but are limited to specific cancers, making their identification labour-intensive. TAAs, while more prevalent, are typically less immunogenic due to their recognition as self-antigens by the host immune system. Furthermore, many TSAs and TAAs are oncoproteins (e.g., HPV E6 and E7, KRAS, Survivin), posing potential safety risks when delivered via viral vectors. ROP (recombinant overlapping peptides) technology addresses these challenges by rearranging known antigen sequences, preserving T and B cell epitopes while abolishing the conformation and functions of oncoproteins.1-3 This transformation effectively converts wild-type TAAs into safer, more immunogenic neoantigens, enhancing the efficacy of tumour vaccines. Our extensive research demonstrates that ROP can overcome MHC restriction, inducing robust CD8+ and CD4+ immune responses across diverse HLA phenotypes.1-3 Our lead agent, OVM-200, targets the TAA Survivin (ROP-SVN) and has completed preclinical testing, now progressing through a first-in-human Phase 1 clinical trial (ClinicalTrials.gov Identifier: NCT05104515).2 Survivin, an oncoprotein overexpressed in many cancers, promotes unchecked growth, metastasis, and resistance to standard treatments. As a TAA derived from the host genome, Survivin is not naturally immunogenic and is unsafe for direct use as a vaccine. By redesigning the sequence of wild-type Survivin (WT-SVN), OVM-200 (ROP-SVN) retains critical T and B cell epitopes while eliminating the oncoprotein’s conformational structure and reducing homology to below 50%. This redesign renders OVM-200 safer and more immunogenic, functioning as a neoantigen-like vaccine.
Methods The clinical trial, conducted across four UK hospitals, focuses on safety and immune response in patients with NSCLC, prostate cancer, and ovarian cancer. Phase 1a included 12 late-stage cancer patients who had exhausted first- and second-line treatments, with each group receiving subcutaneous doses of 250 μg, 500 μg, 1000 μg, or 2000 μg per inoculation (figure 1).
Results All doses were safe, with Phase 1a results showing robust immune responses, including high antibody titres (up to 1:300,000) and significant T cell ELISPOTs (SFU=1500/million PBMCs) (figures 2,3). Patients at the optimal dose showed stabilised disease, with no tumour growth, metastasis, or new lesions. Notably, a prostate cancer patient experienced significant reductions in PSA levels (figure 4).
Conclusions ROP is a valuable technology that can convert tumour-associated antigens (TAAs) into highly immunogenic, neoantigen-like vaccines.
Acknowledgements We acknowledge the invaluable contributions of our clinical trial participants and the support of our research team. Special thanks to the funding bodies and collaborating institutions for their unwavering support.
Trial Registration First-in-human Study of OVM-200 as a Therapeutic Cancer Vaccine ClinicalTrials.gov ID NCT05104515 Sponsor Oxford Vacmedix UK Ltd. Information provided by Oxford Vacmedix UK Ltd. (Responsible Party) Last Update Posted 2024-04-05 The first part (Phase 1a) comprises a first-in-human (FIH) multiple-dose, sequential-cohort 3+3 design to establish a dose of OVM-200 that is safe and tolerable, and that elicits an immune response in humans. This dose will be taken forward into the second part (Phase 1b) of the study. Phase 1b will further assess the safety and tolerability of the selected dose and investigate the immune and tumour response in 3 expansion cohorts of additional patients with NSCLC, ovarian cancer, and prostate cancer.
References
Zhang Y, Zhou Y, Gong M, Zhang Q, Zheng Q, Shen Y, Lu W, Jiang S. Survivin-based recombinant overlapping peptides induce T lymphocyte cytotoxicity and prolong the survival in in vivo melanoma model. Advanced Therapeutics. 2023:2300253. https://doi.org/10.1002/adtp.202300253
Stephens AJ, Burgess-Brown NA, Jiang S. Beyond just peptide antigens: the complex world of peptide-based cancer vaccines. Frontiers in Immunology. 2021;12:696791. http://doi.org/10.3389/fimmu.2021.696791
Li Y, Lu W, Yang J, Edwards M, Jiang S. Survivin as a biological biomarker for diagnosis and therapy. Expert Opin Biol Ther 2021;21(11):1429-1441. http://doi.org/10.1080/14712598.2021.1918672
Ethics Approval Study title: A Phase 1, Multicenter, Open-label, Nonrandomized, First-in-human Study of OVM-200 as a Therapeutic Vaccine in Patients with Locally Advanced or Metastatic Non Small Cell Lung Cancer, Ovarian Cancer, and Prostate Cancer IRAS project ID: 299207 EudraCT number: 2021-001545-12 Protocol number: OVM-200-100 REC reference: 21/FT/0080 Sponsor Oxford Vacmedix UK Ltd. I am pleased to confirm that HRA and Health and Care Research Wales (HCRW) Approval has been given for the above referenced study, on the basis described in the application form, protocol, supporting documentation and any clarifications received. You should not expect to receive anything further relating to this application. Please now work with participating NHS organisations to confirm capacity and capability, in line with the instructions provided in the ‘Information to support study set up’ section towards the end of this letter.
Patients grouping
T cell activity
Antibody level
Cancer Biomarker
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