Abstract 5003: Vaccibody DNA vaccine platform VB10.NEO induces strong neo-antigen specific CD8+ T cell responses critical to cure established tumors in pre-clinical models

Abstract

BACKGROUND: Recent advances in the field of cancer immunotherapy have identified CD8+ T cell responses against tumor-specific neoantigens as a key driver of tumor regression and prolonged survival. VB10.NEO is a highly potent DNA plasmid vaccine with intrinsic adjuvant effect designed for efficient delivery of personalized tumor-specific neoantigens. VB10.NEO plasmid is translated in vivo and the secreted protein will covalently bind to endocytic receptors on APC by a targeting unit expressing CCL3 (MIP-1α) allowing efficient uptake and presentation of the neoantigens. In addition, CCL3 will attract immune cells by chemotaxis and induce maturation of APC locally. The objective of this study is to demonstrate the potential of VB10.NEO to induce tumor-specific T cell responses and control tumor growth. METHODS: VB10.NEO was delivered i.m to study CD8+ and CD4+ neoantigen-specific T cell responses in four different pre-clinical mouse models. Immunogenicity was compared with delivery of neoantigen as traditional peptide-adjuvant immunization. The tumor protective effect of VB10.NEO in the presence or absence of anti-PD-1 therapy was investigated in the CT26 colon carcinoma model. RESULTS: Vaccibody DNA Vaccine Platform VB10.NEO is flexible and can hold up to at least 40 neoepitopes. VB10.NEO vaccination induced strong neoantigen-specific T cell responses. Homologous boost vaccinations further augmented the response. T cell responses against predicted CD8+ T cell epitopes previously reported as non-immunogenic or activating only weak T cell responses using a conventional peptide-adjuvant or RNA immunization showed strong CD8+ T cell responses when delivered in the Vaccibody format, demonstrating a unique and strong priming of CD8+ T cells using VB10.NEO. The response was also accompanied by CD4+ T cell responses. In a therapeutic tumor setting VB10.NEO vaccinated mice (monotherapy) induced tumor protective responses. The effect was augmented when combining VB10.NEO with anti-PD-1 where complete regression of large established tumors was observed. All tumour-free mice rechallenged with a lethal tumor dose were protected indicating induction of long-lasting memory responses. Furthermore, the critical role of CD8+ T cells for the observed tumour protection was confirmed when depleting CD8+ T cells. CONCLUSION: VB10.NEO immunotherapy induce strong CD8+ T cell responses critical for anti-tumor effect which demonstrate the unique characteristic of the Vaccibody platform to potentiate activation of CD8+ T cells. VB10.NEO in combination with anti-PD-1 further synergize the potent immune responses resulting in durable complete tumor regression in pre-clinical models supporting the scientific rational for the current ongoing clinical trial investigating VB10.NEO in combination with CPI in patients with advanced solid tumors. Citation Format: Elisabeth Stubsrud, Stine Granum, Helene Zell-Flagstad, Audun Bersaas, Lise Madelene Skullerud, Monika Sekelja, Karoline Schjetne, Agnete Fredriksen. Vaccibody DNA vaccine platform VB10.NEO induces strong neo-antigen specific CD8+ T cell responses critical to cure established tumors in pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5003.

Fueling Cancer Vaccines to Improve T Cell-Mediated Antitumor Immunity

“…Similarly, combining NKTR-214 with the AH1 vaccine more effectively limited CT26 growth than the vaccine alone. In a phase 1/2a clinical study (NCT03548467) in patients with locally advanced or metastatic solid tumors, the feasibility, safety, and efficacy of NKTR-214 (Bempegaldesleukin) is being evaluated as an immune modulator to the VB10.NEO DNA plasmid neoantigen vaccine ( 115 ).…”

Id-neoantigen vaccine induces therapeutic CD8+T cells against multiple myeloma: H chain-loss escapees cause FLC MM

“…In this respect, DNA vaccines similar to the present vaccines, but using human CCL3 (LD78b) 49 and jet delivery, are currently being tested as neoantigen vaccines in humans with a variety of cancers. 50 Efficacy of CCL3-targeted DNA vaccination of MM patients might be improved by multiple immunizations, more powerful means of inducing Id-specific CD4 + T cells and inclusion of check point inhibitors.…”

Cancer vaccines in the clinic

“…VB10.Neo, manufactured by Nykode Therapeutics and licensed to Genentech, is a neoantigen DNA vaccine that can hold up to 40 neoantigens, and encodes CCL3 as a targeting element for APC uptake (NCT03548467, NCT05018273). 76 Overall, the majority of trials (17/20, 85%) use a combination approach (Figure 5d ). Of all the listed combination therapies, immune checkpoint blockade is the most common (10/24, 41.7%), followed by cytokines (ex.…”

“…Overall, antigens expressed by the DNA vaccines primarily include TAAs (12/20, 60%), the most common being HER2 (breast cancer, three trials), although some utilize a personalized approach with neoantigens (6/20, 30%) (Figure 5c). VB10.Neo, manufactured by Nykode Therapeutics and licensed to Genentech, is a neoantigen DNA vaccine that can hold up to 40 neoantigens, and encodes CCL3 as a targeting element for APC uptake (NCT03548467, NCT05018273) 76 . Overall, the majority of trials (17/20, 85%) use a combination approach (Figure 5d).…”