Therapeutic vaccines do not turn a cold tumour into hot. Neutrophils/m1 macrophages are attracted to the tumour and are required for therapeutic T cell-based vaccine efficacy. The pre-treatment tumour microenvironment composition (cellular ecosystem) determines vaccine efficacy.

Progress on the development and clinical results with VB10.16, an off-the-shelf antigen-presenting cell-targeting therapeutic cancer vaccine for HPV-16 induced tumours will be presented. The use of HPV ctDNA as a biomarker in HPV-induced tumours will also be discussed.

The results from profiling more than 1500 tumor biopsies and TME evaluations will be presented, including characterization of camyopeptides derived from tumor-specifc IncRNAs. Understanding immunological responses reveal first-in-class potential of shared tumor targets. Progress in the design of mRNA-LNP vaccines will be discussed.

Curative cancer vaccination rely in on the induction of potent antigen-specific T cells. In silico epitope discovery (i.e. through NetMHCpan), aids in the selection of potential epitopes. However, discrepancies exist between predictions and actual binding within the MHC peptide groove. Using UV-mediated ligand exchange, we show that some peptides predicted to bind in silico do not bind in vitro, and vice versa. A case study demonstrates this, where patient-specific predicted peptides were evaluated as therapeutic agents and T cell responses were followed via flow-cytometric tetramer combinatorial coding.

Cancer vaccine efficacy relies on robust T-cell activation requiring co-presentation of both CD4 and CD8 epitopes. To enhance this activation, we developed a new vaccine strategy with artificial synthetic long peptides (aSLP) containing CD4 and CD8 epitopes linked via a cathepsin-sensitive cleavable linker. This vaccine enhances the activation of CD8 lymphocytes through cross-presentation, limits the competition for processing between the two epitopes and allow careful selection of the most immunogenic epitopes. We are now developing a second generation of vaccine with a new CD4/CD8 epitopes combination exploiting a “universal” CD4 epitope that can be presented by a large variety of HLA class-II molecules and an immunogenic tumor-specific CD8 epitope translated from lncRNA like the melanoma-specific antigen MELOE-1.

Epitopea is exploiting a new family of mass spec identified wild-type TSAs derived from so-called non-coding DNA. Extensive mass spec and bioinformatic analysis indicates such antigens represent the major opportunity for T cell-mediated control of tumours. Configured into an LNP-mRNA vaccine, the mouse counterparts of these antigens control tumour growth as single agents. Immunogenicity experiments indicate that many, perhaps most, of these TSAs drive specific T cell clone expansion. We are now configuring these TSAs into highly effective cancer vaccines, where each of the Class I TSAs within can be confirmed to be presented by mass spectroscopy.    

Candel’s viral immunotherapies are designed to cause in situ vaccination against the unique antigens presented when tumor cells lyse and stimulate activation of both innate and adaptive immune mechanisms. The patient and tumour-specific memory response has been shown to produce a systemic and sustained anti-cancer effect. Data will be presented showing proof-of-concept in non-small cell lung cancer, pancreatic cancer, prostate cancer, and high-grade glioma.

Tumour mutations give rise to immunogenic HLA-presented neoantigens. Immune suppressive proteins like IDO and PD-L1 are expressed not only by melanoma cells but also by suppressive immune cells. Peptide-based cancer vaccines targeting patient-specific neoantigen or immune suppressive proteins elicit anti-cancer T cell responses and could be attractive therapeutic avenues to augment the effect of checkpoint inhibitor treatments.

Strategies are needed to convert immunologically “cold” MSS CRC to “hot” tumours, responsive to immunotherapies. PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine computationally designed to address both host- and tumor heterogeneities. It has been tested in combination with other therapies in 3 Phase I/II clinical studies in MSS mCRC. PolyPEPI1018 consistently induced multi-antigenic immune responses (both cellular and humoral) in high proportion of subjects, triggered recruitment and infiltration of T-lymphocytes into the tumor and increased expression of PD-L1. These studies show that PolyPEPI1018 has a role in improving clinical outcome for a subset of patients identified with a candidate genetic biomarker.

PDC*line is a new, potent and scalable therapeutic cancer vaccine based on a proprietary allogenic cell line of plasmacytoid dendritic cells. It is much more potent to prime and boost anti-tumour antigens, including neoantigens, specific cytotoxic T cells, than conventional vaccines and improves the response to checkpoint inhibitors. The first results of the ongoing Phase I/II clinical trial for NSCLC patients will be presented.

SCIB1 a DC targeting DNA vaccine gives at impressive 85% response rate in combination with ipilimumab and nivolumab in advanced melanoma. Citrullination occurs in stressed tumor cells and makes an excellent target for a universal cancer vaccine. Modi-1 targeting citrullination is currently in phase II clinical trial

The genetic aberrations of each individual patient with cancer is different, which creates a challenge for the development of therapeutic cancer vaccines. One approach is to characterize the tumor from each individual, so that the vaccine can be tailored precisely for that person in order to be better targeted. This approach is difficult to scale up, takes more time and results in higher cost. The alternative is to develop off-the-shelf vaccines, but the challenge is how to make them sufficiently targeted and effective across a wide range of individuals. The pros and cons of these two approaches will be discussed.

Cancer vaccines based on tumor associated antigens (TAAs) allow to develop off-the-shelf cancer vaccines appropriate to all patients affected by the same malignancy. However, they are self-antigens and may be also presented by HLAs on the surface of non-malignant cells, leading to an immunological tolerance. In order to overcome such limitations, peptides with improved antigenicity and immunogenicity able to elicit a cross-reactive T cell response are needed. Non-self-antigens derived from microorganisms (MoAs), sharing sequence homology with TAAs (“molecular mimicry”), provide a valuable solution. 

In 20-30 % of human breast cancer tumors, HER-2 is overexpressed, which is associated with a more aggressive disease, higher recurrence rate, and increased mortality. A vaccine including the full extracellular domain (ECD) of a HER-2 protein could potentially be safe, cost effective and produce a polyclonal antibody response targeting multiple epitopes overcoming the tumor resistance. We have developed a human HER-2 vaccine candidate based on a proprietary virus-like particle (VLP) platform which allows the assembly of ~50 molecules of HER-2 extracellular domain (ECD) on the surface of each particle. The HER-2-VLP vaccine showed promising therapeutic and prophylactic activities in human HER-2 transgenic studies. The vaccine candidate is ready to enter clinical trials in breast cancer patients in 2024. 

The advent to mRNA technology has unleashed a new wave of medicines, starting with COVID vaccine. The recent exciting data in melanoma and pancreatic cancer portends the power of this platform for unique applications in cancer. This presentation will highlight the latest developments of mRNA technology for immuno-oncology, including emerging clinical and translational data, ongoing studies and future development opportunities with this platform.

Delivering select neoantigens in a heterologous prime-boost vector system (adenoviral prime/samRNA boost) primes strong neoantigen-specific CD8 responses. In patients with advanced cold tumours, can this therapeutic approach drive immune responses, tumour cell destruction and clinical benefit? Clinical trial data addressing these key questions will be reviewed.

The off-the-shelf CD8 neoepitope cancer vaccine OSE2101 has been optimised to break self-tolerance against tumour-associated antigens by increasing neoepitope affinity for TCR/HLA interactions. The presentation describes the development of OSE2101 (Tedopi), the results of the ATALANTE-1 study in  HLA-A2-positive patients with advanced NSCLC and secondary resistance to immunotherapy, and the upcoming pivotal phase III trial in NSCLC. More specifically, in ATALANTE-1, in HLA-A2 patients with NSCLC and secondary resistance to immune checkpoint blockers, OSE2101 significantly improved median OS versus SoC chemotherapy [11.1 versus 7.5 months; HR (95% CI) 0.59 (0.38-0.91), P = 0.017], and significantly improved post-progression survival (HR 0.46, P = 0.004), time to Eastern Cooperative Oncology Group (ECOG) performance status deterioration (HR 0.43, P = 0.006) and Quality of Life Questionnaire Core 30 (QLQ-C30) global health status compared to SoC (P = 0.045). Grade ≥ 3 adverse effects occurred in 11.4% of patients with OSE2101 and 35.1% in SoC (P = 0.002).