Evaxion Biotech has demonstrated promising clinical data from its Phase I/IIa first-in-human study of its DNA-based personalized cancer immunotherapy, EVX-02, in combination with the checkpoint inhibitor nivolumab. The Danish clinical-stage biotechnology company specializing in the development of AI-powered immunotherapies announced that the EVX-02 Phase I/IIa trial met both primary and secondary endpoints.

Evaxion presented the poster, “A personalized neoantigen vaccine is well tolerated and induces a specific T-cell immune response in patients with resected melanoma,” at the American Association for Cancer Research (AACR) Annual Meeting 2023.

Neoantigens—new proteins that form on cancer cells when certain mutations occur in tumor DNA—may play an important role in helping the body make an immune response against cancer cells and have recently emerged as promising targets for cancer immunotherapy. Vaccines delivering tumor-specific neoantigens have demonstrated favorable efficacy and safety in numerous preclinical and early clinical studies. However, selecting therapeutically relevant neoantigens amongst the myriad of cancer mutations has proven challenging.

Evaxion was founded in 2008 as an AI company devoted to building platforms for target discovery that began to focus on personalized cancer immunotherapy seven years ago. Evaxion’s first program, EVX-01, is based on peptides for the treatment of metastatic melanoma. In November 2022, Evaxion submitted an Investigational New Drug Application (IND) along with a Fast Track designation application to the FDA for a Phase IIb clinical trial of EVX-01 in combination with KEYTRUDA® for the treatment of patients with metastatic melanoma. On December 22, 2022, the FDA issued approval for Evaxion to proceed with its Phase IIb trial.

But Per Norlén, CEO of Evaxion, told GEN that while Evaxion has had success with its peptide treatment, they believe that a nucleic acid approach may be the better way to go in terms of personalization and cost. To overcome this, Evaxion developed a proprietary AI-based target discovery platform, PIONEER, to select neoantigens for the personalized DNA vaccine candidate EVX-02.

The detection of neoantigens represents a unique challenge to the immune system due to their high similarity with endogenous ‘self’ proteins. Norlén told GEN that since tumor cells must present their own neoantigens on HLA receptors to be recognized and attacked by the immune system, the three-dimensional fit of the neoantigen with the HLA receptor is really what decides if the immune system will be able to detect these mutations. “To put that in context, there are more than a hundred different subfamilies of HLA receptors, and often thousands of random tumor mutations in each patient, so there are a lot of predictions,” said Norlén. “You need to select mutations that fit perfectly into the patient’s own immune receptors and make an individualized drug containing several such neoantigens, in order to get a really strong cancer vaccination effect.”

Encouraged by preclinical results, Evaxion conducted a first-in-human multicenter Phase I/IIa clinical study of EVX-02 in combination with nivolumab in patients with resected malignant melanoma. “We produce a plasmid for each patient that contains the neoantigens selected based on our AI platform,” said Norlén. “We take a biopsy, sequence the tumor and healthy tissue DNA, and look at mRNA expression to decide what are real mutations and what is just noise. In each melanoma patient, we often find thousands of mutations, and then the AI system predicts which ones are most likely to evoke the immune response in that patient.”

The trial met both primary endpoints on safety, tolerability, and immunogenicity and the secondary endpoint on clinical efficacy. All 10 patients who completed the EVX-02 treatment were relapse-free during the trial and had robust and treatment-specific immune responses, which Norlén said is a clear sign of a protective cancer vaccination effect. “With this trial, we continue to validate the AI platforms for neoantigen prediction and also to validate the new DNA technology, and the proof of concept is pretty clear,” Norlén said. “The results, though with few patients, are quite promising in that we don’t have any relapses.”

Norlén told GEN that Evaxion’s next step is switching to EVX-03, which is based on DNA technology that codes for a chemoattractant for antigen-presenting cells, neoantigen epitopes, and fragments from endogenous retroviruses (ERVs) in the same plasmid. He anticipates that they should have a plan ready to file for an IND application for EVX-03 by the end of 2023. 

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