At the TIDES Europe and US conferences in late 2020, Dr. Jesse Dong from BioNTech US delivered a talk about the personalized neoantigen cancer vaccine NEO-PV-01, in Phase 1b development in tumour settings at the time of presenting.
The vaccine is custom-designed and manufactured for each individual patients’ tumour mutations, focused in combination with checkpoint inhibitors in metastatic disease settings. It uses Next Generation Sequencing and proprietary bioinformatics (RECON, Real-time Epitope Computation for Oncology) to select up to 20 neoantigen peptides from tumour samples.
Initial data shows that vaccine-induced immune responses were durable and safe with no adverse events in all 82 patients with melanoma, bladder, or lung cancer included in the trial. De novo neoantigen-specific CD4 +and CD8 + T cell responses were observed post-vaccination in all of the patients. The vaccine-induced T cells had a cytotoxic phenotype and were capable of trafficking to the tumour and mediating cell killing. In addition, epitope spread to neoantigens not included in the vaccine was detected post-vaccination.
In relation to secondary endpoints including objective response rates, progression-free survival, and overall survival, these were also taken into account by the researchers. The objective response rates among patients with melanoma, lung, and bladder cancer, respectively, were 59%, 29%, and 27%. The median progression-free survival for these three histology groups was 23.5, 8.5, and 5.8 months, respectively, and the one-year overall survival rates were 96%, 83%, and 67%. The median overall survival was not reached for patients with melanoma or lung cancer but was 20.7 months for patients with bladder cancer.
BioNTech US researchers also explored indicators of patients' responses specifically to the vaccine. In a post-hoc analysis, they measured the percentage of all NEO-PV-01 vaccinating peptides that elicited interferon-gamma responses in samples of patients' peripheral blood at three time points: pre-treatment, pre-vaccine, and post-vaccine. Using the IFN Gamma EliSpot Assay, they found that among patients who had sufficient samples at all three time points, significant immune responses to multiple vaccinating peptides were observed, including 52% responses to peptides in patients with melanoma, 47% in patients with lung cancer, and 52% in patients with bladder cancer. An average of 42% and 24% of vaccinating peptides generated CD4+ and CD8+ T-cell responses, respectively.
The researchers also evaluated immune responses in patients' samples 52 weeks after the start the treatment and detected persistent immune responses for 58% of neoepitopes. The data confidently demonstrates that vaccination with NEO-PV-01 and Nivolumab results in the generation of T-cell responses that are specific and durable.
The ability of the patients' CD4+ and CD8+ T-cells to migrate to the solid tumours and kill cancer cells was also evaluated by the researchers, by looking for the expression of CD107a, a marker for T-cell degranulation. Across all three cohorts of patients, the overall surface expression of CD107a was detected in the presence of 58% of the epitopes after vaccination.
In relation to the question whether the neoantigen-specific T cells could release additional epitopes to generate a broader neoantigen-specific immune response, researchers screened several patients' samples for T-cell responses against epitopes that weren't included in the vaccine, and they found peripheral immune responses against a handful of these neoepitopes and noted that these responses had not been present before the administration of the vaccine. As such, the presence of epitope spread could be a surrogate marker for tumour cell killing by neoantigen-specific T cells induced by vaccination.
What is particularly important is that this epitope spread was correlated with patients' progression-free survival across all three tumour types, which further indicated that it may only be necessary to target a subset of neoantigens expressed by the tumour to generate a broad immune response against the expressed neoantigens. As such, the conclusion is that the clinical trial data support the safety and immunogenicity of NEO-PV-01 and Nivolumab in patients with advanced solid tumours; and the data supports future randomized trials with NEO-PV-01.
Find out more about the 2020 TIDES: Oligonucleotide and Peptide Therapeutics virtual event in our full overview here.