“RECON takes into account all of this processing as well as all of the properties of the neoantigens for all of the mutations that are present in the tumor and outputs a numerical quality score for every mutation that the tumor has. So, patients who receive clinical benefit on the study have more mutations that have a higher quality score than patients [who] do not. This suggests that the pipeline can recognize these high-quality–score mutations and we can generate a vaccine for the patient that can be used as a vaccination,” said Dr Srinivasan.

In the trial, while the cancer vaccine is developed, patients are administered nivolumab. This is partly to try and slow the disease down while the vaccine is being manufactured and prime the immune system for receipt of the vaccine.

“Anti PD-1 will remove some of the immunosuppressant mechanism or remove the brakes between the PD-1/PD-L1 axis so that the vaccine-induced T-cells are now able to recognize the tumor cells and kill them,” said Dr Srinivasan.

But considering the vaccine is personalized, the process of biopsy to delivery of the vaccine may take a few months, so the nivolumab treatment is partly an attempt to stop the cancer from progressing.

“It’s very difficult for the patient to do nothing for 12 weeks until the vaccine is generated. Patients start on day 1 with nivolumab; they are given that while the vaccine is manufactured,” said Dr Siwen Hu-Lieskovan, a medical oncologist, who is first author on the AACR presentation and the clinical trial coordinator of the Neon trial at the University of California, Los Angeles (UCLA). UCLA is 1 of 9 centers involved in the study.

Patients enrolled in the trial then receive the personalized vaccine from weeks 12 to 24 of the clinical trial protocol, receiving 7 injections of NEO-PV-01 (5 weekly and then 2 monthly) boosters given over an 8-week period (ClinicalTrials.gov Identifier: NCT02897765)Trial participants then remain on nivolumab for the remainder of the 2-year treatment protocol.

“Previous cancer vaccines generally increase exposure of the tumor to the immune system – but it’s not that effective; certain patients respond, but overall it is not very effective. This approach targets the high-quality neoantigens and tries to amplify the signal,” said Dr Hu-Lieskovan, who is now at the Huntsman Cancer Institute at the University of Utah, Salt Lake City, where she will be running another combination trial featuring NEO-PV-01 (ClinicalTrials.gov Identifier: NCT03597282).

The results presented at AACR showed that treatment with the vaccine resulted in progression-free survival at 36 weeks (which the researchers specified was a durable clinical response, or DCB) for 11 of 23 (approximately 48%) patients, with 8 of 23 (approximately 35%) of patients not achieving this, and the results for the remaining 4 patients (approximately 17%) not available yet.

“The results look pretty good. This is a very small group of patients and is obviously biased because of this small number, but if you look at the demographics of these patients, they are mostly stage 4 M1b and M1c disease — the worst-case scenario,” said Dr Hu-Lieskovan.

Prospective analysis comparing those who achieved a DCB and those who did not found that tumors with a high MHC class II gene signature and signatures indicating infiltration of B cells, cytotoxic T cells and natural killer cells were more likely to achieve a DCB. Tumors where the RECON pipeline was able to identify high-quality neoantigens also were more likely to see the patients achieve DCB.

“The results of this study are encouraging. It demonstrates the T-cell response to the predicted neoepitopes and epitope spreading. T-cell response to neoepitopes and intratumoral infiltration of effector-like/memory-like T cells and B cells correlate with disease control,” said Dr Lei Zheng, MD, PhD, associate professor of oncology at Johns Hopkins Medicine in Baltimore, Maryland. “Pathologic response occurred after receiving neoantigen-based vaccine — not after receiving nivolumab and before receiving vaccine — suggesting that the patients have [a] response to the vaccine treatment,” he added.