Combination treatment of radiofrequency ablation and peptide neoantigen vaccination: Promising modality for future cancer immunotherapy.

Background: The safety and immunogenicity of a personalized neoantigen-based peptide vaccine, iNeo-Vac-P01, was reported previously in patients with a variety of cancer types. The current study investigated the synergistic effects of radiofrequency ablation (RFA) and neoantigen vaccination in cancer patients and tumor-bearing mice. Methods: Twenty-eight cancer patients were enrolled in this study, including 10 patients who had received RFA treatment within 6 months before vaccination (Cohort 1), and 18 patients who had not (Cohort 2). Individualized neoantigen peptide vaccines were designed, manufactured, and subcutaneously administrated with GM-CSF as an adjuvant for all patients. Mouse models were employed to validate the synergistic efficacy of combination treatment of RFA and neoantigen vaccination. Results: Longer median progression free survival (mPFS) and median overall survival (mOS) were observed in patients in Cohort 1 compared to patients in Cohort 2 (4.42 and 20.18 months vs. 2.82 and 10.94 months). The results of ex vivo IFN-γ ELISpot assay showed that patients in Cohort 1 had stronger neoantigen-specific immune responses at baseline and post vaccination. Mice receiving combination treatment of RFA and neoantigen vaccines displayed higher antitumor immune responses than mice receiving single modality. The combination of PD-1 blockage with RFA and neoantigen vaccines further enhanced the antitumor response in mice. Conclusion: Neoantigen vaccination after local RFA treatment could improve the clinical and immune response among patients of different cancer types. The synergistic antitumor potentials of these two modalities were also validated in mice, and might be further enhanced by immune checkpoint inhibition. The mechanisms of their synergies require further investigation. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT03662815.

A Neoantigen-Based Peptide Vaccine for Patients With Advanced Pancreatic Cancer Refractory to Standard Treatment.

Background: Neoantigens are critical targets to elicit robust antitumor T-cell responses. Personalized cancer vaccines developed based on neoantigens have shown promising results by prolonging cancer patients' overall survival (OS) for several cancer types. However, the safety and efficacy of these vaccine modalities remains unclear in pancreatic cancer patients. Methods: This retrospective study enrolled 7 advanced pancreatic cancer patients. Up to 20 neoantigen peptides per patient identified by our in-house pipeline iNeo-Suite were selected, manufactured and administered to these patients with low tumor mutation burden (TMB) (less than 10 mutations/Mb). Each patient received multiple doses of vaccine depending on the progression of the disease. Peripheral blood samples of each patient were collected pre- and post-vaccination for the analysis of the immunogenicity of iNeo-Vac-P01 through ELISpot assay and flow cytometry. Results: No severe vaccine-related adverse effects were witnessed in patients enrolled in this study. The mean OS, OS associated with vaccine treatment and progression free survival (PFS) were reported to be 24.1, 8.3 and 3.1 months, respectively. Higher peripheral IFN-γ titer and CD4+ or CD8+ effector memory T cells count post vaccination were found in patients with relatively long overall survival. Remarkably, for patient P01 who had a 21-month OS associated with vaccine treatment, the abundance of antigen-specific TCR clone drastically increased from 0% to nearly 100%, indicating the potential of iNeo-Vac-P01 in inducing the activation of a specific subset of T cells to kill cancer cells. Conclusions: Neoantigen identification and selection were successfully applied to advanced pancreatic cancer patients with low TMB. As one of the earliest studies that addressed an issue in treating pancreatic cancer with personalized vaccines, it has been demonstrated that iNeo-Vac-P01, a personalized neoantigen-based peptide vaccine, could improve the currently limited clinical efficacy of pancreatic cancer. Clinical Trial Registration: ClinicalTrials.gov, identifier (NCT03645148).Registered August 24, 2018 - Retrospectively registered.