Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer

Abstract

T cells directed against mutant neo-epitopes drive cancer immunity. However, spontaneous immune recognition of mutations is inefficient. We recently introduced the concept of individualized mutanome vaccines and implemented an RNA-based poly-neo-epitope approach to mobilize immunity against a spectrum of cancer mutations. Here we report the first-in-human application of this concept in melanoma. We set up a process comprising comprehensive identification of individual mutations, computational prediction of neo-epitopes, and design and manufacturing of a vaccine unique for each patient. All patients developed T cell responses against multiple vaccine neo-epitopes at up to high single-digit percentages. Vaccine-induced T cell infiltration and neo-epitope-specific killing of autologous tumour cells were shown in post-vaccination resected metastases from two patients. The cumulative rate of metastatic events was highly significantly reduced after the start of vaccination, resulting in a sustained progression-free survival. Two of the five patients with metastatic disease experienced vaccine-related objective responses. One of these patients had a late relapse owing to outgrowth of β2-microglobulin-deficient melanoma cells as an acquired resistance mechanism. A third patient developed a complete response to vaccination in combination with PD-1 blockade therapy. Our study demonstrates that individual mutations can be exploited, thereby opening a path to personalized immunotherapy for patients with cancer.

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

“…Most of the latest and more advanced clinical trials for TSA-specific vaccines are based on the administration of Ag cocktails 47,66 . Another recent approach delivers multiple Ags as an individualized neo-antigen mRNA-polytope vaccine 67-69 which represents a promising alternative to administration of antigens via synthetic peptides. Eliciting a broad immune response against several tumor-specific CD4 and CD8 epitopes has major advantages.…”

The Prediction and Function of Neoantigen in Oncobiology

“…Another study used nearly the same strategy to predict neoantigens, they used RNA minigenes as neoantigen vaccine and injected percutaneously into inguinal lymph nodes. Results showed that all 13 patients developed T cell responses against multiple vaccine neoantigens, 8 of them had no radiologically detectable lesions for 12 to 23 months, and another 2 patient also experienced complete response through additional anti-PD1 therapy [36]. In sum, combined neoantigen vaccine with anti-PD1 antibody, researchers observed the duration of the vaccine induced immune responses over more than 2 years and the increasing diversity of the repertoire of neoantigen-specific T cells.…”

“…To maximize antitumor functions, a combination with checkpoint inhibitor, such as anti-PD1 antibody, may be necessary. Actually, based on the clinical data available till now, neoantigen vaccine plus checkpoint inhibitor antibody combination therapy strategy may be the most promising one [35,36].…”

CD27 stimulation unveils the efficacy of linked class I/II peptide vaccines in poorly immunogenic tumors by orchestrating a coordinated CD4/CD8 T cell response

“…There are a variety of clinically-available peptide vaccines comprised of a tumor-derived class I epitope linked to a universal helper epitope or tumor-derived class II epitope, 13,38,39 which would make for promising vaccine candidates for combination with adjuvant αhCD27. In addition to peptide vaccines targeting high-frequency tumor mutations, we believe that adjuvant αhCD27 may enhance the clinical benefit of peptide vaccines derived from class I-restricted tumor neo-antigens, especially when linked to immunogenic class II epitopes.…”