Immune Responses to Personalized Neoantigen Vaccines Are Durable

The development of anticancer vaccines that induce immune responses to tumor-specific antigens has long been hindered by a lack of ideal target antigens; however, in recent years, advances in sequencing have enabled the development of personalized vaccines based on patients' individual neoantigens. Recently, promising results have been seen with a personalized anticancer vaccine called NeoVax, which consists of long peptides encompassing up to 20 target neoantigens along with the TLR3 and MDA5 agonist poly-ICLC, which is included as an immunostimulant. In a phase I clinical trial, Hu, Leet, Allesøe, and colleagues investigated the use of NeoVax in eight patients with high-risk surgically resected stage IIIB/C or IVM1b melanoma, specifically focusing on the long-term immunologic effects of the vaccine, which had not been investigated previously. Additional treatments, such as immunotherapy with anti–PD-1, were allowed upon disease recurrence following vaccination. After a median follow-up period of nearly four years, all eight patients remained alive, and six (75%) had no evidence of active disease. Transcriptional profiling revealed that CD4⁺ T cells exhibited a naïve-like phenotype prior to vaccination, whereas after vaccination CD4⁺ T cells clustered into groups characterized by either memory-like or cytotoxic gene signatures, with the proportion of memory-like CD4⁺ T cells increasing over time. The clonal composition of neoantigen-specific CD4⁺ T cells also evolved with time, diversifying to include multiple additional T-cell receptor clonotypes. Importantly, the neoantigen-specific T-cell responses that occurred after vaccination were persistent, lasting years after treatment with NeoVax. Additionally, epitope spreading was observed following vaccination, implying release of tumor-associated antigens or tumor neoantigens not included in the vaccine formulation and thus suggesting that the vaccine had on-target cytolytic effects on tumor cells. In summary, this work provides evidence not only that a neoantigen vaccine–induced antitumor immune responses can be durable but also that treatment with such a vaccine can promote epitope spreading, possibly further enhancing its potential efficacy.

Hu Z, Leet DE, Allesøe RL, Oliveira G, Li S, Luoma AM, et al. Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma. Nat Med 2021 Jan 21 [Epub ahead of print].

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