Personalized neoantigen vaccine combined with PD-1 blockade increases CD8⁺tissue-resident memory T-cell infiltration in preclinical hepatocellular carcinoma models

Article

Author: Liu, Wenhan ; Liu, Xiaolong ; Chen, Hengkai ; Zhou, Yang ; Li, Zhenli ; Dong, Xiuqing ; Cai, Zhixiong ; Ouyang, Jiahe ; Qiu, Liman ; Cai, Linsheng ; Ye, Honghao ; Shi, Yingjun ; Chen, Geng

BackgroundPersonalized neoantigen vaccine could induce a robust antitumor immune response in multiple cancers, whose efficacy could be further enhanced by combining with programmed cell death 1 blockade (α-PD-1). However, the corresponding immune response and synergistic mechanisms remain largely unclear. Here, we aimed to develop clinically available combinational therapeutic strategy and further explore its potential antitumor mechanisms in hepatocellular carcinoma (HCC).MethodsNeoantigen peptide vaccine (NeoVAC) for murine HCC cell line Hepa1-6 was developed and optimized by neoantigen screening and adjuvant optimization. Then the synergistic efficacy and related molecular mechanisms of NeoVAC combined with α-PD-1 in HCC were evaluated by orthotopic HCC mouse model, single-cell RNA sequencing, tetramer flow cytometry, immunofluorescence, etc. The tumor-killing capacity of CD8+tissue-resident memory T cells (CD8+TRMs) was assessed by orthotopic HCC mouse model, and autologous patient-derived cells.ResultsNeoVAC, which consisted of seven high immunogenic neoantigen peptides and clinical-grade Poly(I:C), could generate a strong antitumor immune response in HCC mouse models. Significantly, its efficacy could be further improved by combining with α-PD-1, with 80% of durable tumor regression and long-term immune memory in orthotopic HCC models. Moreover, in-depth analysis of the tumor immune microenvironment showed that the percentage of CD8+TRMswas remarkedly increased in NeoVAC plus α-PD-1 treatment group, and positively associated with the antitumor efficacy. In vitro and in vivo T-cell cytotoxicity assay further confirmed the strong tumor-killing capacity of CD8+TRMssorting from orthotopic mouse HCC or patient’s HCC tissue.ConclusionsThis study showed that NeoVAC plus α-PD-1 could induce a strong antitumor response and long-term tumor-specific immune memory in HCC by increasing CD8+TRMsinfiltration, which might serve as a potential immune-therapeutic target for HCC.

01 May 2005·Expert Opinion on Emerging DrugsQ2 · MEDICINE

Emerging melanoma vaccines

Q2 · MEDICINE

Review

Author: Rudolph, Jennifer L. ; Bystryn, Jean-Claude

No satisfactory treatment currently exists for melanoma once it has spread beyond its original site. At present, the only FDA-approved treatment for advanced melanoma is IFN-alpha2b. Vaccines are an experimental therapy intended to stimulate the immune system to react more strongly against patients' own melanoma cells, thereby destroying the tumour or slowing its progression. Unfortunately, the exact tumour antigens that can stimulate an effective tumour-protective response in humans remain unknown. The approach that is increasingly followed to circumvent this problem is to prepare polyvalent vaccines containing a variety of melanoma antigens, as the greater the number of antigens in a vaccine, the greater the chance it will contain the correct antigen(s) to stimulate an antitumour response. Two recent randomised trials suggest that this approach results in vaccines that can be clinically effective. One is a double-blind, placebo-controlled trial of a polyvalent, shed antigen melanoma vaccine developed by Bystryn and licenced to NeoVac; the other is a larger randomised trial of Melacine (Corixa Corp.), a vaccine prepared from the lysate of two melanoma cell lines adjuvanted with Detox, which was developed by Mitchell and commercialized by Corixa. In both cases, tumour progression was delayed in the vaccine-treated patients, although in the latter trial, this was only observed in patients with certain human leukocyte antigen phenotypes. Several other vaccines are currently in Phase III trials, but the results of these trials are still pending. The major issues that need to be addressed are designing more effective melanoma vaccines with a mix of melanoma-associated antigens that can stimulate clinically beneficial antitumour immune responses, and finding an adjuvant that can safely, easily and powerfully boost the frequency and magnitude of these responses.

100 Deals associated with NeoVAC DNA vaccine (Immunetune)

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Preclinical	NL	Immunetune	10 Dec 2021

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