In recent years, new immunotherapies have greatly contributed to the success of cancer treatment. However, cancer cell–specific antigens limit the effectiveness of these immunotherapies. Identification of neoantigens through tumor sequencing and bioinformatics may help advance research into personalized cancer vaccines. This study evaluated a new immunotherapy by developing a cancer cell–specific gene expression technique that uses a nuclear factor-kappa B (NF-κB)-activating gene expression vector to express a protein or peptide on the surface of cancer cells. These proteins or peptides function as an artificial neoantigen to stimulate the immune system to kill cancer cells. The study demonstrated that NF-κB RelA was widely over-activated only in cancer cells. It also showed that a NF-κB-activating gene expression (Nage) vector, which consisted of a NF-κB-specific promoter (DMP) prepared by fusing a NF-κB decoy sequence to a minimal promoter and a downstream effector gene, could specifically express a protein or peptide on the surface of various cancer cells. By packaging the Nage vector in an adeno-associated virus, in vivo tumors can be significantly inhibited or even eradicated via intravenously injected recombinant adeno-associated viruses.
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References
1.
RibasA, WolchokJD. Cancer immunotherapy using checkpoint blockade. Science, 2018; 359:1350–1355.
2.
PostowMA, SidlowR, HellmannMD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med, 2018; 378:158–168.
3.
YipA, WebsterRM. The market for chimeric antigen receptor T cell therapies. Nat Rev Drug Discovery, 2018; 17:161–162.
4.
HartmannJ, Schussler-LenzM, BondanzaA, et al.Clinical development of CAR T cells—challenges and opportunities in translating innovative treatment concepts. EMBO Mol Med, 2017; 9:1183–1197.
5.
EmensLA, AsciertoPA, DarcyPK, et al.Cancer immunotherapy: opportunities and challenges in the rapidly evolving clinical landscape. Eur J Cancer, 2017; 81:116–129.
6.
MahmoodSS, FradleyMG, CohenJV, et al.Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol, 2018; 71:1755–1764.
7.
MoslehiJJ, SalemJE, SosmanJA, et al.Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet, 2018; 391:933.
8.
D'AloiaMM, ZizzariIG, SacchettiB, et al.CAR-T cells: the long and winding road to solid tumors. Cell Death Dis, 2018; 9:282.
9.
PorterDL, LevineBL, KalosM, et al.Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med, 2011; 365:725–733.
10.
Van ZelmMC, ReisliI, Van Der BurgM, et al.An antibody-deficiency syndrome due to mutations in the CD19 gene. N Engl J Med, 2006; 354:1901–1912.
11.
OttPA, HuZ, KeskinDB, et al.An immunogenic personal neoantigen vaccine for patients with melanoma. Nature, 2017; 547:217–221.
12.
SahinU, DerhovanessianE, MillerM, et al.Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature, 2017; 547:222–226.
13.
OeckinghausA, HaydenMS, GhoshS. Crosstalk in NF-kappa B signaling pathways. Nat Immunol, 2011; 12:695–708.
14.
HatadaEN, KrappmannD, ScheidereitC. NF-kappaB and the innate immune response. Curr Opin Immunol, 2000; 12:52–58.
15.
HaydenMS, WestAP, GhoshS. NF-kappaB and the immune response. Oncogene, 2006; 25:6758–6780.
16.
GhoshS, MayMJ, KoppEB. NF-kappa B and rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol, 1998; 16:225–260.
17.
PahlHL. Activators and target genes of Rel/NF-kappa B transcription factors. Oncogene, 1999; 18:6853–6866.
18.
AhnKS, AggarwalBB. Transcription factor NF-kappa B—a sensor for smoke and stress signals. Nat Prod Mol Ther, 2005; 1056:218–233.
19.
PahlHL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene, 1999; 18:6853–6866.
20.
KarinM. Nuclear factor-kappaB in cancer development and progression. Nature, 2006; 441:431–436.
21.
XiaY, ShenS, VermaIM. NF-kappaB, an active player in human cancers. Cancer Immunol Res, 2014; 2:823–830.
22.
BarkettM, GilmoreTD. Control of apoptosis by Rel/NF-kappaB transcription factors. Oncogene, 1999; 18:6910–6924.
23.
TornatoreL, SandomenicoA, RaimondoD, et al.Cancer-selective targeting of the NF-kappaB survival pathway with GADD45beta/MKK7 inhibitors. Cancer Cell, 2014; 26:938.
24.
JinRG, De SmaeleE, ZazzeroniF, et al.Regulation of the gadd45 beta promoter by NF-kappa B. DNA Cell Biol, 2002; 21:491–503.
25.
KarinM. NF-kappa B as a critical link between inflammation and cancer. Cold Spring Harb Perspect Biol, 2009; 1:a000141.
26.
Ben-NeriahY, KarinM. Inflammation meets cancer, with NF-kappaB as the matchmaker. Nat Immunol, 2011; 12:715–723.
27.
DidonatoJA, MercurioF, KarinM. NF-kappa B and the link between inflammation and cancer. Immunol Rev, 2012; 246:379–400.
28.
HoeselB, SchmidJA. The complexity of NF-kappa B signaling in inflammation and cancer. Mol Cancer, 2013; 12:86.
29.
BasseresDS, BaldwinAS. Nuclear factor-kappa B and inhibitor of kappa B kinase pathways in oncogenic initiation and progression. Oncogene, 2006; 25:6817–6830.
30.
BiswasDK, CruzAP, GansbergerE, et al.Epidermal growth factor-induced nuclear factor kappa B activation: a major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells. Proc Natl Acad Sci U S A, 2000; 97:8542–8547.
31.
LaneDP, MidgleyCA, HuppTR, et al.On the regulation of the p53 tumour suppressor, and its role in the cellular response to DNA damage. Philos Trans R Soc Lond B Biol Sci, 1995; 347:83–87.
32.
SenR. Control of B lymphocyte apoptosis by the transcription factor NF-kappaB. Immunity, 2006; 25:871–883.
33.
AinbinderE, RevachM, WolsteinO, et al.Mechanism of rapid transcriptional induction of tumor necrosis factor alpha-responsive genes by NF-kappaB. Mol Cell Biol, 2002; 22:6354–6362.
34.
SuS, ChenJ, YaoH, et al.CD10(+)GPR77(+) cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell, 2018; 172:841–856.e6.
35.
KarinM, YamamotoY, WangQM. The IKK NF-kappa B system: a treasure trove for drug development. Nat Rev Drug Discov, 2004; 3:17–26.
36.
GuptaSC, SundaramC, ReuterS, et al.Inhibiting NF-kappa B activation by small molecules as a therapeutic strategy. Biochim Biophys Acta Gene Regul Mech, 2010; 1799:775–787.
37.
PikarskyE, Ben-NeriahY. NF-kappa B inhibition: a double-edged sword in cancer?. Eur J Cancer, 2006; 42:779–784.
38.
XiaoGT, RabsonAB, YoungW, et al.Alternative pathways of NF-kappa B activation: a double-edged sword in health and disease. Cytokine Growth Factor Rev, 2006; 17:281–293.
39.
ChariotA. 20 years of NF-kappa B. Biochem Pharmacol, 2006; 72:1051–1053.
40.
WangD, TangH, XuX, et al.Control the intracellular NF-kappaB activity by a sensor consisting of miRNA and decoy. Int J Biochem Cell Biol, 2018; 95:43–52.
41.
ChowRD, GuzmanCD, WangG, et al.AAV-mediated direct in vivo CRISPR screen identifies functional suppressors in glioblastoma. Nat Neurosci, 2017; 20:1329–1341.
42.
SamulskiRJ, MuzyczkaN. AAV-mediated gene therapy for research and therapeutic purposes. Annu Rev Virol, 2014; 1:427–451.
43.
GeorgeLA. Hemophilia gene therapy comes of age. Blood Adv, 2017; 1:2591–2599.
44.
MendellJR, Al-ZaidyS, ShellR, et al.Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med, 2017; 377:1713–1722.
45.
ValdmanisPN, KayMA. Future of rAAV gene therapy: platform for RNAi, gene editing, and beyond. Hum Gene Ther, 2017; 28:361–372.
46.
RysgaardCD, MorrisCS, DreesD, et al.Positive hepatitis B surface antigen tests due to recent vaccination: a persistent problem. BMC Clin Pathol, 2012; 12:15.
47.
LiaoX, LiangZ. Strategy vaccination against Hepatitis B in China. Hum Vaccin Immunother, 2015; 11:1534–1539.
48.
CuiF, ShenL, LiL, et al.Prevention of chronic hepatitis B after 3 decades of escalating vaccination policy, China. Emerg Infect Dis, 2017; 23:765–772.
49.
ObeidM, TesniereA, GhiringhelliF, et al.Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med, 2007; 13:54–61.
50.
ChaoMP, JaiswalS, Weissman-TsukamotoR, et al.Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci Transl Med, 2010; 2:63ra94.
51.
GardaiSJ, McphillipsKA, FraschSC, et al.Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell, 2005; 123:321–334.
52.
WuSC, WongSL. Structure-guided design of an engineered streptavidin with reusability to purify streptavidin-binding peptide tagged proteins or biotinylated proteins. PLoS One, 2013; 8:e69530.
53.
Barrette-NgIH, WuSC, TjiaWM, et al.The structure of the SBP-Tag-streptavidin complex reveals a novel helical scaffold bridging binding pockets on separate subunits. Acta Crystallogr D Biol Crystallogr, 2013; 69:879–887.
54.
NiersJM, ChenJW, LewandrowskiG, et al.Single reporter for targeted multimodal in vivo imaging. J Am Chem Soc, 2012; 134:5149–5156.
55.
TsengJC, ZanzonicoPB, LevinB, et al.Tumor-specific in vivo transfection with HSV-1 thymidine kinase gene using a Sindbis viral vector as a basis for prodrug ganciclovir activation and PET. J Nucl Med, 2006; 47:1136–1143.
56.
HamelW, MagnelliL, ChiarugiVP, et al.Herpes simplex virus thymidine kinase/ganciclovir-mediated apoptotic death of bystander cells. Cancer Res, 1996; 56:2697–2702.
57.
NissimL, WuMR, PeryE, et al.Synthetic RNA-based immunomodulatory gene circuits for cancer immunotherapy. Cell, 2017; 171:1138–1150.e5.
58.
HasuiM, SaikawaY, MiuraM, et al.Effector and precursor phenotypes of lymphokine-activated killer cells in mice with severe combined immunodeficiency (SCID) and athymic (nude) mice. Cell Immunol, 1989; 120:230–239.
59.
Moller NielsenI, HeronI. Diet and immune response in nu/nu Balb/c mice. Exp Cell Biol, 1984; 52:137–139.
60.
MinatoN, ReidL, CantorH, et al.Mode of regulation of natural killer cell activity by interferon. J Exp Med, 1980; 152:124–137.
61.
ClarkEA, ShultzLD, PollackSB. Mutations in mice that influence natural-killer (NK) cell-activity. Immunogenetics, 1981; 12:601–613.
62.
CheersC, WallerR. Activated macrophages in congenitally athymic nude mice and in lethally irradiated mice. J Immunol, 1975; 115:844–847.
63.
MogensenSC, AndersenHK. Role of activated macrophages in resistance of congenitally athymic nude-mice to hepatitis induced by herpes-simplex virus type-2. Infect Immun, 1978; 19:792–798.
64.
RaoGR, RawlsWE, PereyDYE, et al.Macrophage activation in congenitally athymic mice raised under conventional or germfree conditions. J Reticuloendothel Soc, 1977; 21:13–20.
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