Combining STING-based neoantigen-targeted vaccine with checkpoint modulators enhances antitumor immunity in murine pancreatic cancer

Kinkead, Heather; Hopkins, Alexander C.; Lutz, Eric R.; Wu, Annie A.; Yarchoan, Mark; Cruz, Kayla; Woolman, Skylar; Vithayathil, Teena; Glickman, Laura Hix; Ndubaku, Chudi; McWhirter, Sarah M.; Dubensky, Thomas W.; Armstrong, Todd D.; Jaffee, Elizabeth M.; Zaidi, Neeha

doi:10.1172/jci.insight.122857

Cited by 135 publications

(149 citation statements)

References 47 publications

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“…Therefore, STING agonists seem capable of promoting several key processes for important for efficacy of checkpoint blockade immunotherapy. Consistent with this idea, STING agonists combined with PD‐1 blockade reduced tumor growth better than either therapy alone . In particular, tumor models that poorly responded to checkpoint blockade were sensitized when combined with STING agonists .…”

Section: Sting Pathway Involvement In Anti‐tumor Immunity In Preclinimentioning

confidence: 67%

“…Consistent with this idea, STING agonists combined with PD-1 blockade reduced tumor growth better than either therapy alone. 139 In particular, tumor models that poorly responded to checkpoint blockade were sensitized when combined with STING agonists. 140 These results are shaping the design of combination clinical trials in cancer patients.…”

Section: Combination Therapiesmentioning

confidence: 99%

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STING pathway agonism as a cancer therapeutic

Flood

Higgs

et al. 2019

Immunological Reviews

243

183

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The fact that a subset of human cancers showed evidence for a spontaneous adaptive immune response as reflected by the T cell‐inflamed tumor microenvironment phenotype led to the search for candidate innate immune pathways that might be driving such endogenous responses. Preclinical studies indicated a major role for the host STING pathway, a cytosolic DNA sensing pathway, as a proximal event required for optimal type I interferon production, dendritic cell activation, and priming of CD8+ T cells against tumor‐associated antigens. STING agonists are therefore being developed as a novel cancer therapeutic, and a greater understanding of STING pathway regulation is leading to a broadened list of candidate immune regulatory targets. Early phase clinical trials of intratumoral STING agonists are already showing promise, alone and in combination with checkpoint blockade. Further advancement will derive from a deeper understanding of STING pathway biology as well as mechanisms of response vs resistance in individual cancer patients.

show abstract

Section: Sting Pathway Involvement In Anti‐tumor Immunity In Preclinimentioning

confidence: 67%

Section: Combination Therapiesmentioning

confidence: 99%

STING pathway agonism as a cancer therapeutic

Flood

Higgs

et al. 2019

Immunological Reviews

243

183

View full text Add to dashboard Cite

show abstract

“…8,17,18 Conversely, checkpoint blockade therapy may improve the effector function of vaccine-induced T cells once they home to the immunosuppressive tumor microenvironment. 25,26 Thus, while immunotherapies have yet to translate into improved survival for patients with GBM, a combinatorial immune-based approach may lead to better outcomes in the future.…”

Section: Discussionmentioning

confidence: 99%

Detection of neoantigen-specific T cells following a personalized vaccine in a patient with glioblastoma

et al. 2019

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Neoantigens represent promising targets for personalized cancer vaccine strategies. However, the feasibility of this approach in lower mutational burden tumors like glioblastoma (GBM) remains unknown. We have previously reported the use of an immunogenomics pipeline to identify candidate neoantigens in preclinical models of GBM. Here, we report the application of the same immunogenomics pipeline to identify candidate neoantigens and guide screening for neoantigen-specific T cell responses in a patient with GBM treated with a personalized synthetic long peptide vaccine following autologous tumor lysate DC vaccination. Following vaccination, reactivity to three HLA class I-and five HLA class II-restricted candidate neoantigens were detected by IFN-γ ELISPOT in peripheral blood. A similar pattern of reactivity was observed among isolated post-treatment tumor-infiltrating lymphocytes. Genomic analysis of pre-and post-treatment GBM reflected clonal remodeling. These data demonstrate the feasibility and translational potential of a therapeutic neoantigen-based vaccine approach in patients with primary CNS tumors.

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“…Personalized cancer vaccines combined with ICB have exhibited early signs in clinical trials against high‐risk melanoma and glioblastoma . In view of the great potential of personalized vaccines, Zaidi et al developed the personalized vaccine PancVAX against murine pancreatic adenocarcinoma, with RpRp dithio 2′,3′‐cGAMP (ADU V16) as an adjuvant . The neoantigen peptide sequences were obtained through whole‐exome sequencing, RNA sequencing and NetMHC (a computer‐aided immunogenicity prediction algorithm).…”

Section: Sting Agonistsmentioning

confidence: 99%

Agonists and inhibitors of the STING pathway: Potential agents for immunotherapy

Zhao

et al. 2019

Medicinal Research Reviews

114

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Since being discovered in 2008, the STING (stimulator of interferon genes) pathway has gradually been recognized as a central and promising target for immunotherapy. The STING pathway can be stimulated by cyclic dinucleotides (CDNs), leading to the type I interferons (IFN) production for immunotherapy for cancer or other diseases. However, the negative charges, hydrophilicity, and instability of CDNs have hindered their further applications. In addition, chronic activation of the STING pathway has been found to be involved in autoimmune diseases as IFN overproduction.Thus, research and development of STING agonists and inhibitors has been a hot field for the treatment of several diseases. The past several years, especially 2018, has seen increasingly rapid advances in this field. Here, this review summarizes the synthesis and modification of CDNs, the identification of nonnucleotide agonists, the recent progress in delivery systems and the medical applications, such as personalized vaccine adjuvants, in detail. In addition, in this review, we summarize the STING inhibitors' advances from two aspects, covalent, and noncovalent inhibitors. K E Y W O R D S agonist, cyclic dinucleotides, immunotherapy, inhibitor, STING

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Combining STING-based neoantigen-targeted vaccine with checkpoint modulators enhances antitumor immunity in murine pancreatic cancer

Cited by 135 publications

References 47 publications

STING pathway agonism as a cancer therapeutic

STING pathway agonism as a cancer therapeutic

Detection of neoantigen-specific T cells following a personalized vaccine in a patient with glioblastoma

Agonists and inhibitors of the STING pathway: Potential agents for immunotherapy

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