Systemically Administered Sindbis Virus in Combination with Immune Checkpoint Blockade Induces Curative Anti-tumor Immunity

Scherwitzl, Iris; Hurtado, Alicia; Pierce, Carolyn M.; Vogt, Sandra; Pampeno, Christine; Meruelo, Daniel

doi:10.1016/j.omto.2018.04.004

Cited by 22 publications

(40 citation statements)

References 62 publications

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“…T cells are critical effectors in antitumor immunity, and enhancement of T cell response is key to treating cancer 27, 28, 29. Recombinant NDV-expressing cytokines that can promote T cell responses will exhibit more powerful effects against cancer.…”

Section: Discussionmentioning

confidence: 99%

Tumor Cells Modified with Newcastle Disease Virus Expressing IL-24 as a Cancer Vaccine

Cheng

Yang

et al. 2019

Molecular Therapy - Oncolytics

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Interleukin-24 (IL-24) is a promising agent for cancer immunotherapy that induces apoptosis of tumor cells and enhances T cell activation and function. In order to improve the antitumor activity induced by Newcastle disease virus (NDV)-modified tumor vaccine, we generated a recombinant NDV expressing IL-24 using reverse genetics. Irradiated tumor cells infected with LX/IL-24 showed stable IL-24 expression. The cytotoxicity assay showed that LX/IL-24-infected murine melanoma cells significantly enhanced the antitumor immune response in vitro . Then, the antitumor effects of virus-infected tumor cells were examined in the murine tumor models. LX/IL-24-infected tumor cells exhibited strong antitumor effects both in prophylaxis and therapeutic models. LX/IL-24-infected tumor cells increased infiltration of CD4 + T cells and CD8 + T cells in tumor sites, and the antitumor activity of the tumor vaccine modified with LX/IL-24 was dependent on CD8 + T cells. Taken together, our data well illustrates that LX/IL-24-modified tumor cells are a promising agent for cancer immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Tumor Cells Modified with Newcastle Disease Virus Expressing IL-24 as a Cancer Vaccine

Cheng

Yang

et al. 2019

Molecular Therapy - Oncolytics

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“…Previously, we used SV carrying NYESO-1, which encodes the cancer testis TAA, NYESO-1, to cure CT26 tumors expressing NYESO-1 [18]. Here we show that systemically disseminated A20 lymphoma can be completely cured by SV plus α4-1BB mAb combination therapy without the need to produce a SV that encodes a TAA known to be present in the A20 lymphoma cells.…”

Section: Introductionmentioning

confidence: 70%

“…After tumors were established, SV and α4-1BB mAb treatment started (designated as day 0). We used a therapeutic protocol similar to that previously described [18]. SV plus α4-1BB mAb combination achieved the best therapeutic effect (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…3 × 10 6 fLuc-A20 cells were inoculated to BALB/C mice by i.p injection. Tumor growth was monitored as previously described [18].…”

Section: Methodsmentioning

confidence: 99%

“…To investigate the phenotype of TIL, all treatments were started 11 days after tumor inoculation, After 7 days treatment, tumor mass was harvested and the phenotype of TIL were analyzed as previously described [18].…”

Section: Methodsmentioning

confidence: 99%

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Molecular and metabolic pathways mediating curative treatment of a non-Hodgkin B cell lymphoma by Sindbis viral vectors and anti-4-1BB monoclonal antibody

Yu¹,

Scherwitzl²,

Opp³

et al. 2019

j. immunotherapy cancer

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Background Limitations to current therapies for treating non-Hodgkin B cell lymphoma include relapse, toxicity and high cost. Thus, there remains a need for novel therapies. Oncolytic viral (OV) therapy has become a promising cancer immunotherapy because of its potential effectiveness, specificity and long-lasting immunity. We describe and characterize a novel cancer immunotherapy combining Sindbis virus (SV) vectors and the agonistic monoclonal antibody (mAb) to the T cell costimulatory receptor, 4-1BB (CD137). Methods A20 lymphoma was transfected with luciferase and tumor cells were inoculated to BALB/c mice. Tumor growth was monitored by IVIS imaging. Tumor bearing mice were treated with Sindbis virus, α4-1BB Ab or SV plus α4-1BB Ab. On day 7 after treatment, splenocytes were harvested and surface markers, cytokines, and transcription factors were measured by flow cytometry or Elispot. Splenic T cells were isolated and RNA transcriptome analysis was performed. Tumor cured mice were rechallenged with tumor for testing immunological memory. Results SV vectors in combination with α4-1BB monoclonal antibody (mAb) completely eradicated a B-cell lymphoma in a preclinical mouse model, a result that could not be achieved with either treatment alone. Tumor elimination involves a synergistic effect of the combination that significantly boosts T cell cytotoxicity, IFNγ production, T cell proliferation, migration, and glycolysis. In addition, all mice that survived after treatment developed long lasting antitumor immunity, as shown by the rejection of A20 tumor rechallenge. We identified the molecular pathways, including upregulated cytokines, chemokines and metabolic pathways in T cells that are triggered by the combined therapy and help to achieve a highly effective anti-tumor response. Conclusions Our study provides a novel, alternative method for B cell lymphoma treatment and describes a rationale to help translate SV vectors plus agonistic mAb into clinical applications. Electronic supplementary material The online version of this article (10.1186/s40425-019-0664-3) contains supplementary material, which is available to authorized users.

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Cytotoxic T lymphocyte‐associated protein 4 antibody aggrandizes antitumor immune response of oncolytic virus M1 via targeting regulatory T cells

Liu

et al. 2021

Intl Journal of Cancer

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Oncolytic virotherapies are perceived as remarkable immunotherapies coming into view and represent highly promising cancer treatments, yet to figure out its specific immune responses and underlying barriers remains critical. Albeit recent studies have demonstrated that oncolytic viruses (OVs) could fine tune tumor microenvironment (TME) to elicit tumor suppression mainly due to effective Tcell responses, the interaction between suppressive T cells and OVs is barely undetermined. Herein, we found that regulatory T cells (Treg cells) were increased in the TME following systemic administration of oncolytic virus M1 along with the higher expression of relative cytokines and chemokines in both mouse RM-1 prostatic carcinoma model and mouse B16F10 melanoma model. Besides, Treg cells expressed high levels of CD25 post-M1 treatment, and its suppressive effect on CD8 + T cells was also elevated. Depletion of Treg cells in M1-treated groups significantly reinforced antitumor effect of M1. Specific targeting of Treg cells using cytotoxic T lymphocyte-associated protein 4 (CTLA-4) antibody (Ab) in combination with M1 treatment elicited a more profound tumor suppression and longer overall survival time than M1 alone in both tumor models. Moreover, CTLA-4 Ab further aggrandized antitumor immune response elicited by M1, including increased infiltration of CD45 + immune cells and CD8 + or CD4 + T lymphocytes, decreased ratio of Treg cells to CD4 + T lymphocytes, the intensified lymphocytotoxicity and elevated secretion of cytotoxic cytokines like interferon-γ, granzyme B and perforin. Therefore, our findings constituted a suggestive evidence that targeting Treg cells in M1-based oncolytic virotherapy may achieve a highly response in clinical cancer research.

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Systemically Administered Sindbis Virus in Combination with Immune Checkpoint Blockade Induces Curative Anti-tumor Immunity

Cited by 22 publications

References 62 publications

Tumor Cells Modified with Newcastle Disease Virus Expressing IL-24 as a Cancer Vaccine

Tumor Cells Modified with Newcastle Disease Virus Expressing IL-24 as a Cancer Vaccine

Molecular and metabolic pathways mediating curative treatment of a non-Hodgkin B cell lymphoma by Sindbis viral vectors and anti-4-1BB monoclonal antibody

Cytotoxic T lymphocyte‐associated protein 4 antibody aggrandizes antitumor immune response of oncolytic virus M1 via targeting regulatory T cells

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