Correction to: Delivery of oncolytic vaccinia virus by matched allogeneic stem cells overcomes critical innate and adaptive immune barriers

BackgroundOncolytic virotherapy has been recognized as a promising new therapy for cancer for decades but only few viruses have been approved worldwide. The therapeutic potential of oncolytic viruses can be severely restricted by innate and adaptive immune barriers making oncolytic virus clinically inefficient. To overcome this obstacle, we utilized adipose-derived stem cells (AD-MSC) loaded with tumor selective CAL1 oncolytic vaccinia virus to generate a new therapeutic agent called SNV1 (SuperNova-1).MethodsCAL1 vaccinia virus was tested for its ability to replicate and selectively kill various human cancer cell lines in vitro and in vivo. Additionally, CAL1 was loaded into adipose-derived mesenchymal stem cells to generate SuperNova1 (SNV1). Both CAL1 and SNV1 were tested for their ability to kill cancer cells in the presence of active complement and neutralizing antibodies in cell culture as well as in mice. Immune cell infiltration of the treated and untreated tumors was analyzed by flow cytometry.ResultsCAL1 showed preferential amplification and killed various tested human (PC3, FaDu, MDA-MB-231, RPMI) and mouse cancer cells (CT26, EMT6, TRAMP-C2, RM1). In animals, CAL1 caused tumor regression in PC3 and CT26 mouse models without signs of toxicity. SNV1 significantly enhanced protection of CAL1 virus from clearance by the immune system as compared to naked CAL1 virus, leading to higher therapeutic efficacy in animals. Five days after SNV1 administration, tumor infiltrating lymphocytes (TILs) from both treated and untreated tumors showed increased CD4 and CD8 T-cell infiltrations. Importantly, we documented a decreased frequency of Tregs, and improved effector to Treg ratios, which was associated with inhibition of tumor growth at the treated tumor site and also at distant untreated sites.ConclusionsCAL1 is potentially used as an oncolytic agent. In addition, SNV1 cell-based platform protects and potentiates oncolytic vaccinia virus by circumventing humoral innate and adaptive immune barriers, resulting in enhanced oncolytic virotherapy. Particularly, SNV1 provided instantly active viral particles for immediate infection and simultaneous release of therapeutic proteins in the injected tumors.

Download Full-text

Delivery of oncolytic vaccinia virus by matched allogeneic stem cells overcomes critical innate and adaptive immune barriers

Journal of Translational Medicine ◽

10.1186/s12967-019-1829-z ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 8

Author(s):

Dobrin D. Draganov ◽

Antonio F. Santidrian ◽

Ivelina Minev ◽

Duong Nguyen ◽

Mehmet Okyay Kilinc ◽

...

Keyword(s):

Stem Cells ◽

Vaccinia Virus ◽

Adaptive Immune ◽

Immune Barriers

Download Full-text

A cell-based platform to potentiate oncolytic virus: Potential approach for cancer therapies.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.5_suppl.21 ◽

2020 ◽

Vol 38 (5_suppl) ◽

pp. 21-21

Author(s):

Duong Nguyen ◽

Alberto Gomez ◽

Ashley Alamillo ◽

Forrest Neuharth ◽

Ivelina Minev ◽

...

Keyword(s):

Tumor Growth ◽

Vaccinia Virus ◽

Cell Lines ◽

Cancer Cell ◽

Therapeutic Potential ◽

Cancer Cell Lines ◽

Oncolytic Viruses ◽

Oncolytic Virotherapy ◽

Adaptive Immune ◽

Immune Barriers

21 Background: Oncolytic virotherapy has been pursued by multiple companies and institutions with few candidates reaching the clinic and demonstrating limited efficacy. The therapeutic potential of oncolytic viruses can be severely restricted by innate and adaptive immune barriers. To overcome this obstacle, we load and protect tumor selective CAL1 oncolytic vaccinia virus into adipose-derived stem cells (AD-MSC) to generate a new therapeutic agent called SNV1(SuperNova1). Methods: SNV1s were generated by incubating AD-MSC with CAL1 virus. SNV1 was analyzed for its ability to kill cancer cell lines and protect virus in the presence of active neutralizing antibodies and complement. In animals, SNV1 was intratumorally injected in various xenograft and syngeneic models. Viral biodistribution was also evaluated by PCR. Immune infiltration were analyzed using flow cytometry. Results: Compared to the naked virus, SNV1 showed improved protection against the humoral barriers and efficient eradication of various human cancer cell lines in vitro. Intratumoral SNV1 treatment showed statistically significant and potentiated tumor growth inhibition compared to control or CAL1 naked virus treatment in all tested models (prostate, breast, melanoma, colon, and prostate cancers). Importantly, local administration of SNV1 induced systemic therapeutic effects. Five days after SNV1 administration, tumor infiltrating lymphocytes (TILs) from both treated and untreated tumors showed increased CD4 and CD8 T-cell populations. As well as decreased frequency of Tregs, and improved effector to Treg ratios, which was associated with inhibition of tumor growth at the treated tumor site and also at distant untreated sites. Ongoing and persistent virus infection could be detected in the treated tumor as late as 15 days after administration. Conclusions: This study demonstrates the ability of our cell-based platform to protect and potentiate oncolytic vaccinia virus by circumventing the innate and adaptive immune barriers, resulting in enhanced oncolytic virotherapy. These findings provide fundamental rationale for the development of cell-based platforms to maximize the therapeutic potential of various oncolytic viruses.

Download Full-text

Neutrophil subtypes shape HIV-specific CD8 T-cell responses after vaccinia virus infection

npj Vaccines ◽

10.1038/s41541-021-00314-7 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Mauro Di Pilato ◽

Miguel Palomino-Segura ◽

Ernesto Mejías-Pérez ◽

Carmen E. Gómez ◽

Andrea Rubio-Ponce ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Vaccinia Virus ◽

Adaptive Immune System ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Responses ◽

Adaptive Immune

AbstractNeutrophils are innate immune cells involved in the elimination of pathogens and can also induce adaptive immune responses. Nα and Nβ neutrophils have been described with distinct in vitro capacity to generate antigen-specific CD8 T-cell responses. However, how these cell types exert their role in vivo and how manipulation of Nβ/Nα ratio influences vaccine-mediated immune responses are not known. In this study, we find that these neutrophil subtypes show distinct migratory and motility patterns and different ability to interact with CD8 T cells in the spleen following vaccinia virus (VACV) infection. Moreover, after analysis of adhesion, inflammatory, and migration markers, we observe that Nβ neutrophils overexpress the α4β1 integrin compared to Nα. Finally, by inhibiting α4β1 integrin, we increase the Nβ/Nα ratio and enhance CD8 T-cell responses to HIV VACV-delivered antigens. These findings provide significant advancements in the comprehension of neutrophil-based control of adaptive immune system and their relevance in vaccine design.

Download Full-text