Modulating Oncolytic Adenovirus Immunotherapy by Driving Two Axes of the Immune System by Expressing 4-1BBL and CD40L

Lu, Shao-Chia; Hansen, Michael J.; Hemsath, Jack R.; Parrett, Brian J.; Zell, Brady; Barry, Michael A.

doi:10.1089/hum.2021.197

Cited by 8 publications

(4 citation statements)

References 44 publications

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“…PDL1 blockade and/or activation of CD40 or 4-1BB pathways into the TME are proven effective ways to enhance the anti-tumor immune response, particularly in combination with OV treatment ( Liu et al, 2017 ; Lu et al, 2022 ). While anti-PDL1 treatments are relatively well tolerated, the systemic administration of CD40 or 4-1BB agonists triggers some on-target-off-tumor toxicity which hampers their clinical use.…”

Section: Discussionmentioning

confidence: 99%

Design and selection of anti-PD-L1 single-domain antibody and tumor necrosis factor superfamily ligands for an optimal vectorization in an oncolytic virus

Remy,

Pintado,

Dunlop

et al. 2023

Front. Bioeng. Biotechnol.

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Arming oncolytic viruses with transgenes encoding immunomodulators improves their therapeutic efficacy by enhancing and/or sustaining the innate and adaptive anti-tumoral immune responses. We report here the isolation, selection, and vectorization of a blocking anti-human PDL1 single-domain antibody (sdAb) isolated from PDL1-immunized alpacas. Several formats of this sdAb were vectorized into the vaccinia virus (VV) and evaluated for their programmed cell death protein 1 (PD1)/PD1 ligand (PDL1) blocking activity in the culture medium of tumor cells infected in vitro. In those conditions, VV-encoded homodimeric sdAb generated superior PDL1 blocking activity compared to a benchmark virus encoding full-length avelumab. The sdAb was further used to design simple, secreted, and small tumor necrosis factor superfamily (TNFSF) fusions with the ability to engage their cognate receptors (TNFRSF) only in the presence of PDL1-positive cells. Finally, PDL1-independent alternatives of TNFRSF agonists were also constructed by fusing different variants of surfactant protein-D (SP-D) oligomerization domains with TNFSF ectodomains. An optimal SP-D–CD40L fusion with an SP-D collagen domain reduced by 80% was identified by screening with a transfection/infection method where poxvirus transfer plasmids and vaccinia virus were successively introduced into the same cell. However, once vectorized in VV, this construct had a much lower CD40 agonist activity compared to the SP-D–CD40L construct, which is completely devoid of the collagen domain that was finally selected. This latest result highlights the importance of working with recombinant viruses early in the payload selection process. Altogether, these results bring several complementary solutions to arm oncolytic vectors with powerful immunomodulators to improve their immune-based anti-tumoral activity.

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Section: Discussionmentioning

confidence: 99%

Design and selection of anti-PD-L1 single-domain antibody and tumor necrosis factor superfamily ligands for an optimal vectorization in an oncolytic virus

Remy,

Pintado,

Dunlop

et al. 2023

Front. Bioeng. Biotechnol.

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show abstract

“…While they demonstrated an effective anti-tumour response and designed the vector with reduced anti-vector responses in mind, they did not confirm if their approach had any effect on vector immune evasion [262]. The same vector was also evaluated for use in vaccines in 2019 [263], as well as oncolytic applications in 2022 [264] but without evaluation of the effect of HVR swap on anti-vector immunity.…”

Section: Penaloza-macmaster Et Al Investigated T-cell Responses To Ve...mentioning

confidence: 99%

The Immune System – Friend or Foe for Adenovirus Based Therapies?

Wallace,

Bliss,

Parker

2024

Preprint

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Pathogenic adenovirus (Ad) infections are widespread but typically mild and transient, except in the immunocompromised. As vectors for gene therapy, vaccine and oncology applications, Ad based platforms offer advantages including ease of genetic manipulation, scale of production and well established safety profiles, making them attractive tools for therapeutic development. However, the immune system often poses a significant challenge that may need to be overcome for adenovirus based therapies to be truly efficacious. Both pre-existing anti-Ad immunity in the population as well as the rapid development of an immune response against engineered adenoviral vectors can have detrimental effects upon the downstream impact of an adenovirus-based therapeutic. This review focusses on the different challenges posed, including pre-existing natural immunity and anti-vector immunity induced by a therapeutic, both in context of the innate and adaptive immune responses. We summarize different approaches developed with the aim of tackling these problems, as well as their outcomes and potential future applications.

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“…While they demonstrated an effective anti-tumour response and designed the vector with reduced anti-vector responses in mind, they did not confirm if their approach had any effect on vector immune evasion [ 268 ]. The same vector was also evaluated for use in vaccines in 2019 [ 269 ], as well as oncolytic applications in 2022 [ 270 ], but without evaluation of the effect of HVR swap on anti-vector immunity.…”

Section: Engineering Ads For Immune Evasionmentioning

confidence: 99%

The Immune System—A Double-Edged Sword for Adenovirus-Based Therapies

Wallace,

Bliss,

Parker

2024

Viruses

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Pathogenic adenovirus (Ad) infections are widespread but typically mild and transient, except in the immunocompromised. As vectors for gene therapy, vaccine, and oncology applications, Ad-based platforms offer advantages, including ease of genetic manipulation, scale of production, and well-established safety profiles, making them attractive tools for therapeutic development. However, the immune system often poses a significant challenge that must be overcome for adenovirus-based therapies to be truly efficacious. Both pre-existing anti-Ad immunity in the population as well as the rapid development of an immune response against engineered adenoviral vectors can have detrimental effects on the downstream impact of an adenovirus-based therapeutic. This review focuses on the different challenges posed, including pre-existing natural immunity and anti-vector immunity induced by a therapeutic, in the context of innate and adaptive immune responses. We summarise different approaches developed with the aim of tackling these problems, as well as their outcomes and potential future applications.

show abstract

Modulating Oncolytic Adenovirus Immunotherapy by Driving Two Axes of the Immune System by Expressing 4-1BBL and CD40L

Cited by 8 publications

References 44 publications

Design and selection of anti-PD-L1 single-domain antibody and tumor necrosis factor superfamily ligands for an optimal vectorization in an oncolytic virus

Design and selection of anti-PD-L1 single-domain antibody and tumor necrosis factor superfamily ligands for an optimal vectorization in an oncolytic virus

The Immune System – Friend or Foe for Adenovirus Based Therapies?

The Immune System—A Double-Edged Sword for Adenovirus-Based Therapies

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