Enhanced anti-melanoma efficacy through a combination of the armed oncolytic adenovirus ZD55-IL-24 and immune checkpoint blockade in B16-bearing immunocompetent mouse model

AbstractAlthough the recent treatment in melanoma through the use of anti-PD-1 immunotherapy is successful, the efficacy of this approach remains to be improved. Here, we explore the feasibility of combination strategy with the armed oncolytic adenovirus ZD55-IL-24 and PD-1 blockade. We find that combination therapy with localized ZD55-IL-24 and systemic PD-1 blockade leads to synergistic inhibition of both local and distant established tumors in B16-bearing immunocompetent mouse model. Our further mechanism investigation reveals that synergistic therapeutic effect is associated with marked promotion of tumor immune infiltration and recognition in both local and distant tumors as well as spleens. PD-1 blockade has no obvious effect on promotion of tumor immune infiltration and recognition. Localized therapy with ZD55-IL-24, however, can help PD-1 blockade to overcome the limitation of relatively low tumor immune infiltration and recognition. This study provides a rationale for investigation of such combination therapy in the clinic.

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Relaxin-expressing oncolytic adenovirus induces remodeling of physical and immunological aspects of cold tumor to potentiate PD-1 blockade

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-000763 ◽

2020 ◽

Vol 8 (2) ◽

pp. e000763 ◽

Cited By ~ 2

Author(s):

Bo-Kyeong Jung ◽

Hae Young Ko ◽

Hyunji Kang ◽

JinWoo Hong ◽

Hyo Min Ahn ◽

...

Keyword(s):

Combination Therapy ◽

Immune Checkpoint ◽

Immune Checkpoint Blockade ◽

Oncolytic Adenovirus ◽

Therapeutic Effects ◽

Tumor Models ◽

Activated T Cells ◽

Therapy Regimen ◽

Gm Csf ◽

Positron Emission

BackgroundCurrently, several antibody (Ab)-based therapies have shown excellent therapeutic effects in the clinic. Nonetheless, Ab penetration into tumor tissues is limited due to abnormal vasculature, tumor interstitial pressure, and excessive extracellular matrix (ECM) accumulation, thus demanding novel strategies to overcome these barriers.MethodsThe intratumoral distribution of therapeutic Abs were detected by fluorescence microscopy or positron emission tomography in both human gastric xenograft and syngeneic pancreatic hamster tumor models. The antitumor efficacy by combination of oncolytic adenovirus (Ad), which coexpresses relaxin (RLX), interleukin (IL)-12, and granulocyte macrophage colony-stimulating factor (GM-CSF) (oAd/IL12/GM-RLX) and antibody against the programmed cell death protein 1 (αPD-1) was examined in hamster subcutaneous and orthotopic pancreatic tumor models. The immunological aspects of these combination therapy regimen were assessed by flow cytometry or immunohistochemistry in subcutaneous hamster tumor models.ResultsRelaxin-expressing oncolytic Ad effectively degraded tumor ECM and enhanced the tumor penetration of trastuzumab in comparison with trastuzumab monotherapy. Based on these results, an oAd/IL12/GM-RLX was used to enhance the potency of immune checkpoint blockade. The combination of the oAd/IL12/GM-RLX and αPD-1 promoted a concomitant degradation of the tumor ECM and amelioration of the immunosuppressive tumor niches, ultimately enhanced intratumoral infiltration of both αPD-1 and activated T cells. Of note, the combination therapy was able to elicit a potent and durable antitumor immune response against cold tumors that were refractory to immune checkpoint inhibitor monotherapy.ConclusionsOur findings are the first to demonstrate that expression of four genes (IL-12p35, IL-12p40, GM-CSF, and RLX) mediated by a single oncolytic Ad vector can promote remodeling of both physical and immunological aspects of the tumor niches to overcome the major limitations of Ab-based therapies that have emerged in recent clinical trials.

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Optimization of the administration strategy for the armed oncolytic adenovirus ZD55-IL-24 in both immunocompromised and immunocompetent mouse model

Human Gene Therapy ◽

10.1089/hum.2021.036 ◽

2021 ◽

Author(s):

Hai-Jun Hu ◽

Xiu Liang ◽

Hai-Lang Li ◽

Huai-Yuan Wang ◽

Jin-Fa Gu ◽

...

Keyword(s):

Mouse Model ◽

Oncolytic Adenovirus ◽

Immunocompetent Mouse

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Abstract LB-129: CD8+ T cell response mediates the therapeutic effects of oncolytic adenovirus in an immunocompetent mouse model

10.1158/1538-7445.am2012-lb-129 ◽

2012 ◽

Author(s):

Yajun Yang ◽

Xiaozhu Li ◽

Yaohe Wang ◽

Shengdian Wang

Keyword(s):

T Cell ◽

Mouse Model ◽

Cell Response ◽

Cd8 T Cell ◽

T Cell Response ◽

Oncolytic Adenovirus ◽

Therapeutic Effects ◽

Immunocompetent Mouse

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The armed oncolytic adenovirus ZD55-IL-24 eradicates melanoma by turning the tumor cells from the self-state into the nonself-state besides direct killing

Cell Death and Disease ◽

10.1038/s41419-020-03223-0 ◽

2020 ◽

Vol 11 (11) ◽

Author(s):

Hai-Jun Hu ◽

Xiu Liang ◽

Hai-Lang Li ◽

Chun-Ming Du ◽

Jia-Li Hao ◽

...

Keyword(s):

Mouse Model ◽

Tumor Cells ◽

Antitumor Immunity ◽

Oncolytic Adenovirus ◽

The Self ◽

Indirect Pathway ◽

Immunocompetent Mouse ◽

Tumor Cell Death ◽

Immunocompromised Mouse ◽

Direct Killing

AbstractZD55-IL-24 is similar but superior to the oncolytic adenovirus ONYX-015, yet the exact mechanism underlying the observed therapeutic effect is still not well understood. Here we sought to elucidate the underlying antitumor mechanism of ZD55-IL-24 in both immunocompetent and immunocompromised mouse model. We find that ZD55-IL-24 eradicates established melanoma in B16-bearing immunocompetent mouse model not through the classic direct killing pathway, but mainly through the indirect pathway of inducing systemic antitumor immunity. Inconsistent with the current prevailing view, our further results suggest that ZD55-IL-24 can induce antitumor immunity in B16-bearing immunocompetent mouse model in fact not due to its ability to lyse tumor cells and release the essential elements, such as tumor-associated antigens (TAAs), but due to its ability to put a “nonself” label in tumor cells and then turn the tumor cells from the “self” state into the “nonself” state without tumor cell death. The observed anti-melanoma efficacy of ZD55-IL-24 in B16-bearing immunocompetent mouse model was practically caused only by the viral vector. In addition, we also notice that ZD55-IL-24 can inhibit tumor growth in B16-bearing immunocompetent mouse model through inhibiting angiogenesis, despite it plays only a minor role. In contrast to B16-bearing immunocompetent mouse model, ZD55-IL-24 eliminates established melanoma in A375-bearing immunocompromised mouse model mainly through the classic direct killing pathway, but not through the antitumor immunity pathway and anti-angiogenesis pathway. These findings let us know ZD55-IL-24 more comprehensive and profound, and provide a sounder theoretical foundation for its future modification and drug development.

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