An Oncolytic Adenovirus Targeting Transforming Growth Factor β Inhibits Protumorigenic Signals and Produces Immune Activation: A Novel Approach to Enhance Anti-PD-1 and Anti-CTLA-4 Therapy

Yang, Yuefeng; Xu, Weidong; Peng, Di; Wang, Hao; Zhang, Xiaoyan; Wang, Hua; Xiao, Fengjun; Zhu, Yangyong; Ji, Yuan; Gulukota, Kamalakar; Helseth, Donald L.; Mangold, Kathy A.; Sullivan, Megan; Kaul, Karen L.; Wang, Edward; Prabhakar, Bellur S.; Li, Jinnan; Wu, Xuejie; Wang, Lisheng; Seth, Prem

doi:10.1089/hum.2019.059

Cited by 41 publications

(44 citation statements)

References 64 publications

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“…Parts of the lungs were processed for H&E staining according to our published protocol. 18 Pulmonary metastatic burden was quantified by using ImageJ software (NIH) for each lung section.…”

Section: T1 Xenograft Model and Therapeutic Analysis With/without Icismentioning

confidence: 99%

“…16,17 In the breast and renal immunocompetent mouse models, direct inoculation of a similar sTGFbRIIFc expressing oncolytic virus rAd.sT into subcutaneous tumors inhibited protumorigenic signals and produced immune activation. 18 rAd.sT can also overcome resistance to immune checkpoint inhibitors (ICIs) and improve the antitumor effects of anti-PD-1 and anti-CTLA-4 antibody therapy. 18 To treat metastatic cancers, the preferred route to deliver adenoviral vectors would be via systemic administration.…”

Section: Introductionmentioning

confidence: 99%

“…18 rAd.sT can also overcome resistance to immune checkpoint inhibitors (ICIs) and improve the antitumor effects of anti-PD-1 and anti-CTLA-4 antibody therapy. 18 To treat metastatic cancers, the preferred route to deliver adenoviral vectors would be via systemic administration. Two key limitations in the use of Ad5-based adenoviruses (Ads) for systemic administration are the limited tumor tropism and liver/systemic toxicities.…”

Section: Introductionmentioning

confidence: 99%

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LyP-1-Modified Oncolytic Adenoviruses Targeting Transforming Growth Factor β Inhibit Tumor Growth and Metastases and Augment Immune Checkpoint Inhibitor Therapy in Breast Cancer Mouse Models

Yang

et al. 2020

Human Gene Therapy

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We report here the development of oncolytic adenoviruses (Ads) that have reduced toxicity, enhanced tumor tropism, produce strong antitumor response, and can overcome resistance to immune checkpoint inhibitor therapy in breast cancer. We have shown that LyP-1 receptor (p32) is highly expressed on the surface of breast cancer cells and tumors from cancer patients, and that increased stromal expression of transforming growth factor b-1 (TGFb-1) is associated with triple-negative breast cancer. Therefore, we constructed oncolytic Ads, AdLyp.sT and mHAdLyp.sT, in which the p32-binding LyP-1 peptide was genetically inserted into the adenoviral fiber protein. Both AdLyp.sT and mHAdLyp.sT express sTGFbRIIFc, a TGFb decoy that can inhibit TGFb pathways. mHAdLyp.sT is an Ad5/48 chimeric hexon virus in which hypervariable regions (HVRs 1-7) of Ad5 are replaced with the corresponding Ad48 HVRs. AdLyp.sT and mHAdLyp.sT exhibited better binding, replication, and produced higher sTGFbRIIFc protein levels in breast cancer cell lines compared with Ad.sT or mHAd.sT control viruses without LyP-1 peptide modification. Systemic delivery of mHAdLyp.sT in mice resulted in reduced hepatic/systemic toxicity compared with Ad.sT and AdLyp.sT. Intravenous delivery of AdLyp.sT and mHAdLyp.sT elicited a strong antitumor response in a human MDA-MB-231 bone metastasis model in mice, as indicated by bioluminescence imaging, radiographic tumor burden, serum TRACP 5b and calcium, and body weight analyses. Furthermore, intratumoral delivery of AdLyp.sT in 4T1 model in immunocompetent mice inhibited tumor growth and metastases, and augmented anti-PD-1 and anti-CTLA-4 therapy. Based on these studies, we believe that AdLyp.sT and mHAdLyp.sT can be developed as potential targeted immunotherapy agents for the treatment of breast cancer.

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“…Parts of the lungs were processed for H&E staining according to our published protocol. 18 Pulmonary metastatic burden was quantified by using ImageJ software (NIH) for each lung section.…”

Section: T1 Xenograft Model and Therapeutic Analysis With/without Icismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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LyP-1-Modified Oncolytic Adenoviruses Targeting Transforming Growth Factor β Inhibit Tumor Growth and Metastases and Augment Immune Checkpoint Inhibitor Therapy in Breast Cancer Mouse Models

Yang

et al. 2020

Human Gene Therapy

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“…Other methods to inhibit TGF-β signaling such as small molecule inhibitors of the TGF-β type 1 receptor (TGFBR1), TGF-β neutralizing antibody, and oncolytic viruses producing a soluble form of TGFBR2 (sTGF-βRII-Fc) have also been found to be efficient at inhibiting bone metastases [270][271][272][273], and could also be efficient at inhibiting TGF-β-mediated immunosuppression. Using the 4T1 syngeneic breast cancer model, intratumoral delivery of an oncolytic adenovirus expressing sTGF-β-Fc reduced the amount of Tregs in the tumor, while increasing the infiltration of CD8 + T cells and increasing the expression of T cell cytotoxic factors, and caused a reduction of tumor growth [274]. Similarly, combination of the antineoplastic drug cyclophosphamide with the pan-TGF-β neutralizing antibody 1D11 reduced the growth of 4T1 tumors and lung metastases in mice while increasing tumor-infiltration of T cells producing IFN-γ [275].…”

Section: Cell-and Bone-derived Transforming Growth Factor-β (Tgf-β)mentioning

confidence: 99%

Contribution of Macrophages and T Cells in Skeletal Metastasis

Mendoza-Reinoso

McCauley

Fournier

2020

Cancers

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Bone is a common site for metastases with a local microenvironment that is highly conducive for tumor establishment and growth. The bone marrow is replete with myeloid and lymphoid linage cells that provide a fertile niche for metastatic cancer cells promoting their survival and growth. Here, we discuss the role of macrophages and T cells in pro- and anti-tumoral mechanisms, their interaction to support cancer cell growth, and their contribution to the development of skeletal metastases. Importantly, immunotherapeutic strategies targeting macrophages and T cells in cancer are also discussed in this review as they represent a great promise for patients suffering from incurable bone metastases.

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“…Armed-OAds evolve in parallel to the immunotherapy landscape. OAds have been designed to produce soluble ligands of immune checkpoints such as OX40L [138], GITRL [139] or a fusion protein sPD1-CD137L [140], and also targeting crucial molecules for the resistance to anti-PD1/PD-L1 and anti-CTL-4 therapies such as TGF-β [141,142]. Moreover, the generation of bispecific T-cell engagers (BiTE) opened a new opportunity for redirecting the anti-viral lymphocytes against tumor-specific antigen.…”

Section: Oncos-102mentioning

confidence: 99%

Effect of Transgene Location, Transcriptional Control Elements and Transgene Features in Armed Oncolytic Adenoviruses

Farrera-Sal

Fillat

Alemany

2020

Cancers

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Clinical results with oncolytic adenoviruses (OAds) used as antitumor monotherapies show limited efficacy. To increase OAd potency, transgenes have been inserted into their genome, a strategy known as "arming OAds". Here, we review different parameters that affect the outcome of armed OAds. Recombinant adenovirus used in gene therapy and vaccination have been the basis for the design of armed OAds. Hence, early region 1 (E1) and early region 3 (E3) have been the most commonly used transgene insertion sites, along with partially or complete E3 deletions. Besides transgene location and orientation, transcriptional control elements, transgene function, either virocentric or immunocentric, and even the codons encoding it, greatly impact on transgene levels and virus fitness.

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An Oncolytic Adenovirus Targeting Transforming Growth Factor β Inhibits Protumorigenic Signals and Produces Immune Activation: A Novel Approach to Enhance Anti-PD-1 and Anti-CTLA-4 Therapy

Cited by 41 publications

References 64 publications

LyP-1-Modified Oncolytic Adenoviruses Targeting Transforming Growth Factor β Inhibit Tumor Growth and Metastases and Augment Immune Checkpoint Inhibitor Therapy in Breast Cancer Mouse Models

LyP-1-Modified Oncolytic Adenoviruses Targeting Transforming Growth Factor β Inhibit Tumor Growth and Metastases and Augment Immune Checkpoint Inhibitor Therapy in Breast Cancer Mouse Models

Contribution of Macrophages and T Cells in Skeletal Metastasis

Effect of Transgene Location, Transcriptional Control Elements and Transgene Features in Armed Oncolytic Adenoviruses

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