Adenovirus-Mediated Inducible Expression of a PD-L1 Blocking Antibody in Combination with Macrophage Depletion Improves Survival in a Mouse Model of Peritoneal Carcinomatosis

Buñuales, María; Ballesteros-Briones, María Cristina; González-Aparicio, Manuela; Hervás-Stubbs, Sandra; Martišová, Eva; Mancheño, Uxua; Ricobaraza, Ana; Lumbreras, Sara; Smerdou, Cristian; Hernández-Alcoceba, Rubén

doi:10.3390/ijms22084176

Cited by 9 publications

(4 citation statements)

References 45 publications

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“…They have been used to express an anti-PD-L1 antibody from a mifepristone-inducible expression system. Local administration of this high-capacity adenoviral vector (HCA-EFZP-aPDL1) in subcutaneous lesions led to a significant reduction in tumor growth, with minimal antibody release to the circulation [114].…”

Section: Adenovirus Vectorsmentioning

confidence: 99%

Leading Edge: Intratumor Delivery of Monoclonal Antibodies for the Treatment of Solid Tumors

Blanco

Chocarro

Fernández-Rubio

et al. 2023

IJMS

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Immunotherapies based on immune checkpoint blockade have shown remarkable clinical outcomes and durable responses in patients with many tumor types. Nevertheless, these therapies lack efficacy in most cancer patients, even causing severe adverse events in a small subset of patients, such as inflammatory disorders and hyper-progressive disease. To diminish the risk of developing serious toxicities, intratumor delivery of monoclonal antibodies could be a solution. Encouraging results have been shown in both preclinical and clinical studies. Thus, intratumor immunotherapy as a new strategy may retain efficacy while increasing safety. This approach is still an exploratory frontier in cancer research and opens up new possibilities for next-generation personalized medicine. Local intratumor delivery can be achieved through many means, but an attractive approach is the use of gene therapy vectors expressing mAbs inside the tumor mass. Here, we summarize basic, translational, and clinical results of intratumor mAb delivery, together with descriptions of non-viral and viral strategies for mAb delivery in preclinical and clinical development. Currently, this is an expanding research subject that will surely play a key role in the future of oncology.

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Section: Adenovirus Vectorsmentioning

confidence: 99%

Leading Edge: Intratumor Delivery of Monoclonal Antibodies for the Treatment of Solid Tumors

Blanco

Chocarro

Fernández-Rubio

et al. 2023

IJMS

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“…These high-capacity vectors allow the cloning of up to 35 kb of foreign DNA, making it possible to express large transgenes or complex regulatory systems [ 142 ]. This approach has been recently used by our group to deliver an anti-PD-L1 mAb to tumors based on the MC38 cell line [ 143 ]. The expression of anti-PD-L1 mAb from this vector was regulated by a mifepristone-inducible promoter, which allowed for tight control of mAb levels in vivo.…”

Section: Viral Vectors To Deliver Immunomodulatory Antibodiesmentioning

confidence: 99%

Local Delivery of Immunomodulatory Antibodies for Gastrointestinal Tumors

Silva-Pilipich

Covo-Vergara

Smerdou

2023

Cancers

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Cancer therapy has experienced a breakthrough with the use of immune checkpoint inhibitors (ICIs) based on monoclonal antibodies (mAbs), which are able to unleash immune responses against tumors refractory to other therapies. Despite the great advancement that ICIs represent, most patients with gastrointestinal tumors have not benefited from this therapy. In addition, ICIs often induce adverse effects that are related to their systemic use. Local administration of ICIs in tumors could concentrate their effect in the malignant tissue and provide a higher safety profile. A new and attractive approach for local delivery of ICIs is the use of gene therapy vectors to express these blocking antibodies in tumor cells. Several vectors have been evaluated in preclinical models of gastrointestinal tumors to express ICIs against PD-1, PD-L1, and CTLA-4, among other immune checkpoints, with promising results. Vectors used in these settings include oncolytic viruses, self-replicating RNA vectors, and non-replicative viral and non-viral vectors. The use of viral vectors, especially when they have replication capacity, provides an additional adjuvant effect that has been shown to enhance antitumor responses. This review covers the most recent studies involving the use of gene therapy vectors to deliver ICIs to gastrointestinal tumors.

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“…Antibodies to PDL1 expression. A high-capacity inducible adenoviral vector (HCA-EFZP-aPDL1) for the controlled expression of PD-L1 blocking antibody was engineered [ 193 ]. The vector was tested in an immune-competent mouse model of colorectal cancer (MC38).…”

Section: Viral Vectors Used For Tme Programmingmentioning

confidence: 99%

Recombinant Viral Vectors for Therapeutic Programming of Tumour Microenvironment: Advantages and Limitations

2022

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Viral vectors have been widely investigated as tools for cancer immunotherapy. Although many preclinical studies demonstrate significant virus-mediated tumour inhibition in synergy with immune checkpoint molecules and other drugs, the clinical success of viral vector applications in cancer therapy currently is limited. A number of challenges have to be solved to translate promising vectors to clinics. One of the key elements of successful virus-based cancer immunotherapy is the understanding of the tumour immune state and the development of vectors to modify the immunosuppressive tumour microenvironment (TME). Tumour-associated immune cells, as the main component of TME, support tumour progression through multiple pathways inducing resistance to treatment and promoting cancer cell escape mechanisms. In this review, we consider DNA and RNA virus vectors delivering immunomodulatory genes (cytokines, chemokines, co-stimulatory molecules, antibodies, etc.) and discuss how these viruses break an immunosuppressive cell development and switch TME to an immune-responsive “hot” state. We highlight the advantages and limitations of virus vectors for targeted therapeutic programming of tumour immune cell populations and tumour stroma, and propose future steps to establish viral vectors as a standard, efficient, safe, and non-toxic cancer immunotherapy approach that can complement other promising treatment strategies, e.g., checkpoint inhibitors, CAR-T, and advanced chemotherapeutics.

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Adenovirus-Mediated Inducible Expression of a PD-L1 Blocking Antibody in Combination with Macrophage Depletion Improves Survival in a Mouse Model of Peritoneal Carcinomatosis

Cited by 9 publications

References 45 publications

Leading Edge: Intratumor Delivery of Monoclonal Antibodies for the Treatment of Solid Tumors

Leading Edge: Intratumor Delivery of Monoclonal Antibodies for the Treatment of Solid Tumors

Local Delivery of Immunomodulatory Antibodies for Gastrointestinal Tumors

Recombinant Viral Vectors for Therapeutic Programming of Tumour Microenvironment: Advantages and Limitations

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