Local delivery of optimized nanobodies targeting the PD-1/PD-L1 axis with a self-amplifying RNA viral vector induces potent antitumor responses

Silva-Pilipich, Noelia; Blanco, Ester; Lozano, Teresa; Martišová, Eva; Igea, Ana; Herrador, Guillermo; Ballesteros-Briones, María Cristina; Gorraiz, Marta; Sarrión, Patricia; González‐Sapienza, Gualberto; Lasarte, Juan José; Vanrell, Lucía; Smerdou, Cristian

doi:10.1016/j.canlet.2023.216139

Cited by 9 publications

(10 citation statements)

References 51 publications

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“…BHK-21 cells (ATCC-CCL10) were grown as described [ 31 ]. LLC cells were grown in DMEM (GIBCO BRL, UK) supplemented with 10% FBS, 2 mM glutamine, and antibiotics.…”

Section: Methodsmentioning

confidence: 99%

“…For example, RNA vectors based on Semliki Forest virus (SFV) have been used to deliver transgenes into target cells. Short local expression of anti-PD-L1 mAb or nanobodies with SFV vectors demonstrated significant therapeutic efficacy in colon adenocarcinoma and melanoma models [ 30 , 31 ]. Infection of tumour cells also caused apoptosis and the induction of potent type I interferon responses which further potentiated antitumour responses.…”

Section: Introductionmentioning

confidence: 99%

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Oleuropein-driven reprogramming of the myeloid cell compartment to sensitise tumours to PD-1/PD-L1 blockade strategies

Blanco,

Silva-Pilipich,

Bocanegra

et al. 2024

Br J Cancer

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Background Previous studies have shown that functional systemic immunity is required for the efficacy of PD-1/PD-L1 blockade immunotherapies in cancer. Hence, systemic reprogramming of immunosuppressive dysfunctional myeloid cells could overcome resistance to cancer immunotherapy. Methods Reprogramming of tumour-associated myeloid cells with oleuropein was studied by quantitative differential proteomics, phenotypic and functional assays in mice and lung cancer patients. Combinations of oleuropein and two different delivery methods of anti-PD-1 antibodies were tested in colorectal cancer tumour models and in immunotherapy-resistant lung cancer models. Results Oleuropein treatment reprogrammed monocytic and granulocytic myeloid-derived suppressor cells, and tumour-associated macrophages towards differentiation of immunostimulatory subsets. Oleuropein regulated major differentiation programmes associated to immune modulation in myeloid cells, which potentiated T cell responses and PD-1 blockade. PD-1 antibodies were delivered by two different strategies, either systemically or expressed within tumours using a self-amplifying RNA vector. Combination anti-PD-1 therapies with oleuropein increased tumour infiltration by immunostimulatory dendritic cells in draining lymph nodes, leading to systemic antitumour T cell responses. Potent therapeutic activities were achieved in colon cancer and lung cancer models resistant to immunotherapies, even leading to complete tumour regression. Discussion Oleuropein significantly improves the outcome of PD-1/PD-L1 blockade immunotherapy strategies by reprogramming myeloid cells.

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“…BHK-21 cells (ATCC-CCL10) were grown as described [ 31 ]. LLC cells were grown in DMEM (GIBCO BRL, UK) supplemented with 10% FBS, 2 mM glutamine, and antibiotics.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Oleuropein-driven reprogramming of the myeloid cell compartment to sensitise tumours to PD-1/PD-L1 blockade strategies

Blanco,

Silva-Pilipich,

Bocanegra

et al. 2024

Br J Cancer

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“…More recently, we have constructed SFV vectors encoding nanobodies against PD-1 and PD-L1 [ 136 ]. Potential advantages of using smaller antibody fragments include improved intratumoral distribution, higher levels of expression in vivo, and the possibility of generating different nanobody-based chimeric proteins.…”

Section: Viral Vectors To Deliver Immunomodulatory Antibodiesmentioning

confidence: 99%

“…This strategy has already been used to optimize nanobodies in several preclinical studies and in some candidates that have reached clinical trials [ 138 ]. SFV vectors encoding these nanobody-Fc fusion proteins showed potent antitumor activity in mouse models of CRC and melanoma, outperforming control vectors encoding conventional antibodies against PD-1 and PD-L1 [ 136 ]. The superior performance of SFV vectors encoding nanobody-Fc constructs could be explained, at least in part, by the significantly higher levels of expression that were achieved compared to conventional antibodies, suggesting that lower doses of the vector could be used in clinical trials.…”

Section: Viral Vectors To Deliver Immunomodulatory Antibodiesmentioning

confidence: 99%

“…Non-viral vectors based on alphaviruses could be used in the form of RNA directly or as DNA, in which the self-amplifying RNA is cloned under the control of a eukaryotic promoter allowing its transcription in the target cell [ 154 , 155 ]. We have previously demonstrated the remarkable antitumor potential of these strategies by delivering SFV RNA and DNA vectors expressing IL-12 or an anti-PD-1 nanobody, respectively, by electroporation in MC38 subcutaneous tumors [ 136 , 156 ]. In addition to the adjuvant effect generated by the immunogenic death of transfected cells, this system would theoretically allow the use of lower vector doses to reach equivalent levels of transgene expression compared to conventional mRNA or DNA vectors [ 154 ].…”

Section: Viral Vectors To Deliver Immunomodulatory Antibodiesmentioning

confidence: 99%

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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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Checkpoint blockade meets gene therapy: Opportunities to improve response and reduce toxicity

Silva-Pilipich

Covo-Vergara

Vanrell

et al. 2023

Viral Vectors in Cancer Immunotherapy

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Local delivery of optimized nanobodies targeting the PD-1/PD-L1 axis with a self-amplifying RNA viral vector induces potent antitumor responses

Cited by 9 publications

References 51 publications

Oleuropein-driven reprogramming of the myeloid cell compartment to sensitise tumours to PD-1/PD-L1 blockade strategies

Oleuropein-driven reprogramming of the myeloid cell compartment to sensitise tumours to PD-1/PD-L1 blockade strategies

Local Delivery of Immunomodulatory Antibodies for Gastrointestinal Tumors

Checkpoint blockade meets gene therapy: Opportunities to improve response and reduce toxicity

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