Intratumoral immunostimulatory AdCD40L gene therapy in patients with advanced solid tumors

Irenaeus, Sandra; Hellström, Vivan; Wenthe, Jessica; Krause, Johan; Sundín, Anders; Åhlström, Håkan; Tufveson, Gunnar; Tötterman, Thomas H.; Loskog, Angelica; Ullenhag, Gustav

doi:10.1038/s41417-020-00271-8

Cited by 5 publications

(1 citation statement)

References 14 publications

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“…49,50 Hence, CD40L has been incorporated into a replication-defective Ad vector, FGAdCD40L, which was able to control tumor growth in immunocompetent murine models 51 and determined to be a safe treatment option for patients with solid cancers, alone or in combination with cyclophosphamide. 52,53 To bolster the effect of CD40L, the replication-competent vector LOAd703 was developed to express two co-stimulatory molecules: first, CD40L featuring a trimerized membrane-bound isoleucine zipper motif (TMZ-CD40L), and second, 4-1BBL. The 4-1BB/4-BBL interaction between T cells and APCs provides a co-stimulatory signal that leads to T cell activation, proliferation, and the production and excretion of cytokines, such as interleukin-2 (IL-2) and IFN-g. 48 LOAd703 is currently being tested in clinical trials for safety and efficacy in several solid tumor types (NCT03555149, NCT03225989, NCT02705196, and NCT04123470).…”

Section: Clinical Trials With Unarmed Oadsmentioning

confidence: 99%

Current development in adenoviral vectors for cancer immunotherapy

Biegert¹,

Shaw²,

Suzuki³

2021

Molecular Therapy - Oncolytics

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Adenoviruses are well characterized and thus easily modified to generate oncolytic vectors that directly lyse tumor cells and can be "armed" with transgenes to promote lysis, antigen presentation, and immunostimulation. Oncolytic adenoviruses (OAds) are safe, versatile, and potent immunostimulants in patients. Since transgene expression is restricted to the tumor, adenoviral transgenes overcome the toxicities and short half-life of systemically administered cytokines, immune checkpoint blockade molecules, and bispecific T cell engagers. While OAds expressing immunostimulatory molecules ("armed" OAds) have demonstrated anti-tumor potential in preclinical solid tumor models, the efficacy has not translated into significant clinical outcomes as a monotherapy. However, OAds synergize with established standards of care and novel immunotherapeutic agents, providing a multifaceted means to address complexities associated with solid tumors. Critically, armed OAds revitalize endogenous and adoptively transferred immune cells while simultaneously enhancing their anti-tumor function. To properly evaluate these novel vectors and reduce the gap in the cycle between bench-to-bedside and back, improving model systems must be a priority. The future of OAds will involve a multidimensional approach that provides immunostimulatory molecules, immune checkpoint blockade, and/or immune engagers in concert with endogenous and exogenous immune cells to initiate durable and comprehensive anti-tumor responses.

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Section: Clinical Trials With Unarmed Oadsmentioning

confidence: 99%

Current development in adenoviral vectors for cancer immunotherapy

Biegert¹,

Shaw²,

Suzuki³

2021

Molecular Therapy - Oncolytics

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Progress in the treatment of drug-loaded nanomaterials in renal cell carcinoma

Li,

Wu,

Zhang

et al. 2023

Biomedicine & Pharmacotherapy

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CD40 stimulation as a molecular adjuvant for cancer vaccines and other immunotherapies

Bullock

2021

Cell Mol Immunol

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The substantial advances attained by checkpoint blockade immunotherapies have driven an expansion in the approaches used to promote T cell access to the tumor microenvironment to provide targets for checkpoint immunotherapy. Inherent in any T cell response to a tumor antigen is the capacity of dendritic cells to initiate and support such responses. Here, the rationale and early immunobiology of CD40 as a master regulator of dendritic cell activation is reviewed, with further contextualization and appreciation for the role of CD40 stimulation not only in cancer vaccines but also in other contemporary immune-oncology approaches.

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Intratumoral immunostimulatory AdCD40L gene therapy in patients with advanced solid tumors

Cited by 5 publications

References 14 publications

Current development in adenoviral vectors for cancer immunotherapy

Current development in adenoviral vectors for cancer immunotherapy

Progress in the treatment of drug-loaded nanomaterials in renal cell carcinoma

CD40 stimulation as a molecular adjuvant for cancer vaccines and other immunotherapies

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