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Nucleic acid-based drugs for patients with solid tumours

Nature Reviews Clinical Oncology (2024)Cite this article

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Abstract

The treatment of patients with advanced-stage solid tumours typically involves a multimodality approach (including surgery, chemotherapy, radiotherapy, targeted therapy and/or immunotherapy), which is often ultimately ineffective. Nucleic acid-based drugs, either as monotherapies or in combination with standard-of-care therapies, are rapidly emerging as novel treatments capable of generating responses in otherwise refractory tumours. These therapies include those using viral vectors (also referred to as gene therapies), several of which have now been approved by regulatory agencies, and nanoparticles containing mRNAs and a range of other nucleotides. In this Review, we describe the development and clinical activity of viral and non-viral nucleic acid-based treatments, including their mechanisms of action, tolerability and available efficacy data from patients with solid tumours. We also describe the effects of the tumour microenvironment on drug delivery for both systemically administered and locally administered agents. Finally, we discuss important trends resulting from ongoing clinical trials and preclinical testing, and manufacturing and/or stability considerations that are expected to underpin the next generation of nucleic acid agents for patients with solid tumours.

Key points

  • Nucleic acid drugs being developed for the treatment of patients with solid tumours can be subdivided into either viral vector-mediated or non-viral nanocarrier-type approaches, with distinct safety and efficacy profiles.

  • New technologies designed to advance drug development, improve tissue tropism and optimize immune responses are rapidly emerging.

  • The tumour microenvironment poses several barriers to both intratumoural and systemically administered nucleic acid-based therapies.

  • When developing nucleic acid treatments, various translational aspects including route of administration, optimal preclinical testing, manufacturing-related aspects and scalability are all important considerations.

  • Clinical trials investigating anticancer nucleic acid-based agents typically involve repeat dosing and are often tested in combination with standard-of-care therapies.

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Fig. 1: Viral nucleic acid drugs for solid tumours typically utilize HSV and adenoviral vectors.
Fig. 2: Non-viral nucleic acid drugs for solid tumours comprise various payloads and nanocarriers.
Fig. 3: Models of non-viral delivery of nucleotides to tumour tissue.
Fig. 4: TME-related delivery barriers that influence intratumoural and intravenous drug administration.
Fig. 5: Summary features of clinical trials testing nucleic acid-based therapies in patients with solid tumours.

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Acknowledgements

The authors thank J. Tindall (Emory University, Atlanta, GA) for copyediting the manuscript. The authors also thank B. Kinkead (University of Utah, Salt Lake City, UT) for critical review. The authors gratefully acknowledge funding support from the FDA Office of Orphan Products Division and R01 DE026941.

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Authors and Affiliations

  1. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA

    Sebastian G. Huayamares, David Loughrey, Hyejin Kim & James E. Dahlman

  2. Emory University School of Medicine, Atlanta, GA, USA

    Sebastian G. Huayamares, David Loughrey, Hyejin Kim, James E. Dahlman & Eric J. Sorscher

  3. Department of Pediatrics, Emory University, Atlanta, GA, USA

    Eric J. Sorscher

  4. Winship Cancer Institute, Emory University, Atlanta, GA, USA

    Eric J. Sorscher

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  1. Sebastian G. Huayamares
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  2. David Loughrey
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  4. James E. Dahlman
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Contributions

S.G.H., D.L., E.J.S., and H.K. researched data for the article, all authors contributed substantially to discussions of content, S.G.H., D.L. and H.K. wrote the article, and all authors reviewed and/or edited the manuscript before submission.

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Correspondence to James E. Dahlman or Eric J. Sorscher.

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Competing interests

J.E.D. has acted as an adviser for GV, Nava Therapeutics and Edge Animal Health. E.J.S. has ownership interests in and serves on the Board of Directors for PNP Therapeutics, and is listed as a co-inventor on patents related to some of the technologies used in the research described in this Review (including Patent IDs 17/908,465, 08/122,321 and 08/702,181). The terms of this arrangement for E.J.S. have been evaluated and approved by Emory University in accordance with its conflict-of-interest policies. The other authors declare no competing interests.

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Nature Reviews Clinical Oncology thanks D. Peer, H. Kaufman and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Huayamares, S.G., Loughrey, D., Kim, H. et al. Nucleic acid-based drugs for patients with solid tumours. Nat Rev Clin Oncol (2024). https://doi.org/10.1038/s41571-024-00883-1

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