Improving cancer immunotherapy using nanomedicines: progress, opportunities and challenges

Abstract

Multiple nanotherapeutics have been approved for patients with cancer, but their effects on survival have been modest and, in some examples, less than those of other approved therapies. At the same time, the clinical successes achieved with immunotherapy have revolutionized the treatment of multiple advanced-stage malignancies. However, the majority of patients do not benefit from the currently available immunotherapies and many develop immune-related adverse events. By contrast, nanomedicines can reduce — but do not eliminate — the risk of certain life-threatening toxicities. Thus, the combination of these therapeutic classes is of intense research interest. The tumour microenvironment (TME) is a major cause of the failure of both nanomedicines and immunotherapies that not only limits delivery, but also can compromise efficacy, even when agents accumulate in the TME. Coincidentally, the same TME features that impair nanomedicine delivery can also cause immunosuppression. In this Perspective, we describe TME normalization strategies that have the potential to simultaneously promote the delivery of nanomedicines and reduce immunosuppression in the TME. Then, we discuss the potential of a combined nanomedicine-based TME normalization and immunotherapeutic strategy designed to overcome each step of the cancer-immunity cycle and propose a broadly applicable ‘minimal combination’ of therapies designed to increase the number of patients with cancer who are able to benefit from immunotherapy.

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Fig. 1: Cancer-immunity TME phenotypes affecting responsiveness to immunotherapy18.
Fig. 2: How nanomedicines can be used to perpetuate the cancer-immunity cycle.
Fig. 3: Normalizing the TME to increase the penetration of combination therapies.

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Acknowledgements

The authors apologize to authors whose work could not be cited owing to space constraints. In general, the authors focused on systemically and locally administered particle-based therapies, so the scope of this article does not include certain nanotechnologies developed for the delivery of immunotherapies, such as injectable scaffolds, which are currently under clinical investigation (NCT01753089). The authors thank M. Kalli (University of Cyprus) for assistance with the preparation of the figures, K. Kakimi (University of Tokyo) for helpful discussions and A. Osada (NanoCarrier Co., Ltd), Y. Huang (Cyrus Tang Haematology Center), M. R. Martin (University of Tokyo), V. Melo (University of Tokyo) and Z. Amoozgar and D. Fukumura (Massachusetts General Hospital) for critical input into the manuscript. The research leading to these results has received funding from the National Foundation for Cancer Research, the Ludwig Center at Harvard, the Jane’s Trust Foundation, the Advanced Medical Research Foundation, the US National Cancer Institute grants P01-CA080124, R01-CA098706, R01-CA208205 and U01-CA224348 and the US Department of Defense Breast Cancer Research Program Innovator Award W81XWH-10-1-0016 (to R.K.J.), the European Research Council grant 838414 and the INFRASTRUCTURE/1216/0052 grant co-financed by the European Regional Development Fund and the Republic of Cyprus through the Research Promotion Foundation (to T.S.), and the Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research B (JP16H03179) and Young Scientists B (JP25750172) to H.C. R.K.J. is a recipient of an Outstanding Investigator Award R35-CA197743 from the U.S. National Cancer Institute. J.D.M was supported by a JSPS Postdoctoral Fellowship, P16731.

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J.D.M. researched data for this article. All authors made a substantial contribution to the discussion of content, writing the manuscript and reviewing and/or editing the manuscript prior to submission.

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Correspondence to Triantafyllos Stylianopoulos or Rakesh K. Jain.

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J.D.M. became a full-time employee of NanoCarrier during the preparation of this manuscript. R.K.J. has received honoraria from Amgen, has acted as a consultant for Chugai, Merck, Ophthotech, Pfizer, SPARC, SynDevRx and XTuit, owns equity in Enlight, Ophthotech and SynDevRx and serves on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund and Tekla World Healthcare Fund. H.C. and T.S. declare no competing interests.

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Martin, J.D., Cabral, H., Stylianopoulos, T. et al. Improving cancer immunotherapy using nanomedicines: progress, opportunities and challenges. Nat Rev Clin Oncol 17, 251–266 (2020). https://doi.org/10.1038/s41571-019-0308-z

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