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Immunotherapy at Large: Balancing tumor immunity and inflammatory pathology

Nature Medicine volume 19, pages 1100–1101 (2013)Cite this article

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Gertrude Elion and George Hitchings, pioneers of cancer chemotherapy, taught that the search for selectivity in drug discovery often involved 'enlightened empiricism' together with a healthy dose of serendipity1. Two recently published clinical trials that report the remarkable antitumor effects of combination therapy using antibodies targeting programmed death-1 (PD-1) and cytotoxic T lymphocyte associated antigen-4 (CTLA-4)2,3, two negative immune regulatory molecules expressed on T cells, illustrate how these principles of drug development apply to cancer immunotherapy.

The passive transfer of tumor-reactive T cells via bone marrow transplantation and the use of tumor-selective antibodies are well-established cancer therapies, but the crafting of effective strategies to stimulate endogenous antitumor immunity has long proved elusive4. As many attempts at amplifying positive immune signaling networks failed to elicit clinically significant tumor destruction, an alternative approach aims to do the opposite—interfering with immune checkpoints that attenuate the function of activated T cells in the tumor microenvironment5. Inspired by promising findings in experimental tumor models, two large randomized studies showing that a fully human antibody to CTLA-4 (ipilimumab) prolonged survival in patients with advanced melanoma, with about 20% of treated subjects achieving durable clinical benefits (which in some cases exceeded ten years), finally took place. However, the treatment also caused a diversity of inflammatory pathologies, most commonly affecting the intestinal tract, skin and endocrine tissues, consistent with the phenotype of mice lacking CTLA-4. Serious toxicity was observed in about 20% of treated subjects, but this could be dissociated from the antitumor effects, indicating that tumor immunity and inflammatory pathology are closely related but, nonetheless, separable.

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Figure 1: The need to balance the antitumor activity and toxicity of single and combinatorial immunotherapies.

Marina Corral Spence

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Authors and Affiliations

  1. Glenn Dranoff is at the Department of Medical Oncology and Cancer Vaccine Center, and Department of Medicine, Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.,

    Glenn Dranoff

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  1. Glenn Dranoff
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Correspondence to Glenn Dranoff.

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Competing interests

G.D. receives research support from Bristol-Myers Squibb and from Novartis, where he is also a consultant. He has been a guest lecturer at Merck and Genentech.

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Dranoff, G. Immunotherapy at Large: Balancing tumor immunity and inflammatory pathology. Nat Med 19, 1100–1101 (2013). https://doi.org/10.1038/nm.3335

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