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  • Review Article
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Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways

Nature Reviews Clinical Oncology volume 19, pages 37–50 (2022)Cite this article

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Abstract

The discovery and clinical implementation of immune-checkpoint inhibitors (ICIs) targeting CTLA4, PD-1 and PD-L1 has revolutionized the treatment of cancer, as recognized by the 2018 Nobel Prize for Medicine and Physiology. This groundbreaking new approach has improved the outcomes of patients with various forms of advanced-stage cancer; however, the majority of patients receiving these therapies, even in combination, do not derive clinical benefit. Further development of agents targeting additional immune checkpoints, co-stimulatory receptors and/or co-inhibitory receptors that control T cell function is therefore critical. In this Review, we discuss the translational potential and clinical development of agents targeting both co-stimulatory and co-inhibitory T cell receptors. Specifically, we describe their mechanisms of action, and provide an overview of ongoing clinical trials involving novel ICIs including those targeting LAG3, TIM3, TIGIT and BTLA as well as agonists of the co-stimulatory receptors GITR, OX40, 41BB and ICOS. We also discuss several additional approaches, such as harnessing T cell metabolism, in particular via adenosine signalling, inhibition of IDO1, and targeting changes in glucose and fatty acid metabolism. We conclude that further efforts are needed to optimize the timing of combination ICI approaches and, most importantly, to individualize immunotherapy based on both patient-specific and tumour-specific characteristics.

Key points

  • Immune-checkpoint inhibitors (ICIs) have revolutionized cancer therapy, although clinically approved agents are currently restricted to those targeting PD-1/PD-L1 or CTLA4. The addition of therapies targeting a wider range of immune checkpoints will enable improved outcomes.

  • Among co-inhibitory immune checkpoints, targets include LAG3, TIM3, TIGIT and BTLA, with agents targeting LAG3 currently the most advanced in terms of clinical development.

  • Antibodies against co-stimulatory targets, such as GITR, OX40, 41BB and ICOS, have considerable potential to complement the currently available ICIs, although optimizing the timing of administration will be important.

  • Changes in tumour cell and T cell metabolism are a source of additional targets, both of which have highly promising preclinical data available, albeit with only modest success in clinical trials thus far.

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Fig. 1: The role of Fcγ receptor (FcγR) engagement.
Fig. 2: T cell metabolism and interactions with co-signalling receptors.

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Acknowledgements

The work of the authors is supported by the Ludwig Institute for Cancer Research, NIH/NCI Cancer Center Support Grant P30 CA008748, the Parker Institute for Cancer Immunotherapy and Swim Across America. The work of L.K. is also supported by the Swiss National Science Foundation.

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Authors and Affiliations

  1. Ludwig Collaborative and Swim Across America Laboratory, MSK, New York, NY, USA

    Lukas Kraehenbuehl, Chien-Huan Weng, Shabnam Eghbali, Jedd D. Wolchok & Taha Merghoub

  2. Parker Institute for Cancer Immunotherapy, MSK, New York, NY, USA

    Lukas Kraehenbuehl, Chien-Huan Weng, Shabnam Eghbali, Jedd D. Wolchok & Taha Merghoub

  3. Human Oncology and Pathogenesis Program, MSK, New York, NY, USA

    Lukas Kraehenbuehl, Chien-Huan Weng, Shabnam Eghbali, Jedd D. Wolchok & Taha Merghoub

  4. Department of Medicine, MSK, New York, NY, USA

    Lukas Kraehenbuehl, Jedd D. Wolchok & Taha Merghoub

  5. Weill Cornell Medicine, New York, NY, USA

    Shabnam Eghbali, Jedd D. Wolchok & Taha Merghoub

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Correspondence to Taha Merghoub.

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Competing interests

S.E. has acted as a consultant for Cabaletta Bio. J.D.W. has acted as a consultant for Adaptive Biotech, Amgen, Apricity, Arsenal IO, Ascentage Pharma, Astellas, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Chugai, Daiichi Sankyo, Dragonfly, Eli Lilly, Elucida, F Star, Georgiamune, Idera, Imvaq, Kyowa Hakko Kirin, Linneaus, Maverick Therapeutics, Merck, Neon Therapeutics, Polynoma, Psioxus, Recepta, Sellas, Serametrix, Surface Oncology, Syndax, Syntalogic, Takara Bio, Trieza, Truvax, Trishula and Werewolf Therapeutics, has received research funding from Bristol Myers Squibb and Sephora, holds equity in Adaptive Biotechnologies, Apricity, Arsenal IO, Beigene, Georgiamune, Imvaq, Linneaus and Tizona Pharmaceuticals, and is listed as a co-inventor on patents relating to the use of anti-CD40 agonistic monoclonal antibodies fused with monophosphoryl lipid A (MPL) for cancer therapy, alphavirus replicon particles expressing TRP2, anti-PD-1 antibodies, anti-CTLA4 antibodies, anti-GITR antibodies and methods of use thereof, CAR T cells targeting differentiation antigens as a means to treat cancer, engineered vaccinia viruses for cancer immunotherapy, identifying and treating patients at risk of checkpoint blockade-associated colitis, genomic signatures to identify responders to ipilimumab in melanoma, immunosuppressive follicular helper-like T cells modulated by immune-checkpoint blockade and phosphatidylserine-targeting agents and uses thereof for adoptive T cell therapies, myeloid-derived suppressor cell (MDSC) assays, Newcastle Disease viruses for cancer therapy, and xenogeneic DNA vaccines. T.M. has acted as a consultant for Immunogenesis, Immunos Therapeutics and Pfizer, has received research support from Adaptive Biotechnologies, Aprea, Bristol Myers Squibb, Infinity Pharmaceuticals, Kyn Therapeutics, Leap Therapeutics, Peregrine Pharmaceuticals and Surface Oncology, is listed as a co-inventor on patents relating to the use of oncolytic viral therapy, alphavirus-based vaccines, antibodies targeting CD40, GITR, OX40, PD-1 and CTLA-4 and neo-antigen modelling, and is a cofounder of and holds an equity in IMVAQ Therapeutics. L.K. and C.-H.W. declare no competing interests.

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Kraehenbuehl, L., Weng, CH., Eghbali, S. et al. Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways. Nat Rev Clin Oncol 19, 37–50 (2022). https://doi.org/10.1038/s41571-021-00552-7

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