Key Points
-
A subset of patients receiving immune-checkpoint inhibitor therapy develop unconventional response patterns (termed 'pseudoprogression'), in which tumour burden decreases after an initial increase, or during or after the appearance of new lesions
-
The evaluation of pseudoprogression provides new challenges in treatment monitoring and therapeutic decision-making because it cannot be evaluated with the existing response-evaluation criteria
-
The establishment of a standardized strategy to evaluate immune-related responses in patients receiving immune-checkpoint inhibitors is extremely important
-
In addition, the development of robust biomarkers to assist prediction of response and clinical benefits of immune-checkpoint inhibitor therapy is essential to further advance the field as precision immuno-oncology
-
The therapeutic activity of immune-checkpoint inhibitors is the result of a complex interplay between multiple factors in the tumour, tumour microenvironment, and immune system, requiring a collaborative approach to translate the emerging knowledge into the clinical context
Abstract
Cancer immunotherapy using immune-checkpoint blockade (ICB) has created a paradigm shift in the treatment of advanced-stage cancers. The promising antitumour activity of monoclonal antibodies targeting the immune-checkpoint proteins CTLA-4, PD-1, and PD-L1 led to regulatory approvals of these agents for the treatment of a variety of malignancies. Patients might experience clinical benefits from treatment with these agents, despite unconventional patterns of tumour response that can be misinterpreted as disease progression, warranting a new, specific approach to evaluate responses to immunotherapy. In addition, biomarkers that can predict responsiveness to ICB are being extensively investigated to further advance precision immunotherapy. Herein, we review the biological mechanisms underlying the unconventional response patterns associated with ICB, describe strategies for the objective assessments of such responses, and also highlight the ongoing efforts to identify biomarkers, in order to guide treatment with ICB. We provide state-of-the-art knowledge of immune-related response evaluations, identify unmet needs requiring further investigations, and propose future directions to maximize the benefits of ICB therapy.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fnrclinonc.2017.88/MediaObjects/41571_2017_Article_BFnrclinonc201788_Fig1_HTML.jpg)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fnrclinonc.2017.88/MediaObjects/41571_2017_Article_BFnrclinonc201788_Fig2_HTML.jpg)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fnrclinonc.2017.88/MediaObjects/41571_2017_Article_BFnrclinonc201788_Fig3_HTML.jpg)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fnrclinonc.2017.88/MediaObjects/41571_2017_Article_BFnrclinonc201788_Fig4_HTML.jpg)
Similar content being viewed by others
References
Lenschow, D. J., Walunas, T. L. & Bluestone, J. A. CD28/B7 system of T cell costimulation. Annu. Rev. Immunol. 14, 233–258 (1996).
Ott, P. A., Hodi, F. S. & Robert, C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin. Cancer Res. 19, 5300–5309 (2013).
Nishino, M. et al. Personalized tumor response assessment in the era of molecular medicine: cancer-specific and therapy-specific response criteria to complement pitfalls of RECIST. AJR Am. J. Roentgenol. 198, 737–745 (2012).
Nishino, M., Tirumani, S. H., Ramaiya, N. H. & Hodi, F. S. Cancer immunotherapy and immune-related response assessment: the role of radiologists in the new arena of cancer treatment. Eur. J. Radiol. 84, 1259–1268 (2015).
Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Nishino, M., Gargano, M., Suda, M., Ramaiya, N. H. & Hodi, F. S. Optimizing immune-related tumor response assessment: does reducing the number of lesions impact response assessment in melanoma patients treated with ipilimumab? J. Immunother. Cancer 2, 17 (2014).
Nishino, M. et al. Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements. Clin. Cancer Res. 19, 3936–3943 (2013).
Nishino, M. et al. Immune-related response assessment during PD-1 inhibitor therapy in advanced non-small-cell lung cancer patients. J. Immunother. Cancer 4, 84 (2016).
Wolchok, J. D. et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin. Cancer Res. 15, 7412–7420 (2009).
Miller, A. B., Hoogstraten, B., Staquet, M. & Winkler, A. Reporting results of cancer treatment. Cancer 47, 207–214 (1981).
Therasse, P. et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J. Natl Cancer Inst. 92, 205–216 (2000).
Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).
Lynch, T. J. et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J. Clin. Oncol. 30, 2046–2054 (2012).
Hodi, F. S. et al. Evaluation of immune-related response criteria and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab. J. Clin. Oncol. 34, 1510–1517 (2016).
Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).
Nishino, M., Jagannathan, J. P., Ramaiya, N. H. & Van den Abbeele, A. D. Revised RECIST guideline version 1.1: what oncologists want to know and what radiologists need to know. AJR Am. J. Roentgenol. 195, 281–289 (2010).
Chiou, V. L. & Burotto, M. Pseudoprogression and immune-related response in solid tumors. J. Clin. Oncol. 33, 3541–3543 (2015).
Nishino, M., Hatabu, H., Johnson, B. E. & McLoud, T. C. State of the art: response assessment in lung cancer in the era of genomic medicine. Radiology 271, 6–27 (2014).
Nishino, M. Immune-related response evaluations during immune-checkpoint inhibitor therapy: establishing a “common language” for the new arena of cancer treatment. J. Immunother. Cancer 4, 30 (2016).
Erasmus, J. J. et al. Interobserver and intraobserver variability in measurement of non-small-cell carcinoma lung lesions: implications for assessment of tumor response. J. Clin. Oncol. 21, 2574–2582 (2003).
Nishino, M. et al. CT tumor volume measurement in advanced non-small-cell lung cancer: performance characteristics of an emerging clinical tool. Acad. Radiol. 18, 54–62 (2011).
Oxnard, G. R. et al. Variability of lung tumor measurements on repeat computed tomography scans taken within 15 minutes. J. Clin. Oncol. 29, 3114–3119 (2011).
Zhao, B. et al. Evaluating variability in tumor measurements from same-day repeat CT scans of patients with non-small cell lung cancer. Radiology 252, 263–272 (2009).
Nishino, M. et al. Immune-related tumor response dynamics in melanoma patients treated with pembrolizumab: identifying markers for clinical outcome and treatment decisions. Clin. Cancer Res. http://dx.doi.org/10.1158/1078-0432.CCR-17-0114 (2017).
Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2015).
Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).
Okada, H. et al. Immunotherapy response assessment in neuro-oncology: a report of the RANO working group. Lancet Oncol. 16, e534–e542 (2015).
Gettinger, S. N. et al. Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J. Clin. Oncol. 33, 2004–2012 (2015).
Bohnsack, O., Hoos, A. & Ludajic, K. Adaptation of the immune-related response criteria: irRECIST [abstract 1070P]. Ann. Oncol. 25, iv369 (2014).
Seymour, L. et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 18, e143–e152 (2017).
[No authors listed.] iRECIST. RECIST http://www.eortc.org/recist/irecist/ (2017).
Herbst, R. S. et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387, 1540–1550 (2016).
Hamid, O. et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369, 134–144 (2013).
Rizvi, N. A. et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 16, 257–265 (2015).
Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).
Borghaei, H. et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med. 373, 1627–1639 (2015).
Rosenberg, J. E. et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387, 1909–1920 (2016).
McDermott, D. F. et al. Atezolizumab, an anti-programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: long-term safety, clinical activity, and immune correlates from a phase Ia study. J. Clin. Oncol. 34, 833–842 (2016).
Motzer, R. J. et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J. Clin. Oncol. 33, 1430–1437 (2015).
Motzer, R. J. et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1803–1813 (2015).
McDermott, D. F. et al. Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab. J. Clin. Oncol. 33, 2013–2020 (2015).
Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).
Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015).
Daud, A. I. et al. Programmed death-ligand 1 expression and response to the anti-programmed death 1 antibody pembrolizumab in melanoma. J. Clin. Oncol. 34, 4102–4109 (2016).
Reck, M. et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375, 1823–1833 (2016).
U.S. Food and Drug Administration. Pembrolizumab (KEYTRUDA) checkpoint inhibitor. FDA https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm526430.htm (2016).
Hansen, A. R. & Siu, L. L. PD-L1 testing in cancer: challenges in companion diagnostic development. JAMA Oncol. 2, 15–16 (2016).
Sacher, A. G. & Gandhi, L. Biomarkers for the clinical use of PD-1/PD-L1 inhibitors in non-small-cell lung cancer: a review. JAMA Oncol. 2, 1217–1222 (2016).
Mahoney, K. M. et al. PD-L1 antibodies to its cytoplasmic domain most clearly delineate cell membranes in immunohistochemical staining of tumor cells. Cancer Immunol. Res. 3, 1308–1315 (2015).
McLaughlin, J. et al. Quantitative assessment of the heterogeneity of PD-L1 expression in non-small-cell lung cancer. JAMA Oncol. 2, 46–54 (2016).
Hirsch, F. R. et al. PD-L1 immunohistochemistry assays for lung cancer: results from phase 1 of the blueprint PD-L1 IHC Assay Comparison Project. J. Thorac. Oncol. 12, 208–222 (2017).
Mandal, R. & Chan, T. A. Personalized oncology meets immunology: the path toward precision immunotherapy. Cancer Discov. 6, 703–713 (2016).
Galon, J. et al. Towards the introduction of the 'Immunoscore' in the classification of malignant tumours. J. Pathol. 232, 199–209 (2014).
Remon, J., Chaput, N. & Planchard, D. Predictive biomarkers for programmed death-1/programmed death ligand immune checkpoint inhibitors in nonsmall cell lung cancer. Curr. Opin. Oncol. 28, 122–129 (2016).
Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).
Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).
Daud, A. I. et al. Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma. J. Clin. Invest. 126, 3447–3452 (2016).
Galon, J. et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964 (2006).
Galon, J. et al. Immunoscore and Immunoprofiling in cancer: an update from the melanoma and immunotherapy bridge 2015. J. Transl Med. 14, 273 (2016).
Bindea, G., Mlecnik, B., Angell, H. K. & Galon, J. The immune landscape of human tumors: implications for cancer immunotherapy. Oncoimmunology 3, e27456 (2014).
Pages, F. et al. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J. Clin. Oncol. 27, 5944–5951 (2009).
Mlecnik, B. et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J. Clin. Oncol. 29, 610–618 (2011).
Ascierto, P. A. et al. The additional facet of immunoscore: immunoprofiling as a possible predictive tool for cancer treatment. J. Transl Med. 11, 54 (2013).
Paulsen, E. E. et al. Assessing PDL-1 and PD-1 in non-small cell lung cancer: a novel immunoscore approach. Clin. Lung Cancer 18, 220–233.e8 (2017).
Shukuya, T. & Carbone, D. P. Predictive markers for the efficacy of anti-PD-1/PD-L1 antibodies in lung cancer. J. Thorac. Oncol. 11, 976–988 (2016).
Taube, J. M. et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci. Transl Med. 4, 127ra37 (2012).
Higgs, B. W. et al. High tumoral IFNg mRNA, PD-L1 protein, and combined IFNγ mRNA/PD-L1 protein expression associates with response to durvalumab (anti-PD-L1) monotherapy in NSCLC patients [abstract]. European Cancer Congress (2015).
Zaretsky, J. M. et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375, 819–829 (2016).
Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).
Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).
Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).
Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).
Rizvi, N. A. et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).
Nathanson, T. et al. Somatic mutations and neoepitope homology in melanomas treated with CTLA-4 blockade. Cancer Immunol. Res. 5, 84–91 (2017).
Martens, A. et al. Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin. Cancer Res. 22, 2908–2918 (2016).
Delyon, J. et al. Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma: an early increase in lymphocyte and eosinophil counts is associated with improved survival. Ann. Oncol. 24, 1697–1703 (2013).
Kelderman, S. et al. Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma. Cancer Immunol. Immunother. 63, 449–458 (2014).
Gebhardt, C. et al. Myeloid cells and related chronic inflammatory factors as novel predictive markers in melanoma treatment with ipilimumab. Clin. Cancer Res. 21, 5453–5459 (2015).
Ku, G. Y. et al. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer 116, 1767–1775 (2010).
Tietze, J. K. et al. The proportion of circulating CD45RO+CD8+ memory T cells is correlated with clinical response in melanoma patients treated with ipilimumab. Eur. J. Cancer 75, 268–279 (2017).
Diem, S. et al. Serum lactate dehydrogenase as an early marker for outcome in patients treated with anti-PD-1 therapy in metastatic melanoma. Br. J. Cancer 114, 256–261 (2016).
Weide, B. et al. Baseline biomarkers for outcome of melanoma patients treated with pembrolizumab. Clin. Cancer Res. 22, 5487–5496 (2016).
Nishino, M. et al. Tumor volume decrease at 8 weeks is associated with longer survival in EGFR-mutant advanced non-small-cell lung cancer patients treated with EGFR TKI. J. Thorac. Oncol. 8, 1059–1068 (2013).
Nishino, M. et al. Volumetric tumor growth in advanced non-small cell lung cancer patients with EGFR mutations during EGFR-tyrosine kinase inhibitor therapy: developing criteria to continue therapy beyond RECIST progression. Cancer 119, 3761–3768 (2013).
Nishino, M. et al. Volumetric tumor response and progression in EGFR-mutant NSCLC patients treated with erlotinib or gefitinib. Acad. Radiol. 23, 329–336 (2016).
Tavare, R. et al. An effective immuno-PET imaging method to monitor CD8-dependent responses to immunotherapy. Cancer Res. 76, 73–82 (2016).
Maute, R. L. et al. Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging. Proc. Natl Acad. Sci. USA 112, E6506–E6514 (2015).
National Institutes of Health. New drug formulary will help expedite use of agents in clinical trials. NIH https://www.nih.gov/news-events/news-releases/new-drug-formulary-will-help-expedite-use-agents-clinical-trials (2017).
Department of Health and Human Services. Cancer Immune Monitoring and Analysis Centers (CIMACs). NIH https://grants.nih.gov/grants/guide/rfa-files/RFA-CA-17-005.html (2017).
Department of Health and Human Services. Cancer Immunologic Data Commons (CIDC). NIH https://grants.nih.gov/grants/guide/rfa-files/RFA-CA-17-006.html (2017).
Acknowledgements
The work of M.N. has been supported by grant 1K23CA157631 from the National Cancer Institute.
Author information
Authors and Affiliations
Contributions
All authors researched data for the article, contributed to discussing the content of the article, and wrote, reviewed, and edited the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
M.N. is a consultant for Bristol-Myers Squibb, Toshiba Medical Systems and WorldCare Clinical, and has received research grants from Canon and the Merck Investigator Studies Program, and honoraria from Bayer. H.H. is a consultant for Toshiba Medical Systems, and has received research support from Canon, Konica-Minolta and Toshiba Medical Systems. F.S.H. has served as a non-paid consultant for Bristol-Myers Squibb, has received clinical trial support from Bristol-Myers Squibb, is an adviser and receives clinical trial support from Genentech and Merck, is a consultant for Amgen, EMD Serono and Novartis, and has a patent relating to tumour antigens (issued), and a patent related to the institution of major histocompatibility complex (MHC) class I polypeptide-related sequence A (MICA) as a target (licensed). N.H.R. declares no competing interests.
Rights and permissions
About this article
Cite this article
Nishino, M., Ramaiya, N., Hatabu, H. et al. Monitoring immune-checkpoint blockade: response evaluation and biomarker development. Nat Rev Clin Oncol 14, 655–668 (2017). https://doi.org/10.1038/nrclinonc.2017.88
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrclinonc.2017.88
This article is cited by
-
S100A9+CD14+ monocytes contribute to anti-PD-1 immunotherapy resistance in advanced hepatocellular carcinoma by attenuating T cell-mediated antitumor function
Journal of Experimental & Clinical Cancer Research (2024)
-
A glutamine tug-of-war between cancer and immune cells: recent advances in unraveling the ongoing battle
Journal of Experimental & Clinical Cancer Research (2024)
-
Characterizing and forecasting neoantigens-resulting from MUC mutations in COAD
Journal of Translational Medicine (2024)
-
Tumor immune dysfunction and exclusion subtypes in bladder cancer and pan-cancer: a novel molecular subtyping strategy and immunotherapeutic prediction model
Journal of Translational Medicine (2024)
-
Identifying microRNAs associated with tumor immunotherapy response using an interpretable machine learning model
Scientific Reports (2024)