Neoadjuvant checkpoint inhibition, in which the therapy is administered before surgery, is a promising new approach to managing bulky but resectable melanoma, and is also being explored in other cancers. This strategy has a high pathologic response rate, which correlates with survival outcomes. The fact that biopsies are routinely available provides a unique opportunity for understanding the responses to therapy and carrying out reverse translation in which these data are used to select therapies in the clinic or in trials that are more likely to improve patient outcomes. In this Perspective, we discuss the rationale for neoadjuvant immunotherapy in resectable solid tumors based on preclinical and human translational data, summarize the results of recent clinical trials and ongoing research, and focus on future directions for enhancing reverse translation.
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2015).
Wolchok, J. D. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377, 1345–1356 (2017).
Schachter, J. et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet 390, 1853–1862 (2017).
Bellmunt, J. et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N. Engl. J. Med. 376, 1015–1026 (2017).
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).
Borghaei, H. et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med. 373, 1627–1639 (2015).
Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med. 378, 1277–1290 (2018).
Eggermont, A. M. et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N. Engl. J. Med. 375, 1845–1855 (2016).
Eggermont, A. M. M. et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N. Engl. J. Med. 378, 1789–1801 (2018).
Weber, J. et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N. Engl. J. Med. 377, 1824–1835 (2017).
Bloemendal, M. et al. Early recurrence in completely resected IIIB and IIIC melanoma warrants restaging prior to adjuvant therapy. Ann. Surg. Oncol. 26, 3945–3952 (2019).
Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018).
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Huang, A. C. et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545, 60–65 (2017).
Joseph, R. W. et al. Baseline tumor size is an independent prognostic factor for overall survival in patients with melanoma treated with pembrolizumab. Clin. Cancer Res. 24, 4960–4967 (2018).
Lee, J. H. J. et al. Metastasis-specific patterns of response and progression with anti-PD-1 treatment in metastatic melanoma. Pigment Cell Melanoma Res. 31, 404–410 (2018).
Akondy, R. S. et al. The yellow fever virus vaccine induces a broad and polyfunctional human memory CD8+ T cell response. J. Immunol. 183, 7919–7930 (2009).
Akondy, R.S. et al. Initial viral load determines the magnitude of the human CD8 T cell response to yellow fever vaccination. Proc. Natl Acad. Sci. USA 112, 3050–3055 (2015).
Liu, J. et al. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov. 6, 1382–1399 (2016).
Blank, C. U. et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat. Med. 24, 1655–1661 (2018).
Tetzlaff, M. T. et al. Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma. Ann. Oncol. 29, 1861–1868 (2018).
Amaria, R. N. et al. Neoadjuvant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium. Lancet Oncol. 20, e378–e389 (2019).
Amaria, R. N. et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat. Med. 24, 1649–1654 (2018).
Forde, P. M. et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N. Engl. J. Med. 378, 1976–1986 (2018).
Spranger, S., Dai, D., Horton, B. & Gajewski, T. F. Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell 31, 711–723.e4 (2017).
Liu, J. et al. Timing of neoadjuvant immunotherapy in relation to surgery is crucial for outcome. OncoImmunol. 8, e1581530 (2019).
Huang, A. C. et al. A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma. Nat. Med. 25, 454–461 (2019).
Lui, V. K., Karpuchas, J., Dent, P. B., McCulloch, P. B. & Blajchman, M. A. Cellular immunocompetence in melanoma: effect of extent of disease and immunotherapy. Br. J. Cancer 32, 323–330 (1975).
Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).
Chen, G. et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 560, 382–386 (2018).
Poggio, M. et al. Suppression of exosomal PD-L1 induces systemic anti-tumor immunity and memory. Cell 177, 414–427.e13 (2019).
Zelenay, S. et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257–1270 (2015).
Tatsumi, T. et al. Disease-associated bias in T helper type 1 (Th1)/Th2 CD4+ T cell responses against MAGE-6 in HLA-DRB10401+ patients with renal cell carcinoma or melanoma. J. Exp. Med. 196, 619–628 (2002).
Chalabi, M. et al. LBA37_PR Neoadjuvant ipilimumab plus nivolumab in early stage colon cancer. Ann. Oncol. https://doi.org/10.1093/annonc/mdy424.047. (2018).
Shrotriya, S., Walsh, D., Bennani-Baiti, N., Thomas, S. & Lorton, C. C-reactive protein is an important biomarker for prognosis tumor recurrence and treatment response in adult solid tumors: a systematic review. PLoS One 10, e0143080 (2015).
Weber, J. S. et al. Serum IL-6 and CRP as prognostic factors in melanoma patients receiving single agent and combination checkpoint inhibition. J. Clin. Oncol. 37, 100 (2019).
Kelderman, S. et al. Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma. Cancer Immunol. Immunother. 63, 449–458 (2014).
Jansen, Y. et al. Correlation between baseline characteristics and clinical outcome of patients with advanced melanoma treated with pembrolizumab (PEMBRO). Ann. Oncol. 27, 379–400 (2016).
Warburg, O., Wind, F. & Negelein, E. The metabolism of tumors in the body. J. Gen. Physiol. 8, 519–530 (1927).
Le Bourgeois, T. et al. Targeting T cell metabolism for improvement of cancer immunotherapy. Front. Oncol. 8, 237 (2018).
Brand, A. et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 24, 657–671 (2016).
Renner, K. et al. Metabolic plasticity of human T cells: preserved cytokine production under glucose deprivation or mitochondrial restriction, but 2-deoxy-glucose affects effector functions. Eur. J. Immunol. 45, 2504–2516 (2015).
Blank, C. U., Haanen, J. B., Ribas, A. & Schumacher, T. N. The “cancer immunogram”. Science 352, 658–660 (2016).
O’Donnell, J. S., Hoefsmit, E. P., Smyth, M. J., Blank, C. U. & Teng, M. W. L. The promise of neoadjuvant immunotherapy and surgery for cancer treatment. Clin. Cancer Res. 25, 5743–5751 (2019).
Schermers, B. et al. Surgical removal of the index node marked using magnetic seed localization to assess response to neoadjuvant immunotherapy in patients with stage III melanoma. Br. J. Surg. 106, 519–522 (2019).
Reijers, I. L. M. et al. Personalized response-driven adjuvant therapy after combination ipilimumab and nivolumab in high-risk resectable stage III melanoma: PRADO trial. J. Clin. Oncol. 37, TPS9605 (2019).
Rozeman, E. A. et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. Lancet Oncol. 20, 948–960 (2019).
Blank, C. U. et al. (Neo-)adjuvant ipilimumab + nivolumab (IPI + NIVO) in palpable stage 3 melanoma—initial data from the OpACIN trial. Ann. Oncol. 27, 1–36 (2016).
Shakhnovich, V. It’s time to reverse our thinking: the reverse translation research paradigm. Clin. Transl. Sci. 11, 98–99 (2018).
Chen, H. et al. Anti-CTLA-4 therapy results in higher CD4+ICOShi T cell frequency and IFN-γ levels in both nonmalignant and malignant prostate tissues. Proc. Natl Acad. Sci. USA 106, 2729–2734 (2009).
Fan, X., Quezada, S. A., Sepulveda, M. A., Sharma, P. & Allison, J. P. Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy. J. Exp. Med. 211, 715–725 (2014).
34th Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2019): part 1. J. Immunother. Cancer 7, 282 (2019).
Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).
Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).
Lemery, S., Keegan, P. & Pazdur, R. First FDA approval agnostic of cancer site—when a biomarker defines the indication. N. Engl. J. Med. 377, 1409–1412 (2017).
Overman, M. J. et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J. Clin. Oncol. 36, 773–779 (2018).
Menzies, A. M. et al. Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC). J. Clin. Oncol. 37, 9503 (2019).
Cortazar, P. et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384, 164–172 (2014).
Petrelli, F. et al. Correlation of pathologic complete response with survival after neoadjuvant chemotherapy in bladder cancer treated with cystectomy: a meta-analysis. Eur. Urol. 65, 350–357 (2014).
Park, I. J. et al. Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J. Clin. Oncol. 30, 1770–1776 (2012).
Lorenzen, S. et al. Impact of pathologic complete response on disease-free survival in patients with esophagogastric adenocarcinoma receiving preoperative docetaxel-based chemotherapy. Ann. Oncol. 24, 2068–2073 (2013).
Ajani, J. A. et al. Paclitaxel-based chemoradiotherapy in localized gastric carcinoma: degree of pathologic response and not clinical parameters dictated patient outcome. J. Clin. Oncol. 23, 1237–1244 (2005).
von Minckwitz, G. et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J. Clin. Oncol. 30, 1796–1804 (2012).
Stein, J. E. et al. Pan-tumor pathologic scoring of response to PD-(L)1 blockade. Clin. Cancer Res. 26, 545–551 (2020).
Long, G. V. et al. Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB-C, BRAF(V600) mutation-positive melanoma (NeoCombi): a single-arm, open-label, single-centre, phase 2 trial. Lancet Oncol. 20, 961–971 (2019).
Hackshaw, A., Knight, A., Barrett-Lee, P. & Leonard, R. Surrogate markers and survival in women receiving first-line combination anthracycline chemotherapy for advanced breast cancer. Br. J. Cancer 93, 1215–1221 (2005).
Khunger, A. et al. Neoadjuvant therapy of locally/regionally advanced melanoma. Ther. Adv. Med. Oncol. 11, 1758835919866959 (2019).
Cottrell, T. R. et al. Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC). Ann. Oncol. 29, 1853–1860 (2018).
Dieu-Nosjean, M. C. et al. Tertiary lymphoid structures, drivers of the anti-tumor responses in human cancers. Immunol. Rev. 271, 260–275 (2016).
32nd Annual Meeting and Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2017): part one. J. Immunother. Cancer 5, 86 (2017).
Al-Shibli, K. I. et al. Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin. Cancer Res. 14, 5220–5227 (2008).
Sharma, P. et al. CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc. Natl Acad. Sci. USA 104, 3967–3972 (2007).
Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).
Rozeman, E. A. et al. (Neo-)adjuvant ipilimumab + nivolumab (IPI + NIVO) in palpable stage 3 melanoma – updated relapse free survival (rfs) data from the OpACIN trial and first biomarker analyses. Ann. Oncol. 28, v428–v448 (2017).
Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015).
Ayers, M. et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J. Clin. Invest. 127, 2930–2940 (2017).
Böttcher, J. P. et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 172, 1022–1037.e14 (2018).
Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).
Hugo, W. et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 165, 35–44 (2016).
Yarchoan, M., Hopkins, A. & Jaffee, E. M. Tumor mutational burden and response rate to PD-1 inhibition. N. Engl. J. Med. 377, 2500–2501 (2017).
Schumacher, T. N., Scheper, W. & Kvistborg, P. Cancer Neoantigens. Annu. Rev. Immunol. 37, 173–200 (2019).
Rozeman, E. A. et al. LBA75 18-months relapse-free survival (RFS) and biomarker analyses of OpACIN-neo: A study to identify the optimal dosing schedule of neoadjuvant (neoadj) ipilimumab (IPI) + nivolumab (NIVO) in stage III melanoma. Ann. Oncol. 30(5), v910 (2019).
Cascone, T. et al. Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for resectable non-small cell lung cancer (NSCLC): clinical and correlative results from the NEOSTAR study. J. Clin. Oncol. 37, 8504 (2019).
van der Heijden, M. S. et al. 904PD Pre-operative ipilimumab and nivolumab in locoregionally advanced, stage III, urothelial cancer (NABUCCO). Ann. Oncol. 30, v358 (2019).
Blank, C. U. et al. 1313PD 3-year relapse-free survival (RFS), overall survival (OS) and long-term toxicity of (neo)adjuvant ipilimumab (IPI) + nivolumab (NIVO) in macroscopic stage III melanoma (OpACIN trial). Ann. Oncol. 30, v535 (2019).
Voorwerk, L. et al. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. Nat. Med. 25, 920–928 (2019).
Wilmott, J. S. et al. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin. Cancer Res. 18, 1386–1394 (2012).
Ribas, A. et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell 170, 1109–1119.e10 (2017).
Gonzalez, M. et al. 1256TiP A phase II, randomised, open label study of neoadjuvant pembrolizumab with/without dabrafenib and trametinib (D+T) in BRAF V600 mutant resectable stage IIIB/C/D melanoma (NeoTrio trial). Ann. Oncol. 28, v428–v448 (2017).
Gonzalez, M. et al. Determining optimal sequencing of anti-PD-1 and BRAF-targeted therapy: a phase II randomised study of neoadjuvant pembrolizumab with/without dabrafenib and trametinib (D+T) in BRAF V600 mutant resectable stage IIIb/c/d melanoma (NeoTrio trial). J. Clin. Oncol. 36, TPS9604 (2018).
Frederick, D. T. et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin. Cancer Res. 19, 1225–1231 (2013).
Deken, M. A. et al. Targeting the MAPK and PI3K pathways in combination with PD1 blockade in melanoma. OncoImmunology 5, e1238557 (2016).
Tokunaga, R. et al. CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation—a target for novel cancer therapy. Cancer Treat. Rev. 63, 40–47 (2018).
Pradelli, E. et al. Antagonism of chemokine receptor CXCR3 inhibits osteosarcoma metastasis to lungs. Int. J. Cancer 125, 2586–2594 (2009).
Blackburn, S. D. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10, 29–37 (2009).
Diab, A. et al. NKTR-214 (CD122-biased agonist) plus nivolumab in patients with advanced solid tumors: Preliminary phase 1/2 results of PIVOT. J. Clin. Oncol. 36, 3006 (2018).
Naing, A. et al. PEGylated IL-10 (pegilodecakin) induces systemic immune activation, CD8+ T cell invigoration and polyclonal T cell expansion in cancer patients. Cancer Cell 34, 775–791.e3 (2018).
Tarhini, A. et al. Neoadjuvant ipilimumab (3 mg/kg or 10 mg/kg) and high dose IFN-α2b in locally/regionally advanced melanoma: safety, efficacy and impact on T-cell repertoire. J. Immunother. Cancer 6, 112 (2018).
G.V.L. is supported by an NHMRC Practitioner Fellowship and the University of Sydney Medical Foundation.
J.M.V. declares no conflict of interests. Both G.V.L. and C.U.B. declare no direct conflicts with this work. For unrelated conflicts, G.V.L. is a consultant advisor to Aduro, Amgen, BMS, Mass-Array, Pierre-Fabre, Novartis, MERCK MSD and Roche. C.U.B. has received research funding from BMS, Novartis and NanoString; has an advisory role for BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre and Third Rock Ventures; and is a stock owner of Uniti Cars, Neon Therapeutics and Forty Seven.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Versluis, J.M., Long, G. & Blank, C.U. Learning from clinical trials of neoadjuvant checkpoint blockade. Nat Med 26, 475–484 (2020). https://doi.org/10.1038/s41591-020-0829-0