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Cited by 838Cancer Immunotherapy and BiomarkersCutaneous Melanoma Detection and ManagementImmunotherapy and Immune Responses

Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma

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Amaria, Rodabe N., Reddy, Sangeetha M., Tawbi, Hussein A., Davies, Michael A., Ross, Merrick I., Glitza, Isabella C., Cormier, Janice N., Lewis, Carol +37 more·2018·Nature Medicine
DOI 10.1038/s41591-018-0197-1PMC PMC6481682
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Abstract

Preclinical studies suggest that treatment with neoadjuvant immune checkpoint blockade is associated with enhanced survival and antigen-specific T cell responses compared with adjuvant treatment1; however, optimal regimens have not been defined. Here we report results from a randomized phase 2 study of neoadjuvant nivolumab versus combined ipilimumab with nivolumab in 23 patients with high-risk resectable melanoma (NCT02519322). RECIST overall response rates (ORR), pathologic complete response rates (pCR), treatment-related adverse events (trAEs) and immune correlates of response were assessed. Treatment with combined ipilimumab and nivolumab yielded high response rates (RECIST ORR 73%, pCR 45%) but substantial toxicity (73% grade 3 trAEs), whereas treatment with nivolumab monotherapy yielded modest responses (ORR 25%, pCR 25%) and low toxicity (8% grade 3 trAEs). Immune correlates of response were identified, demonstrating higher lymphoid infiltrates in responders to both therapies and a more clonal and diverse T cell infiltrate in responders to nivolumab monotherapy. These results describe the feasibility of neoadjuvant immune checkpoint blockade in melanoma and emphasize the need for additional studies to optimize treatment regimens and to validate putative biomarkers. Neoadjuvant combination treatment with nivolumab and ipilimumab in patients with high-risk melanoma results in higher response rates than nivolumab monotherapy and warrants future optimization of dosing regimens to preserve efficacy while limiting toxicity.

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  • Analyses of melanoma samples from patients who received neoadjuvant immune checkpoint inhibitors revealed the three primary T cell infiltration patterns identified in solid tumours.

    “analyses of samples derived from patients with melanoma who received neoadjuvant ICIs112,113 have revealed the presence of the three primary patterns of T cell infiltration identified in solid tumours.”

    From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [113]

    The paper’s immune-profiling results (page unavailable in our copy) report analyses of melanoma samples taken before and during neoadjuvant checkpoint blockade and describe differences in CD8+ T-cell infiltration between responders and non-responders. They do not identify three primary patterns of T-cell infiltration; searches for those patterns and their names found no such classification in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Studies in melanoma using higher dosages of ipilimumab reported enhanced immune infiltration in responding tumors.

    “Studies in melanoma using higher dosages of ipilimumab reported enhanced immune infiltration in responding tumors17.”

    From Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial (2021) · cites this paper as [17]

  • In melanoma, a more clonal T-cell repertoire at baseline correlated with response to neoadjuvant immune checkpoint inhibitor therapy, and pre-existing high-frequency clones expanded further with treatment.

    “Amaria and colleagues17 demonstrated that a more clonal T-cell repertoire at baseline correlated with response to neoadjuvant ICI therapy in patients with melanoma, with further expansion of the pre-existing high-frequency clones with treatment.”

    From Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial (2021) · cites this paper as [17]

  • Key roles of TGF-β1 in suppressing the adaptive immune system are apparent from the lymphoproliferative autoimmune phenotype of Tgfb1−/− mice and similar phenotypes following selective ablation of TGF-β signaling components within CD4+ and CD8+ T cells.

    “Key roles of TGF-β1 in suppressing the adaptive immune system are apparent from the lymphoproliferative autoimmune phenotype of Tgfb1−/− mice197–199, and similar phenotypes following selective ablation of TGF-β signaling components within CD4+ and CD8+ T cells200.”

    From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [198]

  • Neoadjuvant immune checkpoint therapy trials have demonstrated clinical benefit in multiple tumor types including melanoma, Merkel cell carcinoma, NSCLC, MMR-deficient colorectal cancer, urothelial carcinoma, and breast cancer.

    “Clinical trials with ICT in the neoadjuvant setting have now demonstrated clinical benefit in multiple tumor types, including melanoma (173, 174), Merkel cell carcinoma (175), NSCLC (176), MMRdeficient colorectal cancer (177), urothelial carcinoma (21, 178), and breast cancer (179-181).”

    From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [173]

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Authors
Amaria, R. N., Reddy, S. M., Tawbi, H. A., Davies, M. A., Ross, M. I., Glitza, I. C., Cormier, J. N., Lewis, C., Hwu, W.-J., Hanna, E., Diab, A., Wong, M. K., Royal, R., Gross, N., Weber, R., Lai, S. Y., Ehlers, R., Blando, J., Milton, D. R., Woodman, S., Kageyama, R., Wells, D. K., Hwu, P., Patel, S. P., Lucci, A., Hessel, A., Lee, J. E., Gershenwald, J., Simpson, L., Burton, E. M., Posada, L., Haydu, L., Wang, L., Zhang, S., Lazar, A. J., Hudgens, C. W., Gopalakrishnan, V., Reuben, A., Andrews, M. C., Spencer, C. N., Prieto, V., Sharma, P., Allison, J., Tetzlaff, M. T., & Wargo, J. A.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • Parker Institute for Cancer Immunotherapy (US)
Corresponding author
Wargo, Jennifer A.
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2018-10-08
Volume
24
Issue
11
Pages
1649-1654
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-018-0197-1
PMC
PMC6481682
OpenAlex
W2894584497
Semantic Scholar
251ac2984307dc31d5a4596caa7a07c90195b1e8
Cited by
835
References
31
Citations by year
2026: 49 · 2025: 80 · 2024: 102 · 2023: 116 · 2022: 119 · 2021: 130 · 2020: 142 · 2019: 79 · 2018: 12
FWCI
34.49
Type
journal article
Language
en
Update notices
Open access
Licence
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Defense
  • Bristol-Myers Squibb
  • Nature
  • National Institutes of Health (UL1TR000371)
  • University of Texas MD Anderson Cancer Center
  • National Cancer Institute (T32CA009666, K08CA160692)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
melanoma, nivolumab, ipilimumab, combination immunotherapy, pathological complete response, T cell infiltration, lymphocyte infiltration, treatment-related adverse events, biomarkers
MeSH terms
Ipilimumab, Nivolumab, Adult, Antineoplastic Combined Chemotherapy Protocols, Female, Humans, Male, Melanoma, Middle Aged, Neoplasm Staging, Risk Factors, Disease-Free Survival, Neoadjuvant Therapy, Drug-Related Side Effects and Adverse Reactions

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