Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Clinical & Experimental Metastasis
Published in: Clinical & Experimental Metastasis 1/2022

Open Access 01-02-2022 | Checkpoint Inhibitors | Review

Cancer neoantigens as potential targets for immunotherapy

Authors: Weijie Ma, Brian Pham, Tianhong Li

Published in: Clinical & Experimental Metastasis | Issue 1/2022

Login to get access

Abstract

Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programed cell death protein 1 (PD-1) or its ligand PD-L1 have increased the survival and cure rates for patients with many cancer types in various disease settings. However, only 10–40% of cancer patients benefited from these ICIs, of whom ~ 20% have treatment interruption or discontinuation due to immune-related adverse events that can be severe and even fatal. Current efforts in precision immunotherapy are focused on improving biomarker-based patient selection for currently available ICIs and exploring rationale combination and novel strategies to expand the benefit of immunotherapy to more cancer patients. Neoantigens arise from ~ 10% of the non-synonymous somatic mutations in cancer cells, are important targets of T cell-mediated anti-tumor immunity for individual patients. Advances in next generation sequencing technology and computational bioinformatics have enable the identification of genomic alterations, putative neoantigens, and gene expression profiling in individual tumors for personal oncology in a rapid and cost-effective way. Among the genomic biomarkers, defective mismatch DNA repair (dMMR), microsatellite instability high (MSI-H) and high tumor mutational burden (H-TMB) have received FDA approvals for selecting patients for ICI treatment. All these biomarkers measure high neoantigen load and tumor antigenicity, supporting the current development of neoantigen-based personalized cancer vaccines for patients with high TMB tumor. Several studies have shown neoantigen vaccines are feasible, safe and have promising clinical activity in patients with high TMB tumors in both metastatic and adjuvant settings. This review summarizes the emerging data and technologies for neoantigen-based personalized immunotherapy.
Literature
1.
Chen DS, Irving BA, Hodi FS (2012) Molecular pathways: next-generation immunotherapy–inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res 18(24):6580–6587PubMedCrossRef
2.
3.
Jager E, Jager D, Knuth A (2003) Antigen-specific immunotherapy and cancer vaccines. Int J Cancer 106(6):817–820PubMedCrossRef
4.
5.
Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39(1):1–10PubMedCrossRef
6.
Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S et al (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375(19):1823–1833PubMedCrossRef
7.
Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, Felip E, van den Heuvel MM, Ciuleanu TE, Badin F et al (2017) First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med 376(25):2415–2426PubMedPubMedCentralCrossRef
8.
Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M et al (2017) Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 377(20):1919–1929CrossRef
9.
Vaddepally RK, Kharel P, Pandey R, Garje R, Chandra AB (2020) Review of indications of FDA-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence. Cancers (Basel) 12(3):738CrossRef
10.
Ahmed SR, Petersen E, Patel R, Migden MR (2019) Cemiplimab-rwlc as first and only treatment for advanced cutaneous squamous cell carcinoma. Expert Rev Clin Pharmacol 12(10):947–951PubMedCrossRef
11.
Horn L, Mansfield AS, Szczesna A, Havel L, Krzakowski M, Hochmair MJ, Huemer F, Losonczy G, Johnson ML, Nishio M et al (2018) First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med 379(23):2220–2229PubMedCrossRef
12.
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R et al (2019) Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 381(16):1535–1546PubMedCrossRef
13.
Baas P, Scherpereel A, Nowak AK, Fujimoto N, Peters S, Tsao AS, Mansfield AS, Popat S, Jahan T, Antonia S et al (2021) First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet 397(10272):375–386PubMedCrossRef
14.
El-Osta H, Jafri S (2019) Predictors for clinical benefit of immune checkpoint inhibitors in advanced non-small-cell lung cancer: a meta-analysis. Immunotherapy 11(3):189–199PubMedCrossRef
15.
Ma W, Gilligan BM, Yuan J, Li T (2016) Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy. J Hematol Oncol 9(1):47PubMedPubMedCentralCrossRef
16.
Chen JA, Ma W, Yuan J, Li T (2020) Translational biomarkers and rationale strategies to overcome resistance to immune checkpoint inhibitors in solid tumors. Cancer Treat Res 180:251–279PubMedCrossRef
17.
18.
Hellmann MD, Rizvi NA, Goldman JW, Gettinger SN, Borghaei H, Brahmer JR, Ready NE, Gerber DE, Chow LQ, Juergens RA et al (2017) Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol 18(1):31–41PubMedCrossRef
19.
Pillai RN, Behera M, Owonikoko TK, Kamphorst AO, Pakkala S, Belani CP, Khuri FR, Ahmed R, Ramalingam SS (2018) Comparison of the toxicity profile of PD-1 versus PD-L1 inhibitors in non-small cell lung cancer: a systematic analysis of the literature. Cancer 124(2):271–277PubMedCrossRef
20.
Remon J, Mezquita L, Corral J, Vilariño N, Reguart N (2018) Immune-related adverse events with immune checkpoint inhibitors in thoracic malignancies: focusing on non-small cell lung cancer patients. J Thorac Dis 10(Suppl 13):S1516–S1533PubMedPubMedCentralCrossRef
21.
22.
Pan C, Liu H, Robins E, Song W, Liu D, Li Z, Zheng L (2020) Next-generation immuno-oncology agents: current momentum shifts in cancer immunotherapy. J Hematol Oncol 13(1):29PubMedPubMedCentralCrossRef
23.
Zhang Y, Chen L (2016) Classification of advanced human cancers based on tumor immunity in the MicroEnvironment (TIME) for cancer immunotherapy. JAMA Oncol 2(11):1403–1404PubMedPubMedCentralCrossRef
24.
Spranger S (2016) Mechanisms of tumor escape in the context of the T-cell-inflamed and the non-T-cell-inflamed tumor microenvironment. Int Immunol 28(8):383–391PubMedPubMedCentralCrossRef
25.
Maleki Vareki S (2018) High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors. J Immunother Cancer 6(1):157PubMedPubMedCentralCrossRef
26.
Duan Q, Zhang H, Zheng J, Zhang L (2020) Turning cold into hot: firing up the tumor microenvironment. Trends Cancer 6(7):605–618CrossRefPubMed
27.
28.
Anderson AC, Joller N, Kuchroo VK (2016) Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 44(5):989–1004PubMedPubMedCentralCrossRef
29.
Knox MC, Ni J, Bece A, Bucci J, Chin Y, Graham PH, Li Y (2020) A clinician’s guide to cancer-derived exosomes: immune interactions and therapeutic implications. Front Immunol 11:1612PubMedPubMedCentralCrossRef
30.
Castro F, Cardoso AP, Goncalves RM, Serre K, Oliveira MJ (2018) Interferon-gamma at the crossroads of tumor immune surveillance or evasion. Front Immunol 9:847PubMedPubMedCentralCrossRef
31.
Zhang X, Zeng Y, Qu Q, Zhu J, Liu Z, Ning W, Zeng H, Zhang N, Du W, Chen C et al (2017) PD-L1 induced by IFN-gamma from tumor-associated macrophages via the JAK/STAT3 and PI3K/AKT signaling pathways promoted progression of lung cancer. Int J Clin Oncol 22(6):1026–1033PubMedCrossRef
32.
Jacquelot N, Yamazaki T, Roberti MP, Duong CPM, Andrews MC, Verlingue L, Ferrere G, Becharef S, Vetizou M, Daillere R et al (2019) Sustained type I interferon signaling as a mechanism of resistance to PD-1 blockade. Cell Res 29(10):846–861PubMedPubMedCentralCrossRef
33.
Shin DS, Zaretsky JM, Escuin-Ordinas H, Garcia-Diaz A, Hu-Lieskovan S, Kalbasi A, Grasso CS, Hugo W, Sandoval S, Torrejon DY et al (2017) Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov 7(2):188–201PubMedCrossRef
34.
Gao J, Shi LZ, Zhao H, Chen J, Xiong L, He Q, Chen T, Roszik J, Bernatchez C, Woodman SE et al (2016) Loss of IFN-gamma pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell 167(2):397–404399PubMedPubMedCentralCrossRef
35.
Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S et al (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375(19):1823–1833PubMedCrossRef
36.
Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF et al (2018) Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 378(22):2078–2092CrossRefPubMed
37.
38.
Chan TA, Yarchoan M, Jaffee E, Swanton C, Quezada SA, Stenzinger A, Peters S (2019) Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann Oncol 30(1):44–56PubMedCrossRef
39.
Eso Y, Shimizu T, Takeda H, Takai A, Marusawa H (2020) Microsatellite instability and immune checkpoint inhibitors: toward precision medicine against gastrointestinal and hepatobiliary cancers. J Gastroenterol 55(1):15–26PubMedCrossRef
40.
Knepper TC, Montesion M, Russell JS, Sokol ES, Frampton GM, Miller VA, Albacker LA, McLeod HL, Eroglu Z, Khushalani NI et al (2019) The genomic landscape of merkel cell carcinoma and clinicogenomic biomarkers of response to immune checkpoint inhibitor therapy. Clin Cancer Res 25(19):5961–5971PubMedPubMedCentralCrossRef
41.
Klempner SJ, Fabrizio D, Bane S, Reinhart M, Peoples T, Ali SM, Sokol ES, Frampton G, Schrock AB, Anhorn R et al (2020) Tumor mutational burden as a predictive biomarker for response to immune checkpoint inhibitors: a review of current evidence. Oncologist 25(1):e147–e159PubMedCrossRef
42.
Subbiah V, Solit DB, Chan TA, Kurzrock R (2020) The FDA approval of pembrolizumab for adult and pediatric patients with tumor mutational burden (TMB) >/=10: a decision centered on empowering patients and their physicians. Ann Oncol 31(9):1115–1118PubMedCrossRef
43.
Goodman AM, Castro A, Pyke RM, Okamura R, Kato S, Riviere P, Frampton G, Sokol E, Zhang X, Ball ED et al (2020) MHC-I genotype and tumor mutational burden predict response to immunotherapy. Genome Med 12(1):45PubMedPubMedCentralCrossRef
44.
Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, Albright A, Cheng JD, Kang SP, Shankaran V et al (2017) IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest 127(8):2930–2940PubMedPubMedCentralCrossRef
45.
Bareche Y, Buisseret L, Gruosso T, Girard E, Venet D, Dupont F, Desmedt C, Larsimont D, Park M, Rothe F et al (2020) Unraveling triple-negative breast cancer tumor microenvironment heterogeneity: towards an optimized treatment approach. J Natl Cancer Inst 112(7):708–719PubMedCrossRef
46.
AbdulJabbar K, Raza SEA, Rosenthal R, Jamal-Hanjani M, Veeriah S, Akarca A, Lund T, Moore DA, Salgado R, Al Bakir M et al (2020) Geospatial immune variability illuminates differential evolution of lung adenocarcinoma. Nat Med 26(7):1054–1062PubMedPubMedCentralCrossRef
47.
48.
Zhang Y, Zhang Z (2020) The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol Immunol 17(8):807–821PubMedPubMedCentralCrossRef
49.
Wagner S, Mullins CS, Linnebacher M (2018) Colorectal cancer vaccines: tumor-associated antigens vs neoantigens. World J Gastroenterol 24(48):5418–5432PubMedPubMedCentralCrossRef
50.
51.
52.
Rosenthal R, Cadieux EL, Salgado R, Bakir MA, Moore DA, Hiley CT, Lund T, Tanic M, Reading JL, Joshi K et al (2019) Neoantigen-directed immune escape in lung cancer evolution. Nature 567(7749):479–485PubMedPubMedCentralCrossRef
53.
Li N, Yuan J, Tian W, Meng L, Liu Y (2020) T-cell receptor repertoire analysis for the diagnosis and treatment of solid tumor: a methodology and clinical applications. Cancer Commun (Lond) 40(10):473–483CrossRef
54.
Wang T, Wang C, Wu J, He C, Zhang W, Liu J, Zhang R, Lv Y, Li Y, Zeng X et al (2017) The different T-cell receptor repertoires in breast cancer tumors, draining lymph nodes, and adjacent tissues. Cancer Immunol Res 5(2):148–156PubMedCrossRef
55.
Liu X, Cui Y, Zhang Y, Liu Z, Zhang Q, Wu W, Zheng Z, Li S, Zhang Z, Li Y (2019) A comprehensive study of immunology repertoires in both preoperative stage and postoperative stage in patients with colorectal cancer. Mol Genet Genomic Med 7(3):e504PubMedPubMedCentralCrossRef
56.
Song Z, Chen X, Shi Y, Huang R, Wang W, Zhu K, Lin S, Wang M, Tian G, Yang J et al (2020) Evaluating the potential of T cell receptor repertoires in predicting the prognosis of resectable non-small cell lung cancers. Mol Ther Methods Clin Dev 18:73–83PubMedPubMedCentralCrossRef
57.
Poran A, Scherer J, Bushway ME, Besada R, Balogh KN, Wanamaker A, Williams RG, Prabhakara J, Ott PA, Hu-Lieskovan S et al (2020) Combined TCR repertoire profiles and blood cell phenotypes predict melanoma patient response to personalized neoantigen therapy plus anti-PD-1. Cell Rep Med 1(8):100141PubMedPubMedCentralCrossRef
58.
Kidman J, Principe N, Watson M, Lassmann T, Holt RA, Nowak AK, Lesterhuis WJ, Lake RA, Chee J (2020) Characteristics of TCR repertoire associated with successful immune checkpoint therapy responses. Front Immunol 11:587014PubMedPubMedCentralCrossRef
59.
60.
Vroman H, Balzaretti G, Belderbos RA, Klarenbeek PL, van Nimwegen M, Bezemer K, Cornelissen R, Niewold ITG, van Schaik BD, van Kampen AH et al (2020) T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma. J Immunother Cancer 8(1):e000251PubMedPubMedCentralCrossRef
61.
Hosoi A, Takeda K, Nagaoka K, Iino T, Matsushita H, Ueha S, Aoki S, Matsushima K, Kubo M, Morikawa T et al (2018) Increased diversity with reduced “diversity evenness” of tumor infiltrating T-cells for the successful cancer immunotherapy. Sci Rep 8(1):1058PubMedPubMedCentralCrossRef
62.
Litchfield K, Reading JL, Puttick C, Thakkar K, Abbosh C, Bentham R, Watkins TBK, Rosenthal R, Biswas D, Rowan A et al (2021) Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition. Cell 184(3):596-614 e514PubMedPubMedCentralCrossRef
63.
Xu P, Luo H, Kong Y, Lai WF, Cui L, Zhu X (2020) Cancer neoantigen: boosting immunotherapy. Biomed Pharmacother 131:110640PubMedCrossRef
64.
Peng M, Mo Y, Wang Y, Wu P, Zhang Y, Xiong F, Guo C, Wu X, Li Y, Li X et al (2019) Neoantigen vaccine: an emerging tumor immunotherapy. Mol Cancer 18(1):128PubMedPubMedCentralCrossRef
65.
Ott PA, Hu-Lieskovan S, Chmielowski B, Govindan R, Naing A, Bhardwaj N, Margolin K, Awad MM, Hellmann MD, Lin JJ et al (2020) A phase Ib trial of personalized neoantigen therapy plus anti-PD-1 in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. Cell 183(2):347–362324PubMedCrossRef
66.
Vanderlugt CL, Miller SD (2002) Epitope spreading in immune-mediated diseases: implications for immunotherapy. Nat Rev Immunol 2(2):85–95PubMedCrossRef
67.
Hu Z, Leet DE, Allesoe RL, Oliveira G, Li S, Luoma AM, Liu J, Forman J, Huang T, Iorgulescu JB et al (2021) Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma. Nat Med 27:515–525PubMedPubMedCentralCrossRef
68.
Bauman J, Burris H, Clarke J, Patel M, Cho D, Gutierrez M, Julian R, Scott A, Cohen P, Frederick J et al (2020) 798 Safety, tolerability, and immunogenicity of mRNA-4157 in combination with pembrolizumab in subjects with unresectable solid tumors (KEYNOTE-603): an update. J Immunother Cancer 8(Suppl 3):A477
69.
70.
Simon RM, Steinberg SM, Hamilton M, Hildesheim A, Khleif S, Kwak LW, Mackall CL, Schlom J, Topalian SL, Berzofsky JA (2001) Clinical trial designs for the early clinical development of therapeutic cancer vaccines. J Clin Oncol 19(6):1848–1854PubMedCrossRef
71.
Choudhury A, Mosolits S, Kokhaei P, Hansson L, Palma M, Mellstedt H (2006) Clinical results of vaccine therapy for cancer: learning from history for improving the future. Adv Cancer Res 95:147–202PubMedCrossRef
72.
Malonis RJ, Lai JR, Vergnolle O (2020) Peptide-based vaccines: current progress and future challenges. Chem Rev 120(6):3210–3229PubMedCrossRef
73.
Plummer M, de Martel C, Vignat J, Ferlay J, Bray F, Franceschi S (2016) Global burden of cancers attributable to infections in 2012: a synthetic analysis. Lancet Glob Health 4(9):e609-616PubMedCrossRef
74.
Peters KB, Archer GE, Norberg P, Xie W, Threatt S, Lipp ES, Herndon JE, Healy P, Congdon K, Sanchez-Perez L et al (2019) Safety of nivolumab in combination with dendritic cell vaccines in recurrent high-grade glioma. J Clin Oncol 37(15_suppl):e13526–e13526CrossRef
75.
Yarchoan M, Huang CY, Zhu Q, Ferguson AK, Durham JN, Anders RA, Thompson ED, Rozich NS, Thomas DL 2nd, Nauroth JM et al (2020) A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer. Cancer Med 9(4):1485–1494PubMedCrossRef
76.
Pol JG, Acuna SA, Yadollahi B, Tang N, Stephenson KB, Atherton MJ, Hanwell D, El-Warrak A, Goldstein A, Moloo B et al (2019) Preclinical evaluation of a MAGE-A3 vaccination utilizing the oncolytic Maraba virus currently in first-in-human trials. Oncoimmunology 8(1):e1512329PubMedCrossRef
77.
Aris M, Mordoh J, Barrio MM (2017) Immunomodulatory monoclonal antibodies in combined immunotherapy trials for cutaneous melanoma. Front Immunol 8:1024PubMedPubMedCentralCrossRef
78.
van Willigen WW, Bloemendal M, Gerritsen WR, Schreibelt G, de Vries IJM, Bol KF (2018) Dendritic cell cancer therapy: vaccinating the right patient at the right time. Front Immunol 9:2265PubMedPubMedCentralCrossRef
79.
Metadata
Title
Cancer neoantigens as potential targets for immunotherapy
Authors
Weijie Ma
Brian Pham
Tianhong Li
Publication date
01-02-2022
Publisher
Springer Netherlands
Published in
Clinical & Experimental Metastasis / Issue 1/2022
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI
https://doi.org/10.1007/s10585-021-10091-1

Other articles of this Issue 1/2022

Clinical & Experimental Metastasis 1/2022 Go to the issue

Review

Breast cancer disparities in outcomes; unmasking biological determinants associated with racial and genetic diversity

Obituary

Dedication to late Dale Han, MD

Review

Mechanisms of breast cancer metastasis

Review

Empowering study of breast cancer data with application of artificial intelligence technology: promises, challenges, and use cases

Review

The role of sentinel lymph node mapping in colon cancer: detection of micro-metastasis, effect on survival, and driver of a paradigm shift in extent of colon resection

Review

Innovations in radiotherapy and advances in immunotherapy for the treatment of brain metastases
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits