Combination cancer immunotherapy and new immunomodulatory targets
Abstract
Targeting immune checkpoints such as programmed cell death protein 1 (PD1), programmed cell death 1 ligand 1 (PDL1) and cytotoxic T lymphocyte antigen 4 (CTLA4) has achieved noteworthy benefit in multiple cancers by blocking immunoinhibitory signals and enabling patients to produce an effective antitumour response. Inhibitors of CTLA4, PD1 or PDL1 administered as single agents have resulted in durable tumour regression in some patients, and combinations of PD1 and CTLA4 inhibitors may enhance antitumour benefit. Numerous additional immunomodulatory pathways as well as inhibitory factors expressed or secreted by myeloid and stromal cells in the tumour microenvironment are potential targets for synergizing with immune checkpoint blockade. Given the breadth of potential targets in the immune system, critical questions to address include which combinations should move forward in development and which patients will benefit from these treatments. This Review discusses the leading drug targets that are expressed on tumour cells and in the tumour microenvironment that allow enhancement of the antitumour immune response.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
PD1 blockade in patients enhances tumour eradication by T cells and improves survival of these patients, especially in melanoma.
“PD1 blockade in patients enhances tumour eradication by T cells and improves the survival of these patients [78].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [78]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma
Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J. J., Cowey, C. L., Lao, C. D., Schadendorf, D., Dummer, R., Smylie, M., Rutkowski, P., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1504030 · Cited by 8,157 · see citing works
Improved survival with vemurafenib in melanoma with BRAF V600E mutation
Chapman, P. B., Hauschild, A., Robert, C., Haanen, J. B., Ascierto, P., Larkin, J., Dummer, R., Garbe, C., Testori, A., Maio, M., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1103782 · Cited by 7,720 · see citing works
PD-1 blockade induces responses by inhibiting adaptive immune resistance
Tumeh, P. C., Harview, C. L., Yearley, J. H., Shintaku, I. P., Taylor, E. J. M., Robert, L., Chmielowski, B., Spasic, M., Henry, G., Ciobanu, V., et al. (2014) · Nature · doi:10.1038/nature13954 · Cited by 6,609 · see citing works
PD-1 and Its Ligands in Tolerance and Immunity
Keir, M. E., Butte, M. J., Freeman, G. J., & Sharpe, A. H. (2008) · Annual Review of Immunology · doi:10.1146/annurev.immunol.26.021607.090331 · Cited by 5,378 · see citing works
Self-citationTumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion
Dong, H., Strome, S. E., Salomao, D. R., Tamura, H., Hirano, F., Flies, D. B., Roche, P. C., Lu, J., Zhu, G., Tamada, K., et al. (2002) · Nature Medicine · doi:10.1038/nm730 · Cited by 5,025 · see citing works
Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma
Robert, C., Thomas, L., Bondarenko, I., O'Day, S., Weber, J., Garbe, C., Lebbe, C., Baurain, J.-F., Testori, A., Grob, J.-J., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1104621 · Cited by 4,496 · see citing works
Nivolumab plus Ipilimumab in Advanced Melanoma
Wolchok, J. D., Kluger, H., Callahan, M. K., Postow, M. A., Rizvi, N. A., Lesokhin, A. M., Segal, N. H., Ariyan, C. E., Gordon, R.-A., Reed, K., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1302369 · Cited by 4,230 · see citing works
Targeting hypoxia in cancer therapy
Wilson, W. R., & Hay, M. P. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3064 · Cited by 3,172 · see citing works
Molecular mechanisms of T cell co-stimulation and co-inhibition
Chen, L., & Flies, D. B. (2013) · Nature Reviews Immunology · doi:10.1038/nri3405 · Cited by 3,114 · see citing works
Nivolumab and ipilimumab versus ipilimumab in untreated melanoma
Postow, M. A., Chesney, J., Pavlick, A. C., Robert, C., Grossmann, K., McDermott, D., Linette, G. P., Meyer, N., Giguere, J. K., Agarwala, S. S., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1414428 · Cited by 2,781 · see citing works
Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412
Suntharalingam, G., Perry, M. R., Ward, S., Brett, S. J., Castello-Cortes, A., Brunner, M. D., & Panoskaltsis, N. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa063842 · Cited by 2,164 · see citing works
Feig, C., Jones, J. O., Kraman, M., Wells, R. J. B., Deonarine, A., Chan, D. S., Connell, C. M., Roberts, E. W., Zhao, Q., Caballero, O. L., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1320318110 · Cited by 2,100 · see citing works
Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens
Gubin, M. M., Zhang, X., Schuster, H., Caron, E., Ward, J. P., Noguchi, T., Ivanova, Y., Hundal, J., Arthur, C. D., Krebber, W.-J., et al. (2014) · Nature · doi:10.1038/nature13988 · Cited by 1,974 · see citing works
Self-citationHamanishi, J., Mandai, M., Iwasaki, M., Okazaki, T., Tanaka, Y., Yamaguchi, K., Higuchi, T., Yagi, H., Takakura, K., Minato, N., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0611533104 · Cited by 1,378 · see citing works
Garon, E. B., Ciuleanu, T.-E., Arrieta, O., Prabhash, K., Syrigos, K. N., Goksel, T., Park, K., Gorbunova, V., Kowalyszyn, R. D., Pikiel, J., et al. (2014) · The Lancet · doi:10.1016/s0140-6736(14)60845-x · Cited by 1,309 · see citing works
Attia, P., Phan, G. Q., Maker, A. V., Robinson, M. R., Quezado, M. M., Yang, J. C., Sherry, R. M., Topalian, S. L., Kammula, U. S., Royal, R. E., et al. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.06.205 · Cited by 1,012 · see citing works
Frederick, D. T., Piris, A., Cogdill, A. P., Cooper, Z. A., Lezcano, C., Ferrone, C. R., Mitra, D., Boni, A., Newton, L. P., Liu, C., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-1630 · Cited by 944 · see citing works
Ohigashi, Y., Sho, M., Yamada, Y., Tsurui, Y., Hamada, K., Ikeda, N., Mizuno, T., Yoriki, R., Kashizuka, H., Yane, K., et al. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-1469 · Cited by 796 · see citing works
CEACAM1 regulates TIM-3-mediated tolerance and exhaustion
Huang, Y.-H., Zhu, C., Kondo, Y., Anderson, A. C., Gandhi, A., Russell, A., Dougan, S. K., Petersen, B.-S., Melum, E., Pertel, T., et al. (2015) · Nature · doi:10.1038/nature13848 · Cited by 717 · see citing works
Integrin–TGF‐β crosstalk in fibrosis, cancer and wound healing
Margadant, C., & Sonnenberg, A. (2010) · The EMBO Reports · doi:10.1038/embor.2009.276 · Cited by 653 · see citing works
Stability and function of regulatory T cells is maintained by a neuropilin-1–semaphorin-4a axis
Delgoffe, G. M., Woo, S.-R., Turnis, M. E., Gravano, D. M., Guy, C., Overacre, A. E., Bettini, M. L., Vogel, P., Finkelstein, D., Bonnevier, J., et al. (2013) · Nature · doi:10.1038/nature12428 · Cited by 587 · see citing works
Roth, T. J., Sheinin, Y., Lohse, C. M., Kuntz, S. M., Frigola, X., Inman, B. A., Krambeck, A. E., Mckenney, M. E., Karnes, R. J., Blute, M. L., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1068 · Cited by 267 · see citing works
Regulatory T-cell Modulation Using Cyclophosphamide in Vaccine Approaches: A Current Perspective
Le, D. T., & Jaffee, E. M. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-3912 · Cited by 240 · see citing works
Soliman, H. H., Jackson, E., Neuger, T., Dees, E. C., Harvey, R. D., Han, H., Ismail-Khan, R., Minton, S., Vahanian, N. N., Link, C., et al. (2014) · Oncotarget · doi:10.18632/oncotarget.2357 · Cited by 174 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation
Anderson, A. C., Joller, N., & Kuchroo, V. K. (2016) · Immunity · doi:10.1016/j.immuni.2016.05.001 · Cited by 2,096 · see citing works
CD4+ T cell help in cancer immunology and immunotherapy
Borst, J., Ahrends, T., Bąbała, N., Melief, C. J. M., & Kastenmüller, W. (2018) · Nature Reviews Immunology · doi:10.1038/s41577-018-0044-0 · Cited by 1,585 · see citing works
DNA sensing by the cGAS–STING pathway in health and disease
Motwani, M., Pesiridis, S., & Fitzgerald, K. A. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0151-1 · Cited by 1,467 · see citing works
Mechanisms of resistance to immune checkpoint inhibitors
Jenkins, R. W., Barbie, D. A., & Flaherty, K. T. (2018) · British Journal of Cancer · doi:10.1038/bjc.2017.434 · Cited by 1,383 · see citing works
Cyclin D–CDK4 kinase destabilizes PD-L1 via cullin 3–SPOP to control cancer immune surveillance
Zhang, J., Bu, X., Wang, H., Zhu, Y., Geng, Y., Nihira, N. T., Tan, Y., Ci, Y., Wu, F., Dai, X., et al. (2018) · Nature · doi:10.1038/nature25015 · Cited by 1,013 · see citing works
Self-citationKinase inhibitors: the road ahead
Ferguson, F. M., & Gray, N. S. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.21 · Cited by 1,009 · see citing works
Combination cancer immunotherapies tailored to the tumour microenvironment
Smyth, M. J., Ngiow, S. F., Ribas, A., & Teng, M. W. L. (2016) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2015.209 · Cited by 944 · see citing works
CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity
Burr, M. L., Sparbier, C. E., Chan, Y.-C., Williamson, J. C., Woods, K., Beavis, P. A., Lam, E. Y. N., Henderson, M. A., Bell, C. C., Stolzenburg, S., et al. (2017) · Nature · doi:10.1038/nature23643 · Cited by 946 · see citing works
Scharping, N. E., Menk, A. V., Moreci, R. S., Whetstone, R. D., Dadey, R. E., Watkins, S. C., Ferris, R. L., & Delgoffe, G. M. (2016) · Immunity · doi:10.1016/j.immuni.2016.07.009 · Cited by 848 · see citing works
Combined antiangiogenic and anti–PD-L1 therapy stimulates tumor immunity through HEV formation
Allen, E., Jabouille, A., Rivera, L. B., Lodewijckx, I., Missiaen, R., Steri, V., Feyen, K., Tawney, J., Hanahan, D., Michael, I. P., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aak9679 · Cited by 820 · see citing works
CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation
Deng, J., Wang, E. S., Jenkins, R. W., Li, S., Dries, R., Yates, K., Chhabra, S., Huang, W., Liu, H., Aref, A. R., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0915 · Cited by 770 · see citing works
Self-citationArlauckas, S. P., Garris, C. S., Kohler, R. H., Kitaoka, M., Cuccarese, M. F., Yang, K. S., Miller, M. A., Carlson, J. C., Freeman, G. J., Anthony, R. M., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aal3604 · Cited by 669 · see citing works
Self-citationImmune evasion mediated by PD-L1 on glioblastoma-derived extracellular vesicles
Ricklefs, F. L., Alayo, Q., Krenzlin, H., Mahmoud, A. B., Speranza, M. C., Nakashima, H., Hayes, J. L., Lee, K., Balaj, L., Passaro, C., et al. (2018) · Science Advances · doi:10.1126/sciadv.aar2766 · Cited by 610 · see citing works
Self-citationTirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist
Willard, F. S., Douros, J. D., Gabe, M. B. N., Showalter, A. D., Wainscott, D. B., Suter, T. M., Capozzi, M. E., van der Velden, W. J. C., Stutsman, C., Cardona, G. R., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.140532 · Cited by 541 · see citing works
“Data are normalized to 1 μM GIP(1-42) values.”
InfluentialNew insights into the role of <scp>EMT</scp> in tumor immune escape
Terry, S., Savagner, P., Ortiz‐Cuaran, S., Mahjoubi, L., Saintigny, P., Thiery, J., & Chouaib, S. (2017) · Molecular Oncology · doi:10.1002/1878-0261.12093 · Cited by 414 · see citing works
Durable antitumor responses to CD47 blockade require adaptive immune stimulation
Sockolosky, J. T., Dougan, M., Ingram, J. R., Ho, C. C. M., Kauke, M. J., Almo, S. C., Ploegh, H. L., & Garcia, K. C. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1604268113 · Cited by 366 · see citing works
Constantinidou, A., Alifieris, C., & Trafalis, D. T. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.09.008 · Cited by 342 · see citing works
Systematic Immunotherapy Target Discovery Using Genome-Scale In Vivo CRISPR Screens in CD8 T Cells
Dong, M. B., Wang, G., Chow, R. D., Ye, L., Zhu, L., Dai, X., Park, J. J., Kim, H. R., Errami, Y., Guzman, C. D., et al. (2019) · Cell · doi:10.1016/j.cell.2019.07.044 · Cited by 330 · see citing works
“Other immunotherapy targets rapidly emerge, such as TIM-3, LAG3, 4–1BB, CD28, ICOS, OX-40, and VISTA (Johnson and June, 2017; Mahoney et al., 2015).”
Senescence of T Lymphocytes: Implications for Enhancing Human Immunity
Akbar, A. N., Henson, S. M., & Lanna, A. (2016) · Trends in Immunology · doi:10.1016/j.it.2016.09.002 · Cited by 285 · see citing works
Immunosuppressive Activities of Adenosine in Cancer
Allard, B., Beavis, P. A., Darcy, P. K., & Stagg, J. (2016) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2016.04.001 · Cited by 292 · see citing works
Tumour-infiltrating lymphocytes in melanoma prognosis and cancer immunotherapy
Lee, N., Zakka, L. R., Mihm, M. C., & Schatton, T. (2016) · Pathology · doi:10.1016/j.pathol.2015.12.006 · Cited by 250 · see citing works
A Convergence-Based Framework for Cancer Drug Resistance
Konieczkowski, D. J., Johannessen, C. M., & Garraway, L. A. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.03.025 · Cited by 258 · see citing works
Development of PARP and immune-checkpoint inhibitor combinations
Stewart, R. A., Pilié, P. G., & Yap, T. A. (2018) · Cancer Research · doi:10.1158/0008-5472.can-18-2652 · Cited by 239 · see citing works
Targeting the cancer-associated fibroblasts as a treatment in triple-negative breast cancer
Takai, K., Le, A., Weaver, V. M., & Werb, Z. (2016) · Oncotarget · doi:10.18632/oncotarget.12658 · Cited by 207 · see citing works
Nakagawa, H., Sido, J. M., Reyes, E. E., Kiers, V., Cantor, H., & Kim, H.-J. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1604765113 · Cited by 176 · see citing works
Current and future perspectives of PD-1/PDL-1 blockade in cancer immunotherapy
Makuku, R., Khalili, N., Razi, S., Keshavarz-Fathi, M., & Rezaei, N. (2021) · Journal of Immunology Research · doi:10.1155/2021/6661406 · Cited by 136 · see citing works
Huang, M.-Y., Jiang, X.-M., Wang, B.-L., Sun, Y., & Lu, J.-J. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107694 · Cited by 136 · see citing works
Wang, Y., Zhou, Y., Cao, S., Sun, Y., Dong, Z., Li, C., Wang, H., Yao, Y., Yu, H., Song, X., et al. (2021) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2021.104833 · Cited by 96 · see citing works
Global survey of the immunomodulatory potential of common drugs
Vladimer, G. I., Snijder, B., Krall, N., Bigenzahn, J. W., Huber, K. V. M., Lardeau, C.-H., Sanjiv, K., Ringler, A., Berglund, U. W., Sabler, M., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2360 · Cited by 87 · see citing works
Small molecules targeting protein–protein interactions for cancer therapy
Wu, D., Li, Y., Zheng, L., Xiao, H., Ouyang, L., Wang, G., & Sun, Q. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.05.035 · Cited by 71 · see citing works
Yassin, M., Sadowska, Z., Djurhuus, D., Nielsen, B., Tougaard, P., Olsen, J., & Pedersen, A. E. (2019) · Immunology · doi:10.1111/imm.13093 · Cited by 38 · see citing works
- Authors
- Mahoney, K. M., Rennert, P. D., & Freeman, G. J.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Corresponding author
- Freeman, Gordon J.
- Venue
- Nature Reviews Drug Discovery
- Published
- 2015-07-31
- Volume
- 14
- Issue
- 8
- Pages
- 561-584
- ISSN
- 1474-1776 (ISSN-L)
- 1474-1784
- OpenAlex
- W1942897646
- Cited by
- 1,294
- References
- 24
- Citations by year
- 2026: 25 · 2025: 74 · 2024: 111 · 2023: 113 · 2022: 110 · 2021: 147 · 2020: 135 · 2019: 135 · 2018: 166 · 2017: 132 · 2016: 133 · 2015: 11 · 2014: 1
- FWCI
- 15.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Drug Discovery (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (U54CA163125, P50CA101942)
- National Institute of Allergy and Infectious Diseases (P01AI054456, R01AI089955)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- cancer immunotherapy, immune checkpoint blockade, combination therapy, PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, tumor microenvironment, myeloid cells, stromal cells, antitumor immunity
- MeSH terms
- Animals, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Humans, Immunotherapy, Neoplasms, Molecular Targeted Therapy, Tumor Microenvironment, B7-H1 Antigen, CTLA-4 Antigen, Programmed Cell Death 1 Receptor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
