Journal Article
. 2017 May; 114(21):E4223-E4232.
doi: 10.1073/pnas.1617941114.

Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab

Udupi A Ramagopal 1 Weifeng Liu 1 Sarah C Garrett-Thomson 1 Jeffrey B Bonanno 1 Qingrong Yan 2 Mohan Srinivasan 3 Susan C Wong 3 Alasdair Bell 3 Shilpa Mankikar 3 Vangipuram S Rangan 3 Shrikant Deshpande 3 Alan J Korman 4 Steven C Almo 5 
  • PMID: 28484017
  •     55 References
  •     50 citations


Rational modulation of the immune response with biologics represents one of the most promising and active areas for the realization of new therapeutic strategies. In particular, the use of function blocking monoclonal antibodies targeting checkpoint inhibitors such as CTLA-4 and PD-1 have proven to be highly effective for the systemic activation of the human immune system to treat a wide range of cancers. Ipilimumab is a fully human antibody targeting CTLA-4 that received FDA approval for the treatment of metastatic melanoma in 2011. Ipilimumab is the first-in-class immunotherapeutic for blockade of CTLA-4 and significantly benefits overall survival of patients with metastatic melanoma. Understanding the chemical and physical determinants recognized by these mAbs provides direct insight into the mechanisms of pathway blockade, the organization of the antigen-antibody complexes at the cell surface, and opportunities to further engineer affinity and selectivity. Here, we report the 3.0 Å resolution X-ray crystal structure of the complex formed by ipilimumab with its human CTLA-4 target. This structure reveals that ipilimumab contacts the front β-sheet of CTLA-4 and intersects with the CTLA-4:Β7 recognition surface, indicating that direct steric overlap between ipilimumab and the B7 ligands is a major mechanistic contributor to ipilimumab function. The crystallographically observed binding interface was confirmed by a comprehensive cell-based binding assay against a library of CTLA-4 mutants and by direct biochemical approaches. This structure also highlights determinants responsible for the selectivity exhibited by ipilimumab toward CTLA-4 relative to the homologous and functionally related CD28.

Keywords: CTLA-4; X-ray crystallography; cancer; immunotherapy; ipilimumab.

Nivolumab plus ipilimumab in advanced melanoma.
Jedd D Wolchok, Harriet Kluger, +21 authors, Mario Sznol.
N Engl J Med, 2013 Jun 04; 369(2). PMID: 23724867    Free PMC article.
Highly Cited.
Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells.
Mark J Selby, John J Engelhardt, +4 authors, Alan J Korman.
Cancer Immunol Res, 2014 Apr 30; 1(1). PMID: 24777248
Highly Cited.
Expression, refolding, purification, molecular characterization, crystallization, and preliminary X-ray analysis of the receptor binding domain of human B7-2.
Xuewu Zhang, Jean-Claude D Schwartz, Steven C Almo, Stanley G Nathenson.
Protein Expr Purif, 2002 Jun 20; 25(1). PMID: 12071705
Interactions of protein antigens with antibodies.
D R Davies, G H Cohen.
Proc Natl Acad Sci U S A, 1996 Jan 09; 93(1). PMID: 8552677    Free PMC article.
Highly Cited. Review.
Prediction of glycosylation sites using random forests.
Stephen E Hamby, Jonathan D Hirst.
BMC Bioinformatics, 2008 Nov 29; 9. PMID: 19038042    Free PMC article.
Tuning Sensitivity of CAR to EGFR Density Limits Recognition of Normal Tissue While Maintaining Potent Antitumor Activity.
Hillary G Caruso, Lenka V Hurton, +11 authors, Laurence J N Cooper.
Cancer Res, 2015 Sep 04; 75(17). PMID: 26330164    Free PMC article.
Highly Cited.
PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations.
Weiping Zou, Jedd D Wolchok, Lieping Chen.
Sci Transl Med, 2016 Mar 05; 8(328). PMID: 26936508    Free PMC article.
Highly Cited. Review.
Cutting edge: cell-extrinsic immune regulation by CTLA-4 expressed on conventional T cells.
Chun Jing Wang, Rupert Kenefeck, +6 authors, Lucy S K Walker.
J Immunol, 2012 Jul 04; 189(3). PMID: 22753931    Free PMC article.
Cutting edge: CTLA-4 on effector T cells inhibits in trans.
Emily Corse, James P Allison.
J Immunol, 2012 Jul 04; 189(3). PMID: 22753941
Long term survival with cytotoxic T lymphocyte-associated antigen 4 blockade using tremelimumab.
Zeynep Eroglu, Dae Won Kim, +9 authors, Antoni Ribas.
Eur J Cancer, 2015 Sep 15; 51(17). PMID: 26364516    Free PMC article.
Domain association in immunoglobulin molecules. The packing of variable domains.
C Chothia, J Novotný, R Bruccoleri, M Karplus.
J Mol Biol, 1985 Dec 05; 186(3). PMID: 4093982
Highly Cited.
Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients.
Emanuela Romano, Monika Kusio-Kobialka, +7 authors, Daniel E Speiser.
Proc Natl Acad Sci U S A, 2015 Apr 29; 112(19). PMID: 25918390    Free PMC article.
Highly Cited.
Solution structure of human CTLA-4 and delineation of a CD80/CD86 binding site conserved in CD28.
W J Metzler, J Bajorath, +8 authors, P S Linsley.
Nat Struct Biol, 1997 Jul 01; 4(7). PMID: 9228944
Structure of murine CTLA-4 and its role in modulating T cell responsiveness.
D A Ostrov, W Shi, +2 authors, S G Nathenson.
Science, 2000 Oct 29; 290(5492). PMID: 11052947
Nivolumab and ipilimumab versus ipilimumab in untreated melanoma.
Michael A Postow, Jason Chesney, +18 authors, F Stephen Hodi.
N Engl J Med, 2015 Apr 22; 372(21). PMID: 25891304    Free PMC article.
Highly Cited.
Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade.
Nicholas McGranahan, Andrew J S Furness, +33 authors, Charles Swanton.
Science, 2016 Mar 05; 351(6280). PMID: 26940869    Free PMC article.
Highly Cited.
Overview of the CCP4 suite and current developments.
Martyn D Winn, Charles C Ballard, +15 authors, Keith S Wilson.
Acta Crystallogr D Biol Crystallogr, 2011 Apr 05; 67(Pt 4). PMID: 21460441    Free PMC article.
Highly Cited.
Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma.
Dirk Schadendorf, F Stephen Hodi, +7 authors, Jedd D Wolchok.
J Clin Oncol, 2015 Feb 11; 33(17). PMID: 25667295    Free PMC article.
Highly Cited.
The case for open-source software in drug discovery.
Warren L DeLano.
Drug Discov Today, 2005 Feb 15; 10(3). PMID: 15708536
An engineered lipocalin specific for CTLA-4 reveals a combining site with structural and conformational features similar to antibodies.
D Schönfeld, G Matschiner, +8 authors, A Skerra.
Proc Natl Acad Sci U S A, 2009 May 07; 106(20). PMID: 19416843    Free PMC article.
Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study.
Scott Antonia, Sarah B Goldberg, +8 authors, Naiyer A Rizvi.
Lancet Oncol, 2016 Feb 10; 17(3). PMID: 26858122    Free PMC article.
Highly Cited.
The blockade of immune checkpoints in cancer immunotherapy.
Drew M Pardoll.
Nat Rev Cancer, 2012 Mar 23; 12(4). PMID: 22437870    Free PMC article.
Highly Cited. Review.
Improved survival with ipilimumab in patients with metastatic melanoma.
F Stephen Hodi, Steven J O'Day, +26 authors, Walter J Urba.
N Engl J Med, 2010 Jun 08; 363(8). PMID: 20525992    Free PMC article.
Highly Cited.
Crystallization and preliminary X-ray analysis of the complex between human CTLA-4 and B7-2.
X Zhang, J C Schwartz, S G Nathenson, S C Almo.
Acta Crystallogr D Biol Crystallogr, 2001 May 26; 57(Pt 6). PMID: 11375523
Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies.
Karl S Peggs, Sergio A Quezada, +2 authors, James P Allison.
J Exp Med, 2009 Jul 08; 206(8). PMID: 19581407    Free PMC article.
Highly Cited.
The acidity of the tumor microenvironment is a mechanism of immune escape that can be overcome by proton pump inhibitors.
Matteo Bellone, Arianna Calcinotto, +3 authors, Licia Rivoltini.
Oncoimmunology, 2013 Mar 14; 2(1). PMID: 23483769    Free PMC article.
Selection of cell binding and internalizing epidermal growth factor receptor antibodies from a phage display library.
T Heitner, A Moor, +3 authors, J D Marks.
J Immunol Methods, 2001 Feb 27; 248(1-2). PMID: 11223066
Refinement of macromolecular structures by the maximum-likelihood method.
G N Murshudov, A A Vagin, E J Dodson.
Acta Crystallogr D Biol Crystallogr, 1997 May 01; 53(Pt 3). PMID: 15299926
Highly Cited.
Crystal structure of a soluble CD28-Fab complex.
Edward J Evans, Robert M Esnouf, +11 authors, Simon J Davis.
Nat Immunol, 2005 Feb 08; 6(3). PMID: 15696168
Acidity generated by the tumor microenvironment drives local invasion.
Veronica Estrella, Tingan Chen, +10 authors, Robert J Gillies.
Cancer Res, 2013 Jan 05; 73(5). PMID: 23288510    Free PMC article.
Highly Cited.
Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients.
F Stephen Hodi, Marcus Butler, +17 authors, Glenn Dranoff.
Proc Natl Acad Sci U S A, 2008 Feb 22; 105(8). PMID: 18287062    Free PMC article.
Highly Cited.
Processing of X-ray diffraction data collected in oscillation mode.
Z Otwinowski, W Minor.
Methods Enzymol, 1997 Jan 01; 276. PMID: 27754618
Highly Cited.
Pembrolizumab versus Ipilimumab in Advanced Melanoma.
Caroline Robert, Jacob Schachter, +20 authors, KEYNOTE-006 investigators.
N Engl J Med, 2015 Apr 22; 372(26). PMID: 25891173
Highly Cited.
CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells.
Sergio A Quezada, Karl S Peggs, Michael A Curran, James P Allison.
J Clin Invest, 2006 Jun 17; 116(7). PMID: 16778987    Free PMC article.
Highly Cited.
Nimotuzumab, an antitumor antibody that targets the epidermal growth factor receptor, blocks ligand binding while permitting the active receptor conformation.
Ariel Talavera, Rosmarie Friemann, +9 authors, Ernesto Moreno.
Cancer Res, 2009 Jul 09; 69(14). PMID: 19584289
Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses.
C C Stamper, Y Zhang, +7 authors, L Mosyak.
Nature, 2001 Mar 30; 410(6828). PMID: 11279502
Highly Cited.
Affinity-Tuned ErbB2 or EGFR Chimeric Antigen Receptor T Cells Exhibit an Increased Therapeutic Index against Tumors in Mice.
Xiaojun Liu, Shuguang Jiang, +12 authors, Yangbing Zhao.
Cancer Res, 2015 Sep 04; 75(17). PMID: 26330166    Free PMC article.
Highly Cited.
gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma.
Douglas J Schwartzentruber, David H Lawson, +23 authors, Patrick Hwu.
N Engl J Med, 2011 Jun 03; 364(22). PMID: 21631324    Free PMC article.
Highly Cited.
Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4.
Omar S Qureshi, Yong Zheng, +12 authors, David M Sansom.
Science, 2011 Apr 09; 332(6029). PMID: 21474713    Free PMC article.
Highly Cited.
Structure and cancer immunotherapy of the B7 family member B7x.
Hyungjun Jeon, Vladimir Vigdorovich, +13 authors, Xingxing Zang.
Cell Rep, 2014 Dec 02; 9(3). PMID: 25437562    Free PMC article.
Cancer immunotherapy comes of age.
Ira Mellman, George Coukos, Glenn Dranoff.
Nature, 2011 Dec 24; 480(7378). PMID: 22193102    Free PMC article.
Highly Cited. Review.
Structural basis for co-stimulation by the human CTLA-4/B7-2 complex.
J C Schwartz, X Zhang, +2 authors, S C Almo.
Nature, 2001 Mar 30; 410(6828). PMID: 11279501
Breakthrough of the year 2013. Cancer immunotherapy.
Jennifer Couzin-Frankel.
Science, 2013 Dec 21; 342(6165). PMID: 24357284
Highly Cited.
Humanization of an anti-p185HER2 antibody for human cancer therapy.
P Carter, L Presta, +7 authors, H M Shepard.
Proc Natl Acad Sci U S A, 1992 May 15; 89(10). PMID: 1350088    Free PMC article.
Highly Cited.
Acidic extracellular microenvironment and cancer.
Yasumasa Kato, Shigeyuki Ozawa, +4 authors, Yuh Baba.
Cancer Cell Int, 2013 Sep 06; 13(1). PMID: 24004445    Free PMC article.
Highly Cited.
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.
James Larkin, F Stephen Hodi, Jedd D Wolchok.
N Engl J Med, 2015 Sep 24; 373(13). PMID: 26398076
Highly Cited.
Rigid-body ligand recognition drives cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor triggering.
Chao Yu, Andreas F-P Sonnen, +9 authors, Simon J Davis.
J Biol Chem, 2010 Dec 16; 286(8). PMID: 21156796    Free PMC article.
Coot: model-building tools for molecular graphics.
Paul Emsley, Kevin Cowtan.
Acta Crystallogr D Biol Crystallogr, 2004 Dec 02; 60(Pt 12 Pt 1). PMID: 15572765
Highly Cited.
The interpretation of protein structures: estimation of static accessibility.
B Lee, F M Richards.
J Mol Biol, 1971 Feb 14; 55(3). PMID: 5551392
Highly Cited.
Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma.
Antoni Ribas, Richard Kefford, +21 authors, Axel Hauschild.
J Clin Oncol, 2013 Jan 09; 31(5). PMID: 23295794    Free PMC article.
Highly Cited.
Checkpoint blockade in cancer immunotherapy.
Alan J Korman, Karl S Peggs, James P Allison.
Adv Immunol, 2006 May 30; 90. PMID: 16730267    Free PMC article.
Highly Cited. Review.
Considerations for combined immune checkpoint modulation and radiation treatment.
Steven C Almo, Chandan Guha.
Radiat Res, 2014 Jul 09; 182(2). PMID: 25003312    Free PMC article.
Molecular replacement with MOLREP.
Alexei Vagin, Alexei Teplyakov.
Acta Crystallogr D Biol Crystallogr, 2010 Jan 09; 66(Pt 1). PMID: 20057045
Highly Cited.
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981    Free PMC article.
Highly Cited.
CTLA-4 blockade increases IFNgamma-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients.
Chrysoula I Liakou, Ashish Kamat, +5 authors, Padmanee Sharma.
Proc Natl Acad Sci U S A, 2008 Sep 27; 105(39). PMID: 18818309    Free PMC article.
Highly Cited.
Sex bias in MHC I-associated shaping of the adaptive immune system.
Tilman Schneider-Hohendorf, Dennis Görlich, +8 authors, Nicholas Schwab.
Proc Natl Acad Sci U S A, 2018 Feb 15; 115(9). PMID: 29440397    Free PMC article.
A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy.
Xuexiang Du, Fei Tang, +14 authors, Yang Liu.
Cell Res, 2018 Feb 24; 28(4). PMID: 29472691    Free PMC article.
Highly Cited.
Construction, Expression, and Characterization of rSEA-EGF and In Vitro Evaluation of its Antitumor Activity Against Nasopharyngeal Cancer.
Xueting Liu, Liping Zeng, +7 authors, Ailin Tao.
Technol Cancer Res Treat, 2018 Mar 20; 17. PMID: 29551087    Free PMC article.
Anti-CTLA-4 therapy requires an Fc domain for efficacy.
Jessica R Ingram, Olga S Blomberg, +15 authors, Michael Dougan.
Proc Natl Acad Sci U S A, 2018 Mar 28; 115(15). PMID: 29581255    Free PMC article.
Highly Cited.
Anti-CTLA-4 immunotherapy: uncoupling toxicity and efficacy.
Jonathan Pol, Guido Kroemer.
Cell Res, 2018 Mar 30; 28(5). PMID: 29593340    Free PMC article.
Immune checkpoint therapy in liver cancer.
Feng Xu, Tianqiang Jin, Yuwen Zhu, Chaoliu Dai.
J Exp Clin Cancer Res, 2018 May 31; 37(1). PMID: 29843754    Free PMC article.
Highly Cited. Review.
A mathematical modelling tool for unravelling the antibody-mediated effects on CTLA-4 interactions.
Aravindhan Ganesan, Theinmozhi Arulraj, Tahir Choulli, Khaled H Barakat.
BMC Med Inform Decis Mak, 2018 Jun 13; 18(1). PMID: 29890992    Free PMC article.
The CC' loop of IgV domains of the immune checkpoint receptors, plays a key role in receptor:ligand affinity modulation.
Shankar V Kundapura, Udupi A Ramagopal.
Sci Rep, 2019 Dec 18; 9(1). PMID: 31844079    Free PMC article.
Autoimmunity, checkpoint inhibitor therapy and immune-related adverse events: A review.
Shaheen Khan, David E Gerber.
Semin Cancer Biol, 2019 Jul 23; 64. PMID: 31330185    Free PMC article.
Structure and Optimization of Checkpoint Inhibitors.
Sarah L Picardo, Jeffrey Doi, Aaron R Hansen.
Cancers (Basel), 2019 Dec 28; 12(1). PMID: 31877721    Free PMC article.
A functional antibody cross-reactive to both human and murine cytotoxic T-lymphocyte-associated protein 4 via binding to an N-glycosylation epitope.
Dong Li, Jing Li, Huanyu Chu, Zhuozhi Wang.
MAbs, 2020 Feb 15; 12(1). PMID: 32054416    Free PMC article.
CTLA-4: a moving target in immunotherapy.
Behzad Rowshanravan, Neil Halliday, David M Sansom.
Blood, 2017 Nov 10; 131(1). PMID: 29118008    Free PMC article.
Highly Cited. Review.
Combination therapy with F5/35 fiber chimeric conditionally replicative adenoviruses expressing IL-24 enhances the antitumor effect of temozolomide against melanoma.
Ming Yang, Chunsheng Yang, +8 authors, Yanqun Liu.
Cancer Med, 2018 Nov 09; 7(12). PMID: 30406970    Free PMC article.
Combination Strategies to Optimize Efficacy of Dendritic Cell-Based Immunotherapy.
Mandy van Gulijk, Floris Dammeijer, Joachim G J V Aerts, Heleen Vroman.
Front Immunol, 2018 Dec 21; 9. PMID: 30568653    Free PMC article.
Computational Redesign of PD-1 Interface for PD-L1 Ligand Selectivity.
Rojan Shrestha, Sarah C Garrett, Steven C Almo, Andras Fiser.
Structure, 2019 Apr 02; 27(5). PMID: 30930066    Free PMC article.
Determinants of Resistance to Checkpoint Inhibitors.
Linda Tran, Dan Theodorescu.
Int J Mol Sci, 2020 Mar 01; 21(5). PMID: 32111080    Free PMC article.
Development of immune checkpoint therapy for cancer.
Jill M Fritz, Michael J Lenardo.
J Exp Med, 2019 May 10; 216(6). PMID: 31068379    Free PMC article.
Highly Cited. Review.
Preponderance of CTLA4 Variation Associated With Autosomal Dominant Immune Dysregulation in the MYPPPY Motif.
Owen M Siggs, Amanda Russell, +6 authors, Christopher C Goodnow.
Front Immunol, 2019 Aug 10; 10. PMID: 31396201    Free PMC article.
Immune-Related Adverse Events: Pneumonitis.
Linda Zhong, Mehmet Altan, Vickie R Shannon, Ajay Sheshadri.
Adv Exp Med Biol, 2020 Apr 18; 1244. PMID: 32301020    Free PMC article.
T cell costimulation, checkpoint inhibitors and anti-tumor therapy.
Dipankar Nandi, Sanmoy Pathak, +6 authors, Vijayamahantesh.
J Biosci, 2020 Apr 30; 45. PMID: 32345776
Heterogeneous responses in hepatocellular carcinoma: the achilles heel of immune checkpoint inhibitors.
Zuyuan Lin, Di Lu, +2 authors, Xiao Xu.
Am J Cancer Res, 2020 May 06; 10(4). PMID: 32368387    Free PMC article.
Mathematical Prostate Cancer Evolution: Effect of Immunotherapy Based on Controlled Vaccination Strategy.
Dorota Ba Dziul, Paweł Jakubczyk, +4 authors, Sylwia Chmiel-Szajner.
Comput Math Methods Med, 2020 May 16; 2020. PMID: 32411286    Free PMC article.
Impact of the Protein Data Bank on antineoplastic approvals.
John D Westbrook, Rose Soskind, Brian P Hudson, Stephen K Burley.
Drug Discov Today, 2020 Feb 19; 25(5). PMID: 32068073    Free PMC article.
High-Risk HPV Oncoproteins and PD-1/PD-L1 Interplay in Human Cervical Cancer: Recent Evidence and Future Directions.
Soumaya Allouch, Ahmed Malki, +3 authors, Ala-Eddin Al Moustafa.
Front Oncol, 2020 Jul 23; 10. PMID: 32695664    Free PMC article.
Harnessing the Complete Repertoire of Conventional Dendritic Cell Functions for Cancer Immunotherapy.
Lukas Amon, Lukas Hatscher, +2 authors, Christian H K Lehmann.
Pharmaceutics, 2020 Jul 18; 12(7). PMID: 32674488    Free PMC article.
Immunotherapy for hepatocellular carcinoma: recent advances and future perspectives.
Weiqi Xu, Ken Liu, +4 authors, Jiansong Ji.
Ther Adv Med Oncol, 2019 Aug 07; 11. PMID: 31384311    Free PMC article.
Tumor Microenvironment: Implications in Melanoma Resistance to Targeted Therapy and Immunotherapy.
Italia Falcone, Fabiana Conciatori, +4 authors, Michele Milella.
Cancers (Basel), 2020 Oct 11; 12(10). PMID: 33036192    Free PMC article.
Molecular Interactions of Antibody Drugs Targeting PD-1, PD-L1, and CTLA-4 in Immuno-Oncology.
Hyun Tae Lee, Sang Hyung Lee, Yong-Seok Heo.
Molecules, 2019 Mar 29; 24(6). PMID: 30917623    Free PMC article.
The Role of Antigen Processing and Presentation in Cancer and the Efficacy of Immune Checkpoint Inhibitor Immunotherapy.
Anastasia Mpakali, Efstratios Stratikos.
Cancers (Basel), 2021 Jan 08; 13(1). PMID: 33406696    Free PMC article.
The Therapeutic Potential of Regulatory T Cells: Challenges and Opportunities.
Fatemeh Bayati, Mahsa Mohammadi, +3 authors, Ehsan Sharif-Paghaleh.
Front Immunol, 2021 Feb 02; 11. PMID: 33519807    Free PMC article.
PD-L1 and B7-1 Cis-Interaction: New Mechanisms in Immune Checkpoints and Immunotherapies.
Christopher D Nishimura, Marc C Pulanco, +2 authors, Xingxing Zang.
Trends Mol Med, 2020 Nov 18; 27(3). PMID: 33199209    Free PMC article.
Generating tumor-selective conditionally active biologic anti-CTLA4 antibodies via protein-associated chemical switches.
Hwai Wen Chang, Gerhard Frey, +4 authors, Jay M Short.
Proc Natl Acad Sci U S A, 2021 Feb 26; 118(9). PMID: 33627407    Free PMC article.
CTLA-4 in Regulatory T Cells for Cancer Immunotherapy.
Navid Sobhani, Dana Rae Tardiel-Cyril, +3 authors, Yong Li.
Cancers (Basel), 2021 Apr 04; 13(6). PMID: 33809974    Free PMC article.
Cancer immunotherapies revisited: state of the art of conventional treatments and next-generation nanomedicines.
Coral García-Fernández, Anna Saz, Cristina Fornaguera, Salvador Borrós.
Cancer Gene Ther, 2021 Apr 11; 28(9). PMID: 33837365
The Tumor Microenvironment Factors That Promote Resistance to Immune Checkpoint Blockade Therapy.
Bonnie L Russell, Selisha A Sooklal, +2 authors, Monde Ntwasa.
Front Oncol, 2021 Jul 17; 11. PMID: 34268109    Free PMC article.
Molecular Dynamics Simulations Reveal Interactions of an IgG1 Antibody With Selected Fc Receptors.
Sebastjan Kralj, Milan Hodošček, +4 authors, Janez Konc.
Front Chem, 2021 Jul 20; 9. PMID: 34277572    Free PMC article.
A comparative study of immunotherapy as second-line treatment and beyond in patients with advanced non-small-cell lung carcinoma.
Jerónimo Rafael Rodríguez-Cid, Sonia Carrasco-Cara Chards, +14 authors, Patricio Santillán-Doherty.
Lung Cancer Manag, 2021 Aug 20; 10(3). PMID: 34408789    Free PMC article.
Nanobody-based CTLA4 inhibitors for immune checkpoint blockade therapy of canine cancer patients.
Jonathan Marable, Damien Ruiz, +8 authors, Maninder Sandey.
Sci Rep, 2021 Oct 23; 11(1). PMID: 34675296    Free PMC article.
New insights into exosome mediated tumor-immune escape: Clinical perspectives and therapeutic strategies.
Anup S Pathania, Philip Prathipati, Kishore B Challagundla.
Biochim Biophys Acta Rev Cancer, 2021 Sep 07; 1876(2). PMID: 34487817    Free PMC article.
The foundations of immune checkpoint blockade and the ipilimumab approval decennial.
Alan J Korman, Sarah C Garrett-Thomson, Nils Lonberg.
Nat Rev Drug Discov, 2021 Dec 24;. PMID: 34937915
Our current understanding of checkpoint inhibitor therapy in cancer immunotherapy.
Elena Goleva, Taras Lyubchenko, +3 authors, Jeffrey A Kern.
Ann Allergy Asthma Immunol, 2021 Mar 16; 126(6). PMID: 33716146    Free PMC article.
Pulmonary Toxicities of Immunotherapy.
Mehmet Altan, Linda Zhong, Vickie R Shannon, Ajay Sheshadri.
Adv Exp Med Biol, 2022 Jan 02; 1342. PMID: 34972974
The new insight of treatment in Cholangiocarcinoma.
Yuhang Li, Yinghui Song, Sulai Liu.
J Cancer, 2022 Jan 25; 13(2). PMID: 35069894    Free PMC article.
Application of Noninvasive Imaging to Combined Immune Checkpoint Inhibitors for Breast Cancer: Facts and Future.
Zhongquan Cheng, Yang Du, +2 authors, Jie Tian.
Mol Imaging Biol, 2022 Feb 02; 24(2). PMID: 35102468
Biomarkers for response to immune checkpoint inhibitors in gastrointestinal cancers.
Meng Li, Denis Kaili, Lei Shi.
World J Gastrointest Oncol, 2022 Feb 05; 14(1). PMID: 35116101    Free PMC article.
Inborn Errors of Immunity and Their Phenocopies: CTLA4 and PD-1.
Yuwei Hao, Matthew C Cook.
Front Immunol, 2022 Feb 15; 12. PMID: 35154081    Free PMC article.
Cardiotoxicity risk factors with immune checkpoint inhibitors.
Zachary L Brumberger, Mary E Branch, +3 authors, Sujethra Vasu.
Cardiooncology, 2022 Mar 13; 8(1). PMID: 35277208    Free PMC article.
Addressing the Elephant in the Immunotherapy Room: Effector T-Cell Priming versus Depletion of Regulatory T-Cells by Anti-CTLA-4 Therapy.
Megan M Y Hong, Saman Maleki Vareki.
Cancers (Basel), 2022 Mar 26; 14(6). PMID: 35326731    Free PMC article.
Combination targeted and immune therapy in the treatment of advanced melanoma: a valid treatment option for patients?
Shahla Bari, Jameel Muzaffar, Zeynep Eroglu.
Ther Adv Med Oncol, 2022 Apr 29; 14. PMID: 35478991    Free PMC article.
High-throughput virtual screening of small-molecule inhibitors targeting immune cell checkpoints to discover new immunotherapeutics for human diseases.
Satyendra Singh, Ketan Kumar, +3 authors, Vijay Kumar Prajapati.
Mol Divers, 2022 May 29;. PMID: 35633442