PD-1/PD-L1 Blockade: Have We Found the Key to Unleash the Antitumor Immune Response?
Reads0
Chats0
TLDR
Improve understanding of the efficacy of PD-1/PD-L1 blockade immunotherapy, as well as enhance the development of therapeutic strategies to overcome the resistance mechanisms and unleash the antitumor immune response to combat cancer.Abstract:
PD-1-PD-L1 interaction is known to drive T cell dysfunction, which can be blocked by anti-PD-1/PD-L1 antibodies. However, studies have also shown that the function of the PD-1-PD-L1 axis is affected by the complex immunologic regulation network, and some CD8+ T cells can enter an irreversible dysfunctional state that cannot be rescued by PD-1/PD-L1 blockade. In most advanced cancers, except Hodgkin lymphoma (which has high PD-L1/L2 expression) and melanoma (which has high tumor mutational burden), the objective response rate with anti-PD-1/PD-L1 monotherapy is only ~20%, and immune-related toxicities and hyperprogression can occur in a small subset of patients during PD-1/PD-L1 blockade therapy. The lack of efficacy in up to 80% of patients was not necessarily associated with negative PD-1 and PD-L1 expression, suggesting that the roles of PD-1/PD-L1 in immune suppression and the mechanisms of action of antibodies remain to be better defined. In addition, important immune regulatory mechanisms within or outside of the PD-1/PD-L1 network need to be discovered and targeted to increase the response rate and to reduce the toxicities of immune checkpoint blockade therapies. This paper reviews the major functional and clinical studies of PD-1/PD-L1, including those with discrepancies in the pathologic and biomarker role of PD-1 and PD-L1 and the effectiveness of PD-1/PD-L1 blockade. The goal is to improve understanding of the efficacy of PD-1/PD-L1 blockade immunotherapy, as well as enhance the development of therapeutic strategies to overcome the resistance mechanisms and unleash the antitumor immune response to combat cancer.read more
Citations
More filters
Journal ArticleDOI
Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors
TL;DR: Biomarkers reflecting tumor immune microenvironment and tumor cell intrinsic features, such as PD-L1 expression, density of tumor infiltrating lymphocyte (TIL), tumor mutational burden, and mismatch-repair (MMR) deficiency, have been noticed to associate with treatment effect of anti-PD-1/anti-PD.
Journal ArticleDOI
Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis.
Xian Shen,Bin Zhao +1 more
TL;DR: It is suggested that PD-L1 expression status alone is insufficient in determining which patients should be offered PD-1 or PD- L1 blockade therapy, which is a preferable treatment option over conventional therapy for both patients that are PD- l1 positive and PD-l1 negative.
Journal ArticleDOI
PD-1/PD-L1 pathway: Basic biology and role in cancer immunotherapy
Arash Salmaninejad,Arash Salmaninejad,Saeed Farajzadeh Valilou,Arezoo Gowhari Shabgah,Saeed Aslani,Malihe Alimardani,Alireza Pasdar,Alireza Pasdar,Amirhossein Sahebkar +8 more
TL;DR: The promotion of cancer immunotherapy targeting PD‐1 immunoinhibitory pathway is discussed and attempts to identify novel and well‐suited predictive biomarkers are sensed.
Journal Article
RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance (IRC5P.465)
Yanping Xiao,Sanhong Yu,Baogong Zhu,Denis Bedoret,Xia Bu,Loise M. Francisco,Ping Hua,Jonathan S. Duke-Cohan,Dale T. Umetsu,Arlene H. Sharpe,Arlene H. Sharpe,Rosemarie H. DeKruyff,Gordon J. Freeman +12 more
TL;DR: In this article, the authors showed that PD-L2 binding to repulsive guidance molecule b (RGMb) significantly impaired the development of respiratory tolerance by interfering with the initial T cell expansion required for respiratory tolerance.
Journal ArticleDOI
ATR kinase inhibitor AZD6738 potentiates CD8+ T cell–dependent antitumor activity following radiation
Frank P. Vendetti,Pooja Karukonda,David A. Clump,Troy P. Teo,R. Lalonde,Katriana Nugent,Matthew Ballew,Brian F. Kiesel,Jan H. Beumer,Saumendra N. Sarkar,Thomas P. Conrads,Mark J. O'Connor,Robert L. Ferris,Phuoc T. Tran,Greg M. Delgoffe,Christopher J. Bakkenist +15 more
TL;DR: It is shown that the ATR kinase inhibitor AZD6738 combines with conformal radiation therapy to attenuate radiation-induced CD8+ T cell exhaustion and potentiate T cell activity in mouse models of Kras-mutant cancer.
References
More filters
Journal ArticleDOI
Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses.
TL;DR: PD-1 was suggested to be involved in the negative regulation for particular aspects of B cell proliferation and differentiation including class switching.
Journal ArticleDOI
Avelumab, an Anti-Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study.
Andrea B. Apolo,Jeffrey R. Infante,Ani Sarkis Balmanoukian,Manish R. Patel,Ding Wang,Karen Kelly,Anthony Mega,Carolyn D. Britten,Alain Ravaud,Alain C. Mita,Howard Safran,Thomas E. Stinchcombe,Marko Srdanov,Arnold B. Gelb,Michael Schlichting,Kevin M. Chin,James L. Gulley +16 more
TL;DR: Avelumab was well tolerated and associated with durable responses and prolonged survival in patients with refractory metastatic metastatic UC and PD-L1–associated clinical activity.
Journal ArticleDOI
Pembrolizumab for Platinum- and Cetuximab-Refractory Head and Neck Cancer: Results From a Single-Arm, Phase II Study.
Joshua Bauml,Tanguy Y. Seiwert,David G. Pfister,Francis P. Worden,Stephen V. Liu,Jill Gilbert,Nabil F. Saba,Jared Weiss,Lori J. Wirth,Ammar Sukari,Hyunseok Kang,Michael K. Gibson,Erminia Massarelli,Steven M. Powell,Amy Meister,Xinxin Shu,Jonathan D. Cheng,Robert I. Haddad +17 more
TL;DR: Pembrolizumab exhibited clinically meaningful antitumor activity and an acceptable safety profile in recurrent/metastatic head and neck squamous cell carcinoma previously treated with platinum and cetuximab and in subgroups on the basis of programmed death ligand 1 (PD-L1) expression and human papillomavirus (HPV) status.
Journal ArticleDOI
Deubiquitination and Stabilization of PD-L1 by CSN5
Seung Oe Lim,Chia Wei Li,Weiya Xia,Jong Ho Cha,Li Chuan Chan,Yun Wu,Shih Shin Chang,Shih Shin Chang,Wan Chi Lin,Jung Mao Hsu,Yi Hsin Hsu,Taewan Kim,Wei Chao Chang,Jennifer L. Hsu,Hirohito Yamaguchi,Qingqing Ding,Yan Wang,Yi Yang,Chung-Hsuan Chen,Aysegul A. Sahin,Dihua Yu,Dihua Yu,Gabriel N. Hortobagyi,Mien Chie Hung +23 more
TL;DR: It is demonstrated that COP9 signalosome 5 (CSN5), induced by NF-κB p65, is required for TNF-α-mediated PD-L1 stabilization in cancer cells, and inhibition of CSN5 by curcumin diminished cancer cell PD- L1 expression and sensitized cancer cells to anti-CTLA4 therapy.
Journal ArticleDOI
Programmed Death-Ligand 1 Expression and Response to the Anti–Programmed Death 1 Antibody Pembrolizumab in Melanoma
Adil Daud,Jedd D. Wolchok,Caroline Robert,Wen-Jen Hwu,Jeffrey S. Weber,Antoni Ribas,F. Stephen Hodi,Anthony M. Joshua,Richard F. Kefford,Richard F. Kefford,Richard F. Kefford,Peter Hersey,Richard W. Joseph,Tara C. Gangadhar,Roxana S. Dronca,Amita Patnaik,Hassane M. Zarour,Charlotte Roach,Grant Toland,Jared Lunceford,Xiaoyun Nicole Li,Kenneth Emancipator,Marisa Dolled-Filhart,S. Peter Kang,Scot Ebbinghaus,Omid Hamid +25 more
TL;DR: PD-L 1 expression in pretreatment tumor biopsy samples was correlated with response rate, PFS, and OS; however, patients with PD-L1-negative tumors may also achieve durable responses.
Related Papers (5)
Oncology Meets Immunology: The Cancer-Immunity Cycle
PD-1 blockade induces responses by inhibiting adaptive immune resistance
Paul C. Tumeh,Christina L. Harview,Jennifer H. Yearley,I. Peter Shintaku,Emma Taylor,Lidia Robert,Bartosz Chmielowski,Marko Spasic,Gina Henry,Voicu Ciobanu,Alisha N. West,Manuel Carmona,Christine Kivork,Elizabeth Seja,Grace Cherry,Antonio Gutierrez,Tristan Grogan,Christine Mateus,Gorana Tomasic,John A. Glaspy,Ryan O. Emerson,Harlan Robins,Robert H. Pierce,David Elashoff,Caroline Robert,Antoni Ribas +25 more
Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer
Julie R. Brahmer,Scott S. Tykodi,Scott S. Tykodi,Laura Q.M. Chow,Wen-Jen Hwu,Suzanne L. Topalian,Patrick Hwu,Charles G. Drake,Luis H. Camacho,John S. Kauh,Kunle Odunsi,Henry C. Pitot,Omid Hamid,Shailender Bhatia,Renato G. Martins,Keith D. Eaton,Shuming Chen,Theresa M. Salay,Suresh Alaparthy,Joseph F. Grosso,Alan J. Korman,Susan M. Parker,Shruti Agrawal,Stacie M. Goldberg,Drew M. Pardoll,Ashok Kumar Gupta,Jon M. Wigginton +26 more