Background
History of anti-PD drug development and the roles of Lieping Chen
Contributions | CTLA-4 | PD-1 | PD-L1 (B7-H1) |
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Gene Cloning | Pierre Goldstein (1987) [59] | Tasuku Honjo (1992) [57] |
Lieping Chen (1999) [47] |
Inhibitory Function | Jeffery Bluestone (1994) [30] Arlene Sharpe (1995) [32] Tak Mak (1995) [33] | Tasuku Honjo (1999) [60] |
Lieping Chen (1999) [47] Tasuku Honjo, Clive Wood (2000) [57] b
Lieping Chen (2004) [68] |
Ligand-receptor Interaction | Peter Linsley (1991) [25] | Tasuku Honjo, Clive Wood (2000) [57] b
| Tasuku Honjo, Clive Wood (2000) [57] b
|
Function in cancer immunity | James Allison (1996) [34] | NagahiroMinato (2002) [63]
Lieping Chen (2005) [70] Tasuku Honjo (2005) [71] |
Lieping Chen (2002) [56] Nagahiro Minato (2002) [63] |
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In 1992, Tasuku Honjo cloned the PD-1 gene (Pdcd1) from immune cell lines undergoing apoptosis [58].
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In 1994, Jeffery Bluestone first identified the inhibitory function of CTLA-4, and also categorized CTLA-4 as the first cell surface T cell inhibitory receptor [30]*.*Note: During the process of drug development targeting this molecule, Pierre Goldstein cloned CTLA-4 gene (Ctla4) [59] and Peter Linsley discovered the receptor-ligand interaction between B7 and CTLA-4 [25] (Table 1). Arlene Sharpe and Tak Mak subsequently reported the fatal autoimmune diseases of Ctla4-deficient mice [32, 33]. James Allison characterized the anti-tumor effect of antibody targeting CTLA-4 [34]. The anti-CTLA-4 antibody, ipilimumab, was later approved by the U.S. Food and Drug Administration (FDA) for treatment of melanoma in 2011 [37].
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In 1997, Lieping Chen identified the potent anti-tumor effect of agonistic antibody targeting 4-1BB, another co-stimulatory receptor on T cells, which further inspired the field of cancer immunotherapy [43].
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Around 1997, given the progress of the Human Genome Project, Lieping Chen’s group started to search for B7-like molecules from the human EST libraries, thus began his seminal works on expanding the members of the B7 family.
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In 1999, Tasuku Honjo discovered that the PD-1 gene (Pdcd1) knockout mice have mild autoimmune symptoms, which revealed the inhibitory function of PD-1 in preventing autoimmunity [60].
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In 2000, Tasuku Honjo and Clive Wood discovered the interaction between B7-H1 and PD-1, and changed the name of B7-H1 to PD-L1 [57].
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In 2001, Arlene Sharpe and Gordon Freeman discovered another PD-1 ligand, PD-L2 (Programmed Death Ligand 2), which also shows inhibitory activity to T cells [61]. Drew Pardoll’s group identified PD-L2 around the same time, and named this molecule B7-DC for its specific expression on dendritic cells [62].
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In 2002, Lieping Chen discovered the critical role of B7-H1 (PD-L1) as a potential immune evasion mechanism in the tumor microenvironment. B7-H1 is found to be overexpressed in many human tumor tissues, but minimally detected in the normal tissues, which was mainly regulated by IFN-γ [56]. Most importantly, antibody-targeting B7-H1 could restore T cell function and control tumor growth both in vitro and in vivo [56]. Subsequent works by Nagahiro Minato [63] and Weiping Zou [64] further supported this finding. Moreover, Chen’s study suggested the existence of other receptor(s) for B7-H1, which was later validated by a follow-up mutation study made by Chen [65], and finally led to the discovery of B7-1 as another B7-H1 inhibitory receptor by Arlene Sharpe and Gordon Freeman [66].
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In 2003, Scott Strome and Lieping Chen showed that B7-H1 overexpression in tumor cells and T cell activation are two indispensable pre-conditions for the potent anti-cancer effect of antibodies blocking this pathway [67].
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In 2004, Lieping Chen discovered that the B7-H1 gene (Cd274) null mice have some spontaneous accumulation of activated CD8+ T cells in the liver, but do not have overt autoimmune manifestations. This work further proved the inhibitory function of B7-H1 and predicted the acceptable safety profile of B7-H1-targeted therapy [68]. An independent study by Arlene Sharpe and Gordon Freeman using Cd274-deficient mice also proved that PD-L1 negatively regulates T cells [69].
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In 2004, Lieping Chen joined the Johns Hopkins University School of Medicine, and contributed to the development of the first-in-human trial concept on antibodies targeting the PD-1/PD-L1 pathway for the treatment of advanced cancers.
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In 2005, Lieping Chen demonstrated that antibodies blocking either B7-H1 or PD-1 could promote antitumor immune responses, and proposed the “Molecular Shield” mechanism of PD-L1 on tumors that offers resistance to cytotoxic T lymphocytes (CTL) [70]. Tasuku Honjo also demonstrated that PD-1 blockade by genetic manipulation or antibody treatment inhibited hematogenous spreading of tumor cells [71].
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In 2006, Rafi Ahmed characterized a role of the PD-1/PD-L1 pathway in T cell exhaustion with the lymphocytic choriomeningitis virus (LCMV) chronic infection model [72].
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In 2006, the first human cancer clinical trial targeting the PD-1/PD-L1 pathway was launched in the Johns Hopkins Hospital.
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In 2010, the first clinical observation on anti-PD-1 treatment was reported by Suzanne Topalian [73].
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In 2006, Lieping Chen’s group developed a sensitive and effective immunohistochemistry staining protocol for detecting PD-L1 expression in cancer cells, and pointed out the value of PD-L1 staining in tumor sections on the prediction of anti-PD-1/PD-L1 clinical efficacy in 2012. Chen also refined his theory on anti-PD-1/PD-L1 therapy by proposing the adaptive resistance concept [76].