01.12.2017 | Review | Ausgabe 1/2017 Open Access

PD-1, PD-L1 (B7-H1) and Tumor-Site Immune Modulation Therapy: The Historical Perspective
- Zeitschrift:
- Journal of Hematology & Oncology > Ausgabe 1/2017
Background
History of anti-PD drug development and the roles of Lieping Chen
Contributions
|
CTLA-4
|
PD-1
|
PD-L1 (B7-H1)
|
---|---|---|---|
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].
-
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].
-
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].
-
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].
-
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].
-
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.
-
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].