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Overview of immuno-oncology
Overview of immuno-oncologyIn 2011, ipilimumab was approved for the treatment of melanoma, marking the beginning
of the tumor immunotherapy revolution.
Tumor immunotherapy has had a great impact on the comprehensive treatment mode of tumors, and has become a new tumor treatment method
after surgical treatment, chemoradiotherapy and molecular targeted drug therapy.
In 2013, tumor immunotherapy was named the first
scientific breakthrough of the year by Sdmce magazine.
The 2018 Nobel Prize in Physiology or Medicine was awarded to American scientist James Allison and Japanese scientist Yu Honjo for their contributions
to the discovery of therapies for negative immunomodulatory treatment of cancer.
In the past 10 years, tumor immunotherapy has made breakthroughs and obtained good clinical efficacy
.
Tumor immunotherapies represented by immune checkpoint inhibitors, adoptive cell therapies, tumor vaccines, etc.
have entered the market one after another
, bringing more treatment options
to cancer patients.
With the increasing attention of researchers to tumor immunotherapy, more and more potential targets of tumor immunotherapy have been gradually discovered, including programmed death receptor 1/programmed death receptor ligand 1 (
programmed cell death protein 1/programmed cell death ligand-1, PD-l/PDLl), cytotoxicity
CytotoxicT-lymphocyte-associated antigen 4 (CTLA~4), B
B cell maturation antigen (BCMA), T cell immunoglobulin mucin-3
domain and mucin domain-3, TIM-3), lymphocyte activation gene 3 (LAG3).
), blood cell group differentiation antigen (CD) 19, CD4 7, etc
.
At present, the most widely studied tumor immunotherapies are mainly immune checkpoint inhibitors against PD-1/PD-L1 and chimeric antigen receptor T cells
receptor-T cell, CAR-T) therapy
.
As of April I, 2021, there are 11 PD-1/PD-L1 antibody drugs approved for marketing worldwide
The approved indications mainly include melanoma, non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, colorectal cancer, head and neck cancer, Hodgkin lymphoma, etc.
; There are 5 CAR-T cell therapies approved for marketing
, approved indications for lymphoma, acute lymphoblastic leukemia and multiple myeloma and other hematological tumors
.
With the gradual expansion of the clinical application of CAR-T therapy
Some defects have also emerged: therapeutic antibodies can only recognize extracellular proteins, which has limited efficacy on patients, and is accompanied by shortcomings such as poor tissue permeability, long half-life, low bioavailability, difficult production, and high cost; CAR-T
Cell therapy has only made breakthroughs in the field of hematological tumors so far, and has not yet achieved satisfactory results
for solid tumors.
Compared to most antibody drugs, small molecule drugs have better tissue permeability, allowing them to directly target intracellular or extracellular targets to enhance the anti-tumor immune response
.
In addition, the relatively short half-life can reduce the accumulation of small molecule drugs in circulation, thereby reducing the risk of
systemic toxicity.
These characteristics have prompted small molecule tumor immunotherapy drugs to receive widespread attention in recent years, and are expected to be used as a supplement to antibody drugs, further improving the efficacy of immunotherapy and reducing toxicity
.
Small molecule tumor immunotherapy drugs
Small molecule tumor immunotherapy drugsAt present, some positive progress
has been made in the research and development of small molecule immune drugs.
Targets for the action of small molecule immunodrugs in clinical research (see Figure 1)
Mainly including: PD-1/PD-L1, stimulator of interferon genes (STING)
, indoleamine-2,3-dioxygenase (IDO), adenosine2A receptor
receptor, A2AR), chemokine receptor, toll like receptor (TLR), tretinoin-associated orphan receptor γt (
retinoicacid receptor-related orphan receptor γt , RORγt ), arginases (arginases,
ARG), T cell activated immunoglobulin suppressor of T-cell
activation, VISTA), transforming growth factor β
, TGF-β), etc
.
Based on these targets, this article introduces
small molecule immune drugs with rapid development progress.
2.
1 PD-1/PD-L1 inhibitors
1 PD-1/PD-L1 inhibitors
PD-1 was discovered and named by Japanese scholars in 1992 as a type I transmembrane glycoprotein
of the B7/CD28 family.
As a surface receptor for activating T cells, PD-1 is associated with antigen-presenting cells (
Ligands on the surface of antigen presenting cells (APCs) can inhibit the activation of T cells, thereby playing an immunosuppressive role
.
However, tumor cells can use this inhibitory pathway to induce PD-L1 expression on their surface, thereby inhibiting T cells and achieving immune escape
.
Blocks PD-1 and PD-L1
The interaction can reverse the immunosuppressive state and improve the killing ability of the body's immune cells to tumor cells
.
There are already a number of needle-to-PD-L/P D-L
L's therapeutic antibody has been approved for marketing and has achieved good efficacy
.
However, not all patients benefit from existing PD-1 antibody drugs, and PD-1 antibodies are shown in 50% in melanoma treatment
The response rate is around that, but the overall response rate for other solid tumors is generally low, about 20%.
PD-1/PD-L1 small molecule inhibitors as a supplement to antibody drugs, are currently mostly in the early stage of development, and there are 4 drugs under development in the clinical research stage (see Table 1), and the fastest progress is C
The CA-170
jointly developed by URIS and Aurigene.
CA-170 is a dual inhibitor of small molecule PD-L1/VISTA that has been studied in a number of clinical applications including lymphoma, mesothelioma, and non-small cell lung cancer
.
In animal experiments, CA-170 significantly eliminates PD-L1 inhibition of T cells, promotes T cell differentiation and proliferation, and induces interferon 1 (IFN-7).
) production
.
CA-170 exhibits similar antitumor activity
to PD-1 monoclonal antibody in a variety of in vivo tumor models.
From the current clinical data, CA-170 has the best efficacy for non-small cell lung cancer and Hodgkin lymphoma, and the total clinical benefit rate (clinical benefit
rate, CBR) was 70% and 77.
8%, respectively, and the CA-170 low-dose group (400 mg•(T1) was more effective than the low-dose group (800 mgcT1).
In addition, CA-170 is superior to PD-1 monoclonal antibodies in terms of biosafety, at doses up to 1200 rngd
-1 is well tolerated INCB486550, developed by Incyte, is an oral PD-L1
Inhibitors for the treatment of advanced solid tumors with investigational indications for non-small cell lung cancer, urothelial carcinoma, renal cell carcinoma, hepatocellular carcinoma, and melanoma
.
In April 2019, the company was presented at the American Association for Cancer Research (AACR) annual meeting
In vitro data from INCB486550, which induces PD-L1 in cells
Dimerization and reduction of PD-L1
on the cell surface.
In October 2020, the Company initiated an open-label, non-randomized Phase II clinical trial (NCT04629339) to evaluate the safety and efficacy
of INCB486550 as an immune checkpoint inhibitor in patients with solid tumors.
2.
2 STING agonists
2 STING agonists
STING is an important adaptor protein
anchored in the endoplasmic reticulum to sense human invasion of foreign DNA.
STING, as a key signal transduction molecule involved in innate immune responses, is mainly promoted by cyclic guanylate-adenylate syntheses (
The cyclic GMP-AMP synthase (cGAS)-STING signaling pathway plays an important role
in viral infections, autoimmune diseases, and tumor immunotherapy.
CGAS recognizes D N A in the cytoplasm and develops dimerization, catalyzing the reaction of guanosine triphosphate (GTP) to A T P 2
'3'-cyclic guanylate-adenylate (cyclic GMP-AMP, cGAMP) activates the STING protein, resulting in a change
in STING conformation.
SUBSEQUENTLY, STING USED A VESICLE TRANSPORT SYSTEM TO REALIZE THE TRANSPORT OF THE ENDOPLASMIC RETICULUM TO THE URGI APPARATUS, RECRUITING TANK BINDING KINASE 1 IN THE GOLGI APPARATUS
1, TBK1), thereby activating interferon regulatory factor IRF-3, inducing I
Interferon production and regulation of anti-tumor innate immune response
.
At present, regulating the cGASSTING signaling pathway has become an important new immunotherapy strategy for tumors and autoimmune diseases, and STING modulators have also become a successor to PD-1/PD-L1
and other immune checkpoint inhibitors are one of the most potential tumor-free treatment drugs
.
At present, the development of STING agonist antitumor drugs has made great progress, there are 11 small molecule STING agonists in the clinical research stage, and 4 drugs are under research that are advancing rapidly
IMSA-101, ADU-S100, exoSTING and MK-1454 (see Table 2).
From the perspective of molecular structure, the STING agonists currently under research can be mainly divided into 5 categories, namely cyclic dinucleotides and aminobenzimidazoles
, cotonones and acridones, benzothiophenes, and benzodiocenes
.
Originally developed by Aduro Biotechnology and later licensed to Novartis, ADU-S100 is a cyclic dinucleotide immunomodulator administered by direct intratumoral injection, either as a single agent or in combination with cytotoxic chemotherapy, targeted therapy, or checkpoint inhibitors, and is currently undergoing II clinical trials for metastatic head and neck cancer and squamous cell carcinoma (NCT03937141).
)
。
In preclinical studies, ADU-S100 exhibited some ectopic effects , and ADU-S100 may have a remote effect
on tumors not directly administered even when administered topically.
Experimental data from mice suggest that the dose of ST1NG agonist is critical for anti-tumor immunity, and low-dose ADU-S100 treatment can induce durable CD8+ T
Cellular immune response, and high doses of ADU-S100 treatment are likely to induce CD8+ T cell apoptosis, impairing lasting immune responses
.
MK-1454 is a cyclic dinucleotide developed by Merck
STING agonists, intended for the intratumoral treatment
of metastatic solid tumors, lymphomas, or squamous cell carcinoma of the head and neck.
In March 2020, the Company initiated a Phase II clinical trial (NCT04220866) to evaluate M
Efficacy
of K-1454 in combination with pembrolizumab in first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma.
2.
3 IDOl inhibitors
3 IDOl inhibitors
The cynurenine pathway metabolized by tryptophan (L-Trp) plays an important role
in immunomodulation.
The first step on the pathway is also the speed limit step, by
ID01, ID02 and tryptophan 2,3-dioxygenase (TD0) catalyzed
.
1D01, ID0 2, and TD0
Although they all catalyze the same biochemical reactions, they show significant differences
in structure, tissue distribution, and substrate specificity.
ID01 is overexpressed in tumor cells and APCs, creating an immunosuppressive microenvironment for tumor cells to evade effective immune responses
.
TD0 also has a similar immunosuppressive effect, but is abnormally expressed
mainly in liver cancer.
And ID02 catalyzes L-T
The activity of RP metabolism is extremely low, and there is basically no abnormal expression in the pathological state, and whether it is related to tumor immune response is still controversial
.
In animal tumor models, ID01 inhibition at the gene or cellular level activates an anti-tumor immune response
.
In recent years, ID01 single-target inhibitors and
ID01/TD0 dual target inhibitors are considered to be one of
the promising anti-tumor small molecule immunotherapies.
At present, there are 7 small molecule ID01 inhibitors in the clinical research stage, 3 ID01/TD0 dual-target inhibitors, and the drug under development with relatively rapid research and development progress is linrodostat.
Epacadostat and Indoximod (see Table 3).
linrodostat is an oral ID0 1 developed by Bristol-Myers Squibb
Inhibitors, mainly intended for the treatment
of bladder cancer and melanoma.
Currently, linrodostat in combination with nivolumab is used in phase III clinical trials of advanced melanoma (NCT03329846).
), and a Phase III clinical trial evaluating linrodistat in combination with neoadjuvant chemotherapy and nivolumah for the treatment of bladder cancer (NCT03661320) are
ongoing.
epacadostat is an N-merylamidine selective ID0 1 inhibitor developed by Incyte, which is the deepest-studied tryptophan competitive ID0 1
One of the inhibitors, the indications under research include non-small cell lung cancer, colorectal cancer, pancreatic ductal adenocarcinoma, glioblastoma, sarcoma, etc
.
epacadostat is highly selective for the action of ID0 1, inhibiting half of the effective concentration of ID0 1 intracellular to ID0 2
And TDO has a weak inhibitory effect
.
Epacadostat has shown efficacy in melanoma models in frogdonts and is well
tolerated in preclinical toxicology studies.
However, in April 2018, epacadostat was associated with PD-1
The phase III clinical trial (ECHO-301/KEYNOTE-252) of the combination of pembrolizumab in the treatment of metastatic melanoma failed, and the combination did not improve progression-free survival (PFS) and overall survival (〇S)
compared with pembrolizumab alone.
Subsequently, for the combination of drugs, the Company stopped the recruitment of ongoing Phase III clinical trials for kidney cancer, bladder cancer and head and neck cancer, and converted the ongoing Phase III clinical trial of non-small cell lung cancer to a Phase II clinical trial
.
Although the development of ID01 inhibitors has not been smooth, clinical trial data for drugs such as epacadostat give it to the future
The development of ID01 inhibitors has accumulated rich experience and lessons, including the mining of potential biomarkers, the adjustment of drug doses, the selection of tumor types, and the design of clinical trial protocols
.
In addition, the expression of TD0 and ID01 in some tumors is overlapping, and TDO inhibitors and ID01/TD0 dual inhibitors are also one of the directions to be explored in the
future.
At present, there are no selective TDO inhibitors in clinical studies, and there are 3 ID01/TD0 dual inhibitors in clinical I
The phase trials were all developed by Chinese pharmaceutical companies, namely LY41013 developed by Shandong Luye Pharmaceutical Company, DN-14006131 developed by Shanghai Dino Pharmaceutical Company and Jiangsu Hengrui Pharmaceutical Company
SHR-9146
。
2.
4 A2AR antagonists
4 A2AR antagonists
Adenosine is an immunosuppressive metabolite
.
In the tumor microenvironment, adenosine works by acting on A2A R expressed on immune cells
It plays an immunosuppressive role, so that tumor cells have immune escape and cannot be killed by immune cells
.
The CD39-CD73-A2AR pathway is a key pathway
for adenosine to modulate immune responses.
Treg expresses extracellular nucleotidases (CD73, CD39)
As key enzymes that catalyze the production of adenosine, they can form adenosine by synergistic hydrolysis of A TP in tissues, thereby increasing the level of adenosine in the tumor microenvironment and enhancing tumor immune escape caused by the above pathways
.
Therefore, CD39, CD73 and A2A R are all promising to be potential drug targets in anti-tumor immunotherapy
.
At present, there are 8 A2A R anti-agents for tumor treatment that have entered the clinical research stage
The fastest progress is Corvus' ciforadenant (see Table 4)
In addition, iTeos' inupadenant, Novartis' taminadenant, AstraZeneca's im aradenant and A
The etrumadenant developed by RCUS has entered the phase II clinical study stage
.
ciforadenant was originally developed by Vernalis and later licensed
Corvus, Inc.
, is a potential oral therapy
for advanced solid tumors.
At present, the company is actively exploring ciforadenant monotherapy or combination with PD-L1 monoclonal antibody, CD73 monoclonal antibody and CD3
8 anti-tumor effect of monoclonal antibody, indications under research include renal cell carcinoma, non-small cell lung cancer, prostate cancer, breast cancer, melanoma, colorectal cancer, etc
.
In mouse experiments, ciforadenant in combination with anti-PD-L1 antibody or anti-CTLA~4 antibody showed good anti-tumor effect, and Ciforadenant can induce systemic anti-tumor immune memory
.
In January 2018, the Company initiated a Phase Ib/II clinical trial (NCT03337698) in patients with non-small cell lung cancer to evaluate the safety and efficacy
of multiple immunotherapy combinations.
In September 2020, the company held the annual meeting of the European Society for Medical Oncology (ESM0).
(Webinar) Some of the research data
from this trial were published.
The median OS in the ciforadenant and atezolizumab combination group was
11.
5 months, compared with 9.
4 months
.
In addition, the combination therapy group showed a good safety profile, and no development occurred in patients receiving the combination of ciforadenant and atezolizumab5
Grade adverse events or adverse events leading to discontinuation, whereas 1 patient receiving docetaxel chemotherapy had a grade 5 adverse event and 3 had an adverse event leading to discontinuation
.
In addition, in a phase I clinical trial (NCT02655822) of 6 8 patients with renal cell carcinoma (NCT02655822
ciforadenant can safely block adenosine signaling in vivo; In the ciforadenant monotherapy group, 17% of patients achieved stable disease (SD) for at least 6 years
months, the median PFS was 4.
1 month; Of patients receiving ciforadenant and atezumab, 3 to 9 percent achieved SD and continued to do at least6
months, with a median PFS of 5.
8 months
.
CS3005 is an A2A R antagonist developed by CStone Pharmaceuticals, a Chinese pharmaceutical company, that blocks adenosine and its A2A
R binds, thereby reversing the immunosuppressive effects of adenosine, activating the immune response and improving the response rate to immune checkpoint inhibitors
.
CS3005 will be used with other drugs such as anti
PD-1 monoclonal antibody, proteasome inhibitor, etc.
) for the treatment of advanced solid tumors, and is currently in a phase I clinical study for the treatment of solid tumors (NCT04233060).
2.
5 Chemotokine receptor inhibitors
5 Chemotokine receptor inhibitors
Chemotokine receptors are a class of G expressed on immune cells, endothelial cells, and tumor cells
Protein-coupled receptors (GPCRs).
Inhibition of chemokine receptors prevents macrophage infiltration and can induce tumor growth arrest or apoptosis
.
So far, there are about 20 chemokine receptors and 50
ligands have been reported
in the literature.
The chemokine receptors that are expected to become targets of tumor immune small molecule drugs mainly include CXC chemoreceptor factor (CXCR)2, CXCR4, C chemoket factor (CC R)2, C
C R 4 and CCR5
.
Current C X C R 1/2 orange antibiotic SX-682, C X C R 2 antagonist AZD5069, CXCR4 wilt antibody mavorixafor, CCR5
The antagonist maraviroc, the CCR2/5 antagonist BMS-813160, and the CCR4 inhibitor FLX 475 are under clinical development as monotherapy or combined immune checkpoint inhibitors (see Table 5).
)
。
CXCR4
Typically activated in a variety of solid tumors and hematopoietic malignancies, it mediates cell chemotaxis by binding to the human chemokine CXC ligand 12 (CXCL12), which promotes T
REG and myeloid-derived inhibitory cells recruit into the tumor microenvironment and promote epithelial-mesenchymal transformation, invasion, metastasis, and tumor angiogenesis
.
The CXCR4 antioxidant, mavorixafor, was originally developed by Genzyme and licensed to X4 Pharmaceuticals, and is currently being used to treat the rare disease WHIM syndrome (warts
, hypogammaglobulinemia, bacterial infections, as well as ineffective production of chronic neutrocytosis, warts-hypogammaglobulinemia-infections
myelokathexis syndrome, WHIM).
Phase Clinical Trial (NCT03995108); Treatment of metastatic clear cell carcinoma of the kidney (in combination with nivolumab, NCT02923531; In combination with axitinib ,NCT02667886 )
and lymphoma (in combination with irutinib, NCT04274738).
Phase II clinical trials; and phase I clinical trials
for the treatment of neutropenia (NCT04154488) and melanoma (in combination with pembrolizumab, NCT02823405).
SX-682 is a CXCR1 / developed by Syntrix Biosystems.
2 dual inhibitors, indications under research include melanoma, pancreatic ductal adenocarcinoma, colorectal cancer, myelodysplastic syndrome, etc
.
In January 2019, the Company initiated a Phase I/II clinical trial (NCT03161431
to test the safety and efficacy
of SX-682 as a single agent or in combination with pembrolizumab in the treatment of melanoma.
SX-682 has been shown to increase the sensitivity
of /M S-mutant tumor cells to PD-1 antibody therapy.
In October 2020, the company launched another I/
Phase II clinical trial (NCT04599140) to evaluate SX-682 monotherapy or in combination with nivolumab/M
Safety and efficacy
of S-mutant microsatellite stabilization (MSS) in patients with metastatic colorectal cancer.
The CCR5 antagonist maraviroc was acquired in the United States as early as 2007
FDA approved for marketing for the treatment
of AIDS.
A Phase I clinical study (NCT03274804) of this drug in combination with pembrolizumab in the treatment of refractory MSS type metastatic colorectal cancer is ongoing
.
BMS-813160 as CCR2/CCR5
The dual antagonist is being developed by Bristol-Myers Squibb for the oral treatment of advanced solid tumors, with indications under development for metastatic colorectal cancer, pancreatic cancer, pancreatic ductal adenocarcinoma and non-small cell lung cancer
.
The CCR4 orange anti-agent FLX4 7 5 was jointly developed by Hanmi Pharmaceutical and RAPT Therapeutics to suppress T
Migration of REGS exerts anti-tumor effects, and indications include gastric cancer, lymphoma, nasopharyngeal cancer, cervical cancer, breast cancer and non-small cell lung cancer
.
2.
6 Other small molecule tumor immunological drugs
6 Other small molecule tumor immunological drugs
In addition to the drugs under development described above, there are also some relatively in-depth small molecule tumor immunotherapies, including TL R agonists, TGF-p inhibitors, RORγt agonists, and hematopoietic progenitor cytostimulants
Enzyme 1 (hematopoietic progenitor kinase 1, HPK1) inhibitors and ARG inhibitors (see Table 6).
TLR is a type I transmembrane protein that mediates innate immune responses
.
At present, the TLR agonists for clinical research on tumor immunotherapy are mainly TLR7 and TLR8
Agonists, both mainly by mediating the activation of dendritic cells and natural killer cells, inhibiting the activation of Treg to exert their anti-tumor effects
.
imiquimod as a TLR7 agonist has been approved by FDA for the treatment
of external genital warts and basal cell tumors.
Currently the drug in combination with pembrolizumab in the treatment of melanoma I
Phase PHASE CLINICAL TRIAL (NCT03276832) is
ongoing.
Motolid and
Resiquimod has also shown significant immunostimulating activity in many preclinical studies and is currently in clinical development
.
TGF-p is a multifunctional cytokine, and abnormal expression of TGF-p is closely related
to tumor progression, angiogenesis, metastasis, and immune evasion.
Studies have shown that TGF-p
Signaling pathways play a key role
in tumor immune evasion and immune checkpoint inhibitor treatment resistance.
galunisertib and vactosertib are TGF-p receptor I inhibitors and are currently available as monotherapy or in combination PD-1/PD-L1
Antibody drugs are conducted in clinical trials for the treatment
of tumors.
In addition, ARG, R0 R7t and HPK1 were discovered
ARG inhibitors enhance immune function in the tumor environment by blocking the arginine catabolic pathway, and RORV agonists can activate Thl7 and Tcl7
Cells produce anti-tumor effects, and HPK1 inhibitors can reduce the depletion of T cells, producing anti-tumor effects
.
Summary and outlook
Summary and outlookDuring tumors develop and develop, they fight the immune response through a series of "immune evasion mechanisms", which often become more diverse and complex in advanced tumors
.
In recent years, tumor immunotherapy targeting the "immune evasion mechanism" has made breakthrough progress, completely changing the pattern
of human anti-tumor.
Despite PD-1/PD-L1, CTLA4
Immune checkpoint inhibitors have shown excellent efficacy in many tumors such as melanoma, lymphoma, non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, etc.
, but there are still many problems and challenges
in this field.
The tumor immune antibody drugs that have been marketed only have efficacy on a limited number of tumor types, and the overall effective rate needs to be improved
.
Tumor immune small molecule drugs have emerged
with the advantages of good oral bioavailability, tissue permeability, and controllable immune-related adverse reactions.
At present, many small molecule immunotherapies have entered the clinical development stage, which can be used as monotherapy or in combination with antibody drugs and traditional chemotherapy drugs to further improve the anti-tumor efficacy or improve the problem of
checkpoint inhibitor resistance.
Most of these small molecule therapies have shown good safety and efficacy
in early clinical trials.
However, the major failure of the phase III clinical trial of IDOl inhibitor in combination with pembrolizumab in the treatment of melanoma also suggests that researchers should explore the tumor immune mechanism more deeply in the future, and explore reliable biomarkers and clinical design schemes
.
As a supplement to therapeutic antibody drugs, small molecule tumor immunotherapy has a challenging but promising development path
.