key: cord-258117-5gpo8smn
authors: Le Naour, Julie; Galluzzi, Lorenzo; Zitvogel, Laurence; Kroemer, Guido; Vacchelli, Erika
title: Trial watch: IDO inhibitors in cancer therapy
date: 2020-06-14
journal: Oncoimmunology
DOI: 10.1080/2162402x.2020.1777625
sha: 
doc_id: 258117
cord_uid: 5gpo8smn

Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the first, rate-limiting step of the so-called “kynurenine pathway”, which converts the essential amino acid L-tryptophan (Trp) into the immunosuppressive metabolite L-kynurenine (Kyn). While expressed constitutively by some tissues, IDO1 can also be induced in specific subsets of antigen-presenting cells that ultimately favor the establishment of immune tolerance to tumor antigens. At least in part, the immunomodulatory functions of IDO1 can be explained by depletion of Trp and accumulation of Kyn and its derivatives. In animal tumor models, genetic or pharmacological IDO1 inhibition can cause the (re)activation of anticancer immune responses. Similarly, neoplasms expressing high levels of IDO1 may elude anticancer immunosurveillance. Therefore, IDO1 inhibitors represent promising therapeutic candidates for cancer therapy, and some of them have already entered clinical evaluation. Here, we summarize preclinical and clinical studies testing IDO1-targeting interventions for oncologic indications.

L-tryptophan (Trp), one of the essential amino acids, is indispensable for protein synthesis and cell survival. The kynurenine pathway catabolizes Trp to active metabolites such as L-kynurenine (Kyn), kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, picolinic acid and quinolinic acid. This metabolic cascade can be catalyzed by three enzymes, namely, indoleamine 2,3-dioxygenase 1 (IDO1), IDO2, and tryptophan 2,3-dioxygenase (TDO2). [1] [2] [3] [4] IDO1 is by far the beststudied among these enzymes, as it was the first interferon (IFN)-activated gene to be described as early as in the late 1970s. 5 The differential distribution and activity of IDO2 and TDO2 calls for further investigation to elucidate to which extent IDO2 and TDO2 contribute to Trp catabolism in vivo. 1, [5] [6] [7] In 1998 Munn, Mellor and colleagues demonstrated for the first time that IDO1 exerts immunosuppressive functions, as it prevents rejection of allogenic fetuses by the maternal immune system. 6, 8 This conceptual breakthrough initiated an intense wave of research aimed at understanding the molecular and cellular circuitries implicated in the immunomodulatory functions of IDO1.

Subsequent studies revealed that IDO1 is a central driver of cancer development and progression. In particular, IDO1 mediates pathogenic inflammatory processes in malignant, stromal and immune cells that ultimately lead to immune tolerance to tumor antigens. 9 ,10 According to current knowledge, the pleiotropic role of IDO in cancer includes the suppression of cytotoxic T lymphocytes (CTL) [10] [11] [12] [13] and natural killer (NK) cells, 14, 15 the generation and activation of regulatory T (T REG ) cells 16, 17 and myeloid-derived suppressor cells (MDSCs) [17] [18] [19] [20] as well as the promotion of tumor angiogenesis. 10, 17 The immunomodulatory functions of IDO1 can be attributed to Trp starvation and increased Kyn levels. 21, 22 More specifically, Trp depletion induces cell cycle arrest of T cells and apoptosis through inhibition of the mechanistic target of rapamycin complex 1 (mTORC1), 10, 23, 24 while inducing a stress response that activates the general control nondepressible 2 (GCN2). [25] [26] [27] Increased levels of Trp metabolites, especially Kyn, activate the transcription factor aryl hydrocarbon receptor (AHR), which in return induces differentiation of CD4 + T cells into immunosuppressive T REG cells. [28] [29] [30] Alongside, IDO1epxressing dendritic cells (DCs) have been shown to mediate immunosuppressive functions independent of Trp depletion and Kyn accumulation. [31] [32] [33] [34] [35] Moreover, IDO1 has been recently implicated in the microbiota-dependent control of obesity by shifting Trp metabolism from indole derivatives and interleukin 22 (IL-22) synthesis toward kynurenine production. 28, 36 IDO1 is widely overexpressed in tumor cells, which has been predominantly associated with poor prognosis. 8, [37] [38] [39] Similarly, increased circulating levels of Trp metabolites, such as Kyn, have been detected in patients with various cancers and have been attributed a poor predictive value in some cohorts. [40] [41] [42] Also, IDO1 expression in tumor cells has been linked to the status of the oncosuppressor gene bridging integrator 1 (BIN1). 43,44 BIN1 is one of the most frequently downregulated genes in human cancer, 45 due to either abnormal RNA splicing patterns compromising its tumor suppressor function, 46-48 or increased gene methylation abolishing its expression. 49, 50 In particular, BIN1 is absent or underexpressed in various human neoplasms, such as neuroblastoma, 51 melanoma, 46 as well as breast, lung, colorectal and prostate carcinoma. 46, 52, 53 The loss of BIN1 triggers the interferon gamma (IFNγ)-induced expression of IDO1, ultimately favoring tumor growth in immunocompetent, but not in immunodeficient, mice. 43 High levels of IDO not only correlate with poor outcome in some malignancies but they may also be implicated in drug resistance, as this has been reported for IDO1-expressing ovarian cancer patients. 54 Likewise, higher Kyn/Trp ratio have been shown to predict resistance to programmed cell death 1 (PDCD1, best known as PD-1) blockade in patients with non-small cell lung carcinoma (NSCLC). 55, 56 At last, profiling of advanced melanoma and renal cell carcinoma (RCC) patients showed that Kyn/Trp alterations correlated with overall survival upon administration of nivolumab (a PD-1 blocker). 57 Thus, IDO inhibition stands out as a promising strategy to (re)instance cancer immunosurveillance. Indeed, IDO inhibitors demonstrated their ability to successfully cooperate with immunotherapy, radiotherapy or chemotherapy even in tumors that are normally resistant to conventional treatments. 10, 58, 59 In this setting, preclinical studies have revealed an interesting paradox: while IDO inhibitors have a negligible effect on established tumors as single-agent, combination of IDO inhibitors and immunotherapies including checkpoint blockers targeting cytotoxic T lymphocyte-associated protein 4 (CTLA4) or PD-1 yields a synergistic effect to control cancer burden and favor survival. 17, [60] [61] [62] [63] Here, we discuss recent progresses on the use of IDO1 agonists in preclinical and clinical settings as a strategy for the (re)activation of antitumor immune responses.

In this section we summarize the findings of key preclinical studies on the ability of IDO1 inhibitors to (re)instate anticancer immunosurveillance since the publication by Hornyák et al. dealing with this topic. 64

The simple racemic compound 1-methyl-tryptophan (1MT) was first described as a competitive inhibitor of the IDO1 enzyme in the early 1990s. 65 It is by far the most employed IDO inhibitor in the preclinical literature. Unlike its L isomer, which has shown weak inhibitory activity, D-1MT isomer neither binds nor inhibits the purified IDO1 enzyme while demonstrating anticancer activity. [66] [67] [68] Therefore, clinical development focused on D-1MT (best known as indoximod or NLG8189). 69 In contrast to direct enzymatic inhibitors of IDO1, indoximod acts downstream of IDO1 to stimulate mTORC1, possibly lowering risks of drug resistance. 69, 70 Several combinatorial regimens have been developed to increase the antineoplastic effects of indoximod, some of which demonstrated pronounced therapeutic activity in preclinical models of hepatocellular carcinoma (HCC), 71 advanced prostate 72 and lung cancer. 73 Indeed, IDO1 inhibition with 1MT, synergized with radiotherapy to downregulate T REG cells, reduce expression of PD-1 or its ligand CD274 (best known as PD-L1), and to prevent T cell exhaustion in Lewis lung cancer (LLC)-bearing mice. 73 D-1MT and CTLA4 blockers administration mediated improved therapeutic effects in treatment resistant IDO1-overexpressing HCCs in both subcutaneous and hepatic orthotopic models. 71 Additionally, CTLA4 blockade induced the IFNγ-dependent upregulation of IDO1 in chemoresistant (but not sensitive) HCCs in mice. 71 At last, IDO activity positively correlates with disease stage in prostate cancer patients, 72 and both a DNA vaccine encoding the tumorassociated antigen acid phosphatase 3 (ACP3, best known as PAP) and PD-1 blockade with pembrolizumab promotes IDO expression and activity in these individuals. 72 Consistent with the immunosuppressive activity of IDO in this setting, ex vivo stimulation of peripheral blood cells with 1-MT increased T cell responses to vaccination. 72 Recently, Hu et al. also demonstrated that a methyltryptophan-paclitaxel (MP) albumin-bound drug conjugate (that links indoximod to the microtubular poison paclitaxel [74] [75] [76] [77] through an ester bond) not only significantly elevates the tumor levels of indoximod and local CD8 + T populations, but reduces granulocyte-like myeloid derived suppressor cells (G-MDSCs) and T REG cells. 78

Epacadostat, also known as INCB024360, is an orally available reversible competitive IDO1 inhibitor. Wachowska and colleagues reported that photodynamic therapy (PDT) [79] [80] [81] [82] induced IDO1 expression within neoplasms as well as in tumor draining lymph nodes in murine orthotopic breast cancer models. 83 Mechanistically, granulocytic CD11b + Ly6G + myeloid cells were the major source of IDO1 and strongly infiltrated the tumor bed following PDT. 83 Although less abundant after PDT, monocytic CD11b + Ly6C + myeloid cells, could also upregulate IDO1. 83 Interestingly, depending on the therapeutic scheme of PDT administration, IDO-induced immunosuppression can either be beneficial or lead to systemic toxicity. 83 Although IL-6 neutralization restored antitumor efficacy, it abolished the synergistic effect of epacadostat and PDT. 83 This might be explained by the fact that constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, signal transducer and activator of transcription 3 (STAT3) [84] [85] [86] [87] and the AHR. 88

Navoximod (also known as GDC-0919 or NLG-919) was initially developed as an orally bioavailable IDO1/TDO inhibitor with an improved pharmacokinetic and toxicity profile, based on 4-phenylimidazole, a compound that binds the heme moiety within the catalytic site of IDO1. 89 IDO1 inhibition by navoximod has been shown to decrease plasmatic Kyn/Trp ratios and tumor Kyn levels. 90 In sarcoma-bearing mice, navoximod used alone or combined with a PD-L1 blocker could neither efficiently control tumor growth nor affect the tumor immune cell infiltrate. 90 However, in the 4T1 murine breast tumor model, navoximod synergizes with doxorubicin [91] [92] [93] to elicit an antitumoral immune response and to control tumor growth. 94, 95 

PF-06840003 is a highly selective IDO1 inhibitor with favorable pharmacokinetic characteristics and a prolonged half-life in humans, which enable single-dose daily administration. Additionally, its ability to enter the central nervous system (CNS) allows for its use against brain metastases. 96 In several preclinical tumor models in mice, PF-06840003 strongly reduced intratumoral Kyn levels and inhibited tumor growth in both monotherapy and, with an increased efficacy, in combinatorial regimens with PD-L1 or CTLA4 blockers. 97 Recently, BGB-5777, a potent CNS-penetrating IDO1 inhibitor, enabled a durable survival benefit in a fraction of patients with advanced glioblastoma when combined with nivolumab and radiation therapy. 98, 99 

BMS-986205 is an orally available irreversible inhibitor of IDO1. Current clinical studies have shown its dose-dependent efficacy, coupled to better efficiency and pharmacokinetics than epacadostat. 10 Even at a low concentrations, BMS-986205 successfully inhibits IDO1 and lowers Kyn serum levels. 100

A few additional IDO1 inhibitors are in preclinical development, including Trp analogs, 1 imidazoles, 101 phenyl benzenesulfonylhydrazides, 102 N-hydroxyamidines 103 and LW106. 104 Other IDO1 inhibitors being developed by pharmaceutical groups in late preclinical settings, which include IOM2983 (Merck/IO-Met) and RG-70099 (Roche/CuraDev), have not yet publicly disclosed. In contrast, SHR9146 (also known as HTI-1090), an inhibitor of IDO1 and TDO, and KHK2455, an IDO1 inhibitor, have recently entered early clinical development. 1, 105 Overall, these compounds offer abundant possibilities for exploring the effects of specific IDO1 inhibition in the clinics.

A number of translational and clinical results addressing the safety and therapeutic potential of IDO1 inhibitors have been published since the latest survey on this topic (January 2018). 64 Here, we discuss some of these recent studies to recapitulate the current state-of-the-art.

Recent immunohistochemical analyses demonstrate that patchy expression of IDO1 within cervical cancers is associated with an increased systemic Kyn/Trp ratio and poor disease outcome, whereas marginal IDO1 expression pattern in the tumor predicts favorable outcome. 106 At least in part, these observations could be related to T cell infiltration and IFNγ release in the cervical tumor microenvironment. 106 Along similar lines, analyses of 144 cervical tumor samples from The Cancer Genome Atlas (TCGA) revealed a strong and positive correlation between IDO1 and IFNG mRNA expression levels, as well as significantly improved disease-free survival for patients with high IDO1 and IFNG levels. 106 Li and colleagues demonstrated that serum Kyn/Trp ratio increases as an adaptive resistance mechanism associated with worse overall survival in advanced melanoma and RCC patients treated with nivolumab. 57 They further established a correlation in melanoma samples between Kyn/Trp ratio and IDO1 but not TDO mRNA levels 4 weeks after nivolumab administration, 57, 107 suggesting that IDO1 may be the major source of Kyn in this setting. At last, two studies described synergistic effects of agents targeting erb-b2 receptor tyrosine kinase 2 (ERBB2, best known as HER2), 108,109 IDO1 and PD-1. 110, 111 Upon antibody-dependent cellular phagocytosis (ADCP), macrophages inhibit NK cell-mediated antibodydependent cellular cytotoxicity (ADCC) and T cell-mediated cytotoxicity in breast cancers and lymphomas. [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] 110, 112 Mechanistically, following ADCP, absent in melanoma 2 (AIM2) is recruited to the phagosomes by FcγR signaling and activated by DNA from phagocytosed tumor cells. 111, 113 Upon activation, AIM2 upregulates PD-L1 and IDO to cause immunosuppression. Combined treatment with anti-HER2 antibodies and inhibitors of PD-L1 and IDO enhances anti-tumor immunity and anti-HER2 therapeutic efficacy in vitro 111 as well as in mouse models of HER2 + breast carcinoma. 110 Additionally, neoadjuvant trastuzumab 114-120 treatment significantly upregulates PD-L1 and IDO on tumor-associated macrophages (TAMs) from HER2 + breast cancer patients, correlating with poor trastuzumab responses. 110 Collectively, these findings suggest that IDO inhibitors may provide synergistic effects with other targeted immunotherapies.

Komrokji et al. reported preliminary results for the sole published clinical trial monitoring the efficacy of epacadostat administered as standalone intervention. 121 In particular, this Phase II study aimed at evaluating the pharmacodynamics and activity of epacadostat in heavily pre-treated transfusiondependent patients with myelodysplastic syndrome (MDS) after hypomethylating agent (HMA) failure. [122] [123] [124] The IDO1 inhibitor was well tolerated, as no Grade 3 or 4 treatmentrelated adverse events (TRAEs) were recorded. Only one patient (among the 15 included in the trial) developed grade 2 adrenal insufficiency and hypothyroidism, while another showed low testosterone levels. Eighty percent of individuals exhibited stable disease and 20% progressive disease, largely in line with the poor prognosis of this patient population (overall survival of ~18 months in low-risk disease and 4-6 months in high-risk disease). All these findings suggest that future studies should consider to test epacadostat earlier in the disease course, before HMA failure (since expansion of MDSCs probably contribute to myelosuppression). 121 All other clinical studies recently published on IDO1 inhibitors tested these agents in combination with immune checkpoint blockers. In particular, Gibney et al. reported the results for the Phase I/II clinical trial NCT01604889 enrolling patients with unresectable or metastatic melanoma and receiving epacadostat together with ipilimumab. [125] [126] [127] Among the 50 participants, 20 discontinued treatment due to disease progression and 48 experienced TRAEs including hypothyroidism (10%), pruritus (28%), alanine aminotransferase elevation (28%), rash (50%), and aspartate aminotransferase elevation (24%). Dose-limiting toxicities occurred in 11 patients, and doses ≥100 mg BID were not tested due to hepatotoxicity. Among immunotherapy-naive patients (n = 39), objective response rate was 23% by response evaluation criteria in solid tumors (RECIST) and 26% by immune-related response criteria (iRECIST). No objective response was observed in the 11 patients previously treated with immunotherapy. According to the authors, these preliminary findings support continuing the evaluation of epacadostat plus ipilimumab in patients with unresectable or metastatic melanoma. 128 Unfortunately the study was prematurely terminated due to the sponsor's decision, and only the Phase I portion of the trial was completed.

The NCT02298153 ECHO-11O Phase Ib trial evaluated the efficacy, tolerability and safety of the epacadostat administered together with the PD-L1 blocker atezolizumab, [129] [130] [131] to 29 patients with stage IIIB/IV NSCLC previously treated with platinum derivatives 132-136 chemotherapy in conjunction with a folic acid analogue. [137] [138] [139] Seventy-nine percent of enrolled patients experienced TRAEs, 17% discontinued treatment due to such effects, one patient showed anticancer partial response, and the maximum tolerated dose (MTD) was not achieved. Thus, the clinical activity of epacadostat plus atezolizumab against NSCLC was deceptive, in line with the hitherto unclear significance of IDO1 expression in this setting. 140 Ultimately, the ECHO-110 study was prematurely terminated due to slow recruitment.

Additional results have recently lent further support to the controversial efficacy of epacadostat administered in combination with immune checkpoint blockers. 141, 142 In particular, Mitchell et al. reported the results of the Phase I KEYNOTE-037/ECHO-202 (NCT02178722) trial, enrolling 62 individuals with several solid tumors, including 22 melanomas, 12 NSCLCs and 11 RCCs. Eighty-four percent of the patients exhibited tolerable Grade 1/2 TRAEs (such as nausea, pruritus, rash, fatigue and arthralgia), 11% of the subjects discontinued the therapy, and the MTD was not attained. 141 An objective response was observed in 55% of melanoma patients and in some patients with urothelial carcinoma, RCC, head and neck squamous cell carcinoma (HNSCC), endometrial adenocarcinoma or NSCLC (in all cases, independently of PD-L1 expression levels). Altogether, these results suggest an encouraging and durable antitumor activity for this combinatorial regimen that has be to confirmed in additional Phase II studies. 141, 143, 144 Long and colleagues published the first results for the KEYNOTE-252/ECHO-301 (NCT02752074) assay, a phase III randomized, double-blind study evaluating the efficacy of epacadostat combined with pembrolizumab versus placebo plus pembrolizumab in 706 patients with untreated, unresectable or metastatic melanoma. 142 At odds with the findings from ECHO-202 and despite promising preliminary observations, no evidence of improved progression free survival could be documented (4.7 months in the epacadostat plus pembrolizumab arm versus 4.9 months in the pembrolizumab only arm). Overall survival was 74% in both groups, and objective response rates were similar in the two arms. Additionally, the most common TRAE, a lipase increase, occurred with a similar frequency in both groups (9% of patients receiving pembrolizumab monotherapy versus 10% in individuals receiving the combinatorial regimen). 142 These disappointing results suggested that this combinatorial therapy did not improve the clinical outcome of melanoma patients receiving pembrolizumab, confirming that the role of epacadostat (or IDO1 inhibitors in general) in advanced solid tumors with robust PD-1 signaling remains unclear. No less than twelve Phase III clinical assays testing this IDO1 selective inhibitor, alone or in combinatorial regimen in different cancer contexts, have been recently been withdrawn, downsized or suspended. 145 Indeed, it remains to be elucidated whether IDO1 constitutes a robust target for the development of anticancer agents. The results of ongoing clinical trials (see below) may clarify whether IDO1 inhibitors are an option to improve the therapeutic activity of PD-1 blockade in some cancer patient populations. 146 The results of two studies investigating the clinical profile of indoximod have recently been reported. Soliman and colleagues showed that indoximod plus an adenoviral DC vaccine targeting tumor protein p53 (TP53) [147] [148] [149] was well tolerated by metastatic breast cancer patients enrolled in a Phase I/II clinical trial. Patients who did not exhibit particular side effects (none of the toxicities required treatment discontinuation) achieved a median progression-free survival of ~13 weeks and a median overall survival of ~21 weeks, suggesting the absence of a statistically significant effect of indoximod. 150 Moreover, preliminary results from the Phase II NCT02077881 assay, enrolling 104 metastatic pancreatic cancer patients treated with indoximod plus gemcitabine and paclitaxel, have been disclosed by Bahary et al. Median overall survival was ~11 months, overall response rate was 46% (including one patient experiencing a complete response), and no significant toxicities were documented (anemia, nausea and fatigue being the most common). 151 Navoximod has been tested as a standalone intervention in patients with advanced or recurrent solid tumors in a Phase I study aiming to assess the antitumor activity, safety, pharmacokinetics and pharmacodynamics of the IDO inhibitor (NCT02048709). Preliminary results by Nayak-Kapoor and colleagues indicate that the MTD was not reached in the 22 enrolled patients, with a single dose-limiting Grade 4 toxicity (lower gastrointestinal hemorrhage). In ≥20% of patients, regardless of causality, TRAEs included vomiting (27%), nausea (36%), pruritus, cough, decreased appetite (41% of each) and fatigue (59%). Grade ≥ 3 TRAEs, reported in 64% of patients, could be attributed to navoximod in two patients (9%). Overall, navoximod was well tolerated at doses up to 800 mg BID and, among patients evaluated for efficacy, 8 (36%) had stable disease and 10 (46%) progressed. 152 Results from two clinical trials, testing navoximod in combination with the PD-L1 inhibitor atezolizumab, in patients with advanced cancer, have recently been published. 153, 154 Jung et al. reported preliminary results from the NCT02471846 trial, consisting of a 3 + 3 dose-escalation (n = 66) and a tumor-specific expansion (n = 92) phase. Navoximod was given orally every 12 hours for 21 consecutive days of each cycle except for cycle 1, where navoximod administration started on day −1 to measure pharmacokinetics. The maximum administered dose was 1000 mg BID, and the MTD was not reached. Navoximod demonstrated a linear pharmacokinetic profile as plasma Kyn levels decreased in a dose-dependent manner. The most common TRAEs were rash (22%), chromaturia (20%) and fatigue (22%). Some degree of antitumoral activity was observed at all dose levels in various tumor types including breast, cervical, HNSCC, melanoma, neural sheath, NSCLC, ovarian, pancreatic, prostate, RCC and urothelial bladder cancer. Of note, 6 (9%) dose-escalation patients partially responded, and 10 (11%) expansion patients achieved partial or complete responses. Together, these findings proved that this regimen was safe and well tolerated, although there was no clear evidence of benefit from adding navoximod to atezolizumab. 154 At last, results from a dose-escalation study assessing navoximod alone or in combination with atezolizumab, in Japanese individuals with advanced solid tumors, were reported by Ebata and colleagues. 153 Patients received either navoximod alone in stage 1 (n = 10) or in combination with atezolizumab in stage 2 (n = 10). No dose-limiting toxicities were observed. In stage 1, chromaturia (50%) and maculopapular rash (20%) occurred in ≥20% of patients and Grade ≥ 3 TRAEs were reported in two patients (20%; maculopapular rash and increased lipase). In stage 2, chromaturia (60%) and decreased appetite (40%) occurred in ≥30% of patients, while Grade ≥ 3 TRAEs were reported in three patients (30%; alanine and aspartate aminotransferase increased, hyponatremia, lymphoand neutro-paenia). Stable disease was observed in 5 patients (50%) in stage 1 and 8 patients (80%) in stage 2. Overall, these results suggested that navoximod, as monotherapy and in combination with atezolizumab, was well tolerated in patients with advanced solid tumors.

Similarly, Riccuiti, Luke and colleagues [155] [156] [157] [158] reported results for the NCT02658890 study which aimed at testing BMS-986205 administered as monotherapy once daily for 2 weeks followed by nivolumab in advanced bladder cancer. TRAEs (all grades) were reported in 57% of patients with 12% of Grade 3-4 side effects. The most common side effects of any grade were fatigue (15%) and nausea (12%). Nineteen patients (4%) discontinued treatment due to TRAEs, and 3 patients died due to a TRAE (hepatic failure, myocarditis and Stevens-Johnson syndrome). The combination of BMS-986205 and nivolumab was well tolerated in heavily pretreated patients and enhanced tolerability was observed with the 100 mg dose. Preliminary evidence of efficacy was observed in advanced bladder cancer, supporting further evaluation of this combinatorial regimen.

When this Trial Watch was being redacted (May 2020), official sources listed 22 clinical trials launched after January 2018 (Table 1) to evaluate the safety and efficacy of IDO1 targeting intervention in cancer patients (source http://www.clinical trials.gov). Ten of these studies involve BMS-986205, 9 epacadostat, 1 indoximod, 1 KHK2455 and 1 SHR9146.

In particular, epacadostat is being tested together with a brachyury-targeted antitumor vaccine, a transforming growth factor beta (TGFβ) trap-anti-PD-L1 antibody (M7824), and an IL-15/IL-15RA superagonist (ALT-803) in patients affected by metastatic castration-resistant prostate cancer (NCT03493945). 159 BN-Brachyury is a novel recombinant vector-based therapeutic cancer vaccine that enhances an immune response against brachyury, 37 a transcription factor that plays a key role in epithelial-mesenchymal transition (EMT) and is overexpressed in prostate adenocarcinoma. [160] [161] [162] [163] M7824, a bifunctional fusion protein composed by 2 extracellular domains of a TGFβ trap and a human IgG1 anti PD-L1 mAb, 164, 165 is able to reverse the EMT, to promote ADCC in vitro, 165 and promising evidence of immunostimulatory and clinical activity in solid tumors has been provided. 166, 167 ALT-803 is a fusion protein that stimulates both T and NK cells via agonism of the IL-2 and IL-15 receptors, thus supporting ADCC induction in synergy with M7824. 168, 169 This combinatorial regimen is a promising therapeutic option because of the activation of vaccine-derived tumor-specific T cells (by ALT-803) that is boosted by M7824 and epacadostat.

NCT03532295 is the only trial testing the safety and preliminary efficacy of epacadostat in subjects affected by brain tumors. The synergy among this IDO1 inhibitor, radiotherapy, the vascular endothelial growth factor A (VEGFA)-targeting antibody bevacizumab 170, 171 and the humanized, hingestabilized IgG4, targeting the interaction of PD-1 with PD-L1 and PD-L2, INCMGA00012 (also known as MGA012), 172 might activate a pronounced anti-cancer immune response thus leading to tumor regression and improved outcome. Along similar lines, the remaining clinical trials that involve epacadostat assess safety and preliminary efficacy of the IDO1 inhibitor combined with pembrolizumab (and other immunotherapeutic regimens). [173] [174] [175] In particular, NCT03823131 evaluates the efficacy of tavokinogene telseplasmid (tavo) electroporation (EP), pembrolizumab, and epacadostat against unresectable HNSCC (as compared to pembrolizumab monotherapy). Moreover, the tolerability, safety and preliminary efficacy of epacadostat and pembrolizumab were tested in patients affected by (i) advanced pancreatic cancer with chromosomal instability or homologous recombination repair deficiency (HRD) (NCT03432676), (ii) esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma and gastroesophageal adenocarcinoma (NCT03592407), (iii) HNSCC recurring after PD-1/PD-L1 therapy (NCT03463161), and (iv) ovarian clear cell carcinoma (NCT03602586). However, two of these studies are currently listed as "Withdrawn" (NCT03432676, because the trial is no longer financed by the main supporter, and NCT03592407, due to safety concerns), while two other studies have been "Suspended" (NCT03602586, for scheduled interim monitoring) or "Terminated" (NCT03463161, due to a conflict of interest among the investigators). In the Phase II NCT03592407 study, the administration of neoadjuvant epacadostat plus pembrolizumab (followed by standard chemoradiation) aimed at verifying the capacity of this combinatorial regimen to ameliorate the lymphoid compartment of the tumor, thus increasing the abundance of CD8 + CTLs expressing the effector molecule granzyme B (GZMB), 176 and reducing the relative amount of tumor-infiltrating CD4 + CD25 + FOXP3 + T REG cells [177] [178] [179] [180] [181] [182] (with respect to CD8 + cells). Of note, the therapeutic profile of this neoadjuvant combinatorial regimen is currently assessed in a Phase II study (NCT03832673) enrolling patients with muscle-invasive bladder cancer (MIBC). Indeed, the published literature lends robust support to the notion that pembrolizumab not only is an encouraging neoadjuvant therapy for the treatment of PD-L1 + MIBC and neoplasm with high mutational burden, [183] [184] [185] but also increases overall survival (by ~3 months) in advanced urothelial carcinoma 185, 186 and exhibits good tolerability when administered to patients with advanced solid tumors in combination with epacadostat. 141 Moreover, Chu et al. have recently demonstrated that the manipulation of the immune microenvironment with IDO1 inhibition enhances patient responses to existing therapies. 187 Finally, the Phase I trial NCT03516708, evaluating the efficacy of epacadostat administered to locally advanced rectal cancer patients, in the context of the so-called XELOX regimen (capecitabine plus oxaliplatin) [188] [189] [190] [191] for preoperative chemoradiotherapy, has been suspended to ensure patient safety during the Covid19 epidemics. [192] [193] [194] BMS-986205 is mainly being administered to cancer patients simultaneously receiving nivolumab 195 (NCT03792750, NCT03459222, NCT03519256, NCT03661320, NCT04106414, NCT04047706, NCT03695250, NCT03854032, NCT04007588, NCT03417037). Patients affected by advanced solid tumors are treated with BMS-986205 plus nivolumab alone (NCT03792750) or combined with the anti-lymphocyte activating 3 (LAG3) agent relatlimab 54, [196] [197] [198] [199] . The Phase II study NCT03519256, enrolling subjects with high-risk, non-MIBC, is monitoring the therapeutic profile of BMS-986205 combined with two drugs already approved for some types of bladder cancer such as nivolumab [200] [201] [202] [203] [204] and the toll like receptor 2 (TLR2)/TLR4 agonist [205] [206] [207] [208] [209] bacillus Calmette-Guérin (BCG). [210] [211] [212] Along similar lines, the Phase III study NCT03661320 compared the efficacy, tolerability and safety of three therapeutic regimens for MIBC: neoadjuvant standard of care chemotherapy with cisplatin [213] [214] [215] [216] [217] and gemcitabine, 218,219 (NAC) versus NAC combined with nivolumab or nivolumab plus BMS-986205, followed by continuation of adjuvant immunotherapy (nivolumab with or without the IDO1 inhibitor) post radical cystectomy. 220 Additionally, four ongoing studies aim at elucidating the therapeutic profile of BMS-986205 in combination with nivolumab in patients affected by endometrial carcinoma or endometrial carcinosarcoma (NCT04106414), unresectable or metastatic HCC (NCT03695250), stage II to IV HNSCC (NCT03854032), as well as stage III or IV melanoma (NCT04007588). In particular, the NCT04007588 assay was planned to compare the effectiveness of neoadjuvant PD-1 blockade alone or combined with IDO1 inhibition or with the CTLA4 checkpoint blockers ipilimumab. [125] [126] [127] 221, 222 However, NCT04007588 has been "Withdrawn" (due to slow accrual). Untreated stage IV or recurrent NSCLC patients were also to be enrolled in NCT03417037, planned to test the combination of BMS-986205 and nivolumab given with or without chemotherapy. Also, NCT03417037 is currently listed as "Withdrawn" (due to changes in the business objectives of the investors). Finally, the safety, side effects and preliminary efficacy of BMS-986205, nivolumab and standard radiation therapy, with or without temozolomide, are being assessed in individuals with newly diagnosed glioblastoma (NCT04047706).

The NCT03915405 clinical assay explores the therapeutic potential of KHK2455 combined with the PD-L1 blocker avelumab [223] [224] [225] in individuals with locally advanced or metastatic urothelial carcinoma. In particular, the tolerability and safety of the regimen will be evaluated during the first phase of the study (dose-escalation), while pharmacodynamics, pharmacokinetics, and preliminary antitumor activity will be assessed during the expansion phase.

The principal purpose of NCT04049669 is to monitor the efficacy of daily oral administration of indoximod 10,226,227 concomitant to chemo-immunotherapy and radiotherapy (for eligible individuals) in subverting immune tolerance and improving clinical outcome of pediatric patients affected by relapsed or refractory glioblastoma, medulloblastoma or ependymoma, as well as by newly-diagnosed diffuse intrinsic pontine glioma (DIPG). In particular, the core therapeutic regimen consists of oral administration of temozolomide [228] [229] [230] and indoximod, preceded by either low-dose or partial-field radiation (cohort B), or full-dose radiation (cohort C, including all newly diagnosed DIPG patients and some relapsed ependymoma patients), or corresponded to the starting treatment (cohort A, patients not eligible to re-irradiation). If patients accept continuing the indoximod treatment they undergo two "salvage" regimens including either cyclophosphamide 189, 190, 231, 232 plus etoposide 233, 234 or the DNA alkylating agents lomustine [235] [236] [237] and temozolomide.

Finally, the safety and efficacy of SHR9146 (also known as HTI-1090), 238, 239 combined with the experimental PD-1 inhibitor SHR-1210 with or without the vascular endothelial growth factor receptor (VEGFR) inhibitor apatinib, [240] [241] [242] [243] are being assessed in patients with advanced or metastatic solid tumors (NCT03491631).

Most investigators in the field agree that IDO1 inhibition can synergize with immune checkpoint blockers. While immune checkpoint blockers remove molecular brakes on cytotoxic T cells, they also stimulate the production of IDO1, which, in a negative feedback loop involving AHR activation, shuts down the immune response. Thus, IDO1-targeting drugs should enhance immune checkpoint blockers efficacy. Although our understanding of the biological effects of IDO1 inhibitors is incomplete, these compounds appear to trigger efficient antineoplastic effects along with the re(activation) of anticancer immunosurveillance, at least in preclinical tumor models. However, clinical efficacy remains limited. The exact mechanisms by which IDO1 restrains the immune system as well as the nature of the immune cells affected by IDO1 remains unclear. In particular, precisely determining to which extent IDO1 inhibitors operate on-target may allow for the development of novel agents that would exclusively trigger tumor-targeting immune response without systemic side effects. Indeed, some IDO1 inhibitors directly bind to the AHR 88 and could therefore have immunosuppressive effects as Kyn does, which would be the opposite of the drug's intent. Along the same line, the failure of numerous trials implicating epacadostat has highlighted the need of in-depth research of modes of action before launching combinatorial regimens. Therefore, it appears urgent to disentangle the signaling pathways and metabolic circuitries influenced by IDO1. 

Challenges and opportunities in the discovery of new therapeutics targeting the kynurenine pathway

Tryptophan catabolism and regulation of adaptive immunity

The kynurenine pathway as a novel link between allergy and the gut microbiome

Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond

Induction of pulmonary indoleamine 2,3-dioxygenase by interferon

Prevention of allogeneic fetal rejection by tryptophan catabolism

Tryptophan and carcinogenesis: review and update on how tryptophan may act

Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase

Inhibition of T cell proliferation by macrophage tryptophan catabolism

Indoleamine 2,3-dioxygenase and its therapeutic inhibition in cancer

Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer

Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites

Cancer Immunosurveillance by T Cells

Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase

The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46-and NKG2D-activating receptors and regulates NK-cell function

Modulation of tryptophan catabolism by regulatory T cells

Defining the role of the tumor vasculature in antitumor immunity and immunotherapy

Expression of a MYCN-interacting isoform of the tumor suppressor BIN1 is reduced in neuroblastomas with unfavorable biological features

Bin1 ablation in mammary gland delays tissue remodeling and drives cancer progression

Losses of the tumor suppressor BIN1 in breast carcinoma are frequent and reflect deficits in programmed cell death capacity

Next generation of immune checkpoint therapy in cancer: new developments and challenges

Can IDO activity predict primary resistance to anti-PD-1 treatment in NSCLC?

Revisiting IDO and its value as a predictive marker for anti-PD-1 resistance

Metabolomic adaptations and correlates of survival to immune checkpoint blockade

Marrying immunotherapy with chemotherapy: why say IDO?

Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase

Immunomodulatory monoclonal antibodies in combined immunotherapy trials for cutaneous melanoma

Combination regimens with PD-1/PD-L1 immune checkpoint inhibitors for gastrointestinal malignancies

Combining immune checkpoint inhibitors: established and emerging targets and strategies to improve outcomes in melanoma

IDO inhibitors move center stage in immuno-oncology

Cady SG, Sono M. 1-Methyl-DL-tryptophan, beta-(3-benzofuranyl)-DL-alanine (the oxygen analog of tryptophan), and beta-[3-benzo(b)thienyl]-DL-alanine (the sulfur analog of tryptophan) are competitive inhibitors for indoleamine 2,3-dioxygenase

Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses

Levo-but not dextro-1-methyl tryptophan abrogates the IDO activity of human dendritic cells

Efficacy of levo-1-methyl tryptophan and dextro-1-methyl tryptophan in reversing indoleamine-2,3-dioxygenase-mediated arrest of T-cell proliferation in human epithelial ovarian cancer

Indoximod: an immunometabolic adjuvant that empowers T cell activity in cancer

Tryptophan metabolism in inflammaging: from biomarker to therapeutic target

Indoleamine 2,3-dioxygenase provides adaptive resistance to immune checkpoint inhibitors in hepatocellular carcinoma

Increased indoleamine 2,3-dioxygenase activity and expression in prostate cancer following targeted immunotherapy

IDO inhibitor synergized with radiotherapy to delay tumor growth by reversing T cell exhaustion

Anticancer chemotherapy and radiotherapy trigger both non-cell-autonomous and cell-autonomous death

Cyclindependent kinase-1: linking apoptosis to cell cycle and mitotic catastrophe

Improved cellular pharmacokinetics and pharmacodynamics underlie the wide anticancer activity of sagopilone

An albumin-bound drug conjugate of paclitaxel and indoleamine-2,3-dioxygenase inhibitor for enhanced cancer chemo-immunotherapy

Enlightening the impact of immunogenic cell death in photodynamic cancer therapy

ER stress, autophagy and immunogenic cell death in photodynamic therapy-induced anti-cancer immune responses

ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death

Extracorporeal photochemotherapy induces bona fide immunogenic cell death

Inhibition of IDO leads to IL-6-dependent systemic inflammation in mice when combined with photodynamic therapy

Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity

STAT3 inhibition enhances the therapeutic efficacy of immunogenic chemotherapy by stimulating type 1 interferon production by cancer cells

STATs in cancer inflammation and immunity: a leading role for STAT3

Targeting the IL-6/JAK/ STAT3 signalling axis in cancer

Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR

Heme-containing enzymes and inhibitors for tryptophan metabolism

IDO targeting in sarcoma: biological and clinical implications

Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells

Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy

Chemotherapy-induced antitumor immunity requires formyl peptide receptor 1

Inhibition of Indoleamine 2,3-dioxygenase enhances the therapeutic efficacy of immunogenic chemotherapeutics in breast cancer

Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death

PF-06840003: a highly selective IDO-1 inhibitor that shows good in vivo efficacy in combination with immune checkpoint inhibitors

Characterization of the selective indoleamine 2,3-dioxygenase-1 (IDO1) catalytic inhibitor EOS200271/PF-06840003 Supports IDO1 as a critical resistance mechanism to PD-(L)1 blockade therapy

IDO1 inhibition synergizes with radiation and pd-1 blockade to durably increase survival against advanced glioblastoma

Optimising efficacy and reducing toxicity of anticancer radioimmunotherapy

Modulating tumor immunology by inhibiting indoleamine 2,3-dioxygenase (IDO): recent developments and first clinical experiences

Identification of novel imidazoles as IDO1 inhibitors through microwave-assisted one-pot multicomponent reactions

Discovery and structure-activity relationships of phenyl benzenesulfonylhydrazides as novel indoleamine 2,3-dioxygenase inhibitors

Diaryl hydroxylamines as pan or dual inhibitors of indoleamine 2,3-dioxygenase-1, indoleamine 2,3-dioxygenase-2 and tryptophan dioxygenase

3-dioxygenase 1 inhibitor, suppresses tumour progression by limiting stroma-immune crosstalk and cancer stem cell enrichment in tumour micro-environment

Discovery of IDO1 Inhibitors: from Bench to Bedside

Indoleamine 2,3-dioxygenase expression pattern in the tumor microenvironment predicts clinical outcome in early stage cervical cancer

The landscape of cancer cell line metabolism

Recent advances in the development of anti-HER2 antibodies and antibody-drug conjugates

Mechanism of action of anti-HER2 monoclonal antibodies

Immune checkpoint inhibition overcomes ADCP-induced immunosuppression by macrophages

Antibody-dependent cellular cytotoxicity renders macrophages immunosuppressive

Control of metastasis by NK Cells

Cytosolic DNA sensing in organismal tumor control

Natural and therapy-induced immunosurveillance in breast cancer

Blockade of ErbB2 and PD-L1 using a bispecific antibody to improve targeted anti-ErbB2 therapy

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial

Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial

Impact of breast cancer treatment on employment: results of a multicenter prospective cohort study (CANTO)

Trastuzumab deruxtecan in previously treated HER2-positive breast cancer

A phase II study to determine the safety and efficacy of the oral inhibitor of indoleamine 2,3-dioxygenase (IDO) enzyme INCB024360 in patients with myelodysplastic syndromes

Therapy with low-dose azacitidine for MDS in children and young adults: a retrospective analysis of the EWOG-MDS study group

Randomized phase 2 study of low-dose decitabine vs low-dose azacitidine in lower-risk MDS and MDS/MPN

Azacitidine: a review in myelodysplastic syndromes and acute myeloid leukaemia

Development of anti-drug antibodies is associated with shortened survival in patients with metastatic melanoma treated with ipilimumab. Oncoimmunology

PD-L1 expression with immune-infiltrate evaluation and outcome prediction in melanoma patients treated with ipilimumab

Anti-CTLA-4 based therapy elicits humoral immunity to galectin-3 in patients with metastatic melanoma

Phase 1/2 study of epacadostat in combination with ipilimumab in patients with unresectable or metastatic melanoma

Atezolizumab potentiates Tcell-mediated cytotoxicity and coordinates with FAK to suppress cell invasion and motility in PD-L1+triple negative breast cancer cells

A non-linear association between blood tumor mutation burden and prognosis in NSCLC patients receiving atezolizumab

Mutational and antigenic landscape in tumor progression and cancer immunotherapy

Cisplatin resistance associated with PARP hyperactivation

Loss-of-function alleles ofP2RX7 and TLR4 fail to affect the response to chemotherapy in non-small cell lung cancer

Cell cycle regulators and outcome of adjuvant cisplatin-based chemotherapy in completely resected non-small-cell lung cancer: the international adjuvant lung cancer trial biologic program

PT-112 induces immunogenic cell death and synergizes with immune checkpoint blockers in mouse tumor models

DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy

Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial

Adjuvant Chemoradiotherapy with epirubicin, cisplatin, and fluorouracil compared with adjuvant chemoradiotherapy with fluorouracil and leucovorin after curative resection of gastric cancer: results from CALGB 80101 (Alliance)

Perioperative FLOT: new standard for gastric cancer?

Phase 1 study of epacadostat in combination with atezolizumab for patients with previously treated advanced nonsmall cell lung cancer

Epacadostat plus pembrolizumab in patients with advanced solid tumors: phase i results from a multicenter, open-label phase I/ II Trial (ECHO-202/KEYNOTE-037)

Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/ KEYNOTE-252): a phase 3, randomised, double-blind study

Advanced stage melanoma therapies: detailing the present and exploring the future

Epacadostat plus pembrolizumab in patients with advanced RCC: preliminary phase I/II results from ECHO-202/KEYNOTE-037

The evolving landscape of 'next-generation' immune checkpoint inhibitors: A review

A new cancer immunotherapy suffers a setback

The multiple mechanisms that regulate p53 activity and cell fate

Targeting p53 to mitochondria for cancer therapy

Targeting mutant p53 for efficient cancer therapy

A phase-1/2 study of adenovirus-p53 transduced dendritic cell vaccine in combination with indoximod in metastatic solid tumors and invasive breast cancer

Phase 2 trial of the IDO pathway inhibitor indoximod plus gemcitabine/nab-paclitaxel for the treatment of patients with metastatic pancreas cancer

Phase Ia study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) in patients with recurrent advanced solid tumors

Phase I study of the indoleamine 2,3-dioxygenase 1 inhibitor navoximod (GDC-0919) as monotherapy and in combination with the PD-L1 inhibitor atezolizumab in Japanese patients with advanced solid tumours

Phase I Study of the Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) Administered with PD-L1 Inhibitor (Atezolizumab) in Advanced Solid Tumors

Targeting indoleamine-2,3-dioxygenase in cancer: scientific rationale and clinical evidence

BMS-986205, an indoleamine 2, 3-dioxygenase 1 inhibitor (IDO1i), in combination with nivolumab (nivo): updated safety across all tumor cohorts and efficacy in advanced bladder cancer (advBC)

BMS-986205, an indoleamine 2,3-dioxygenase 1 inhibitor (IDO1i), in combination with nivolumab (NIVO): updated safety across all tumor cohorts and efficacy in pts with advanced bladder cancer (advBC)

BMS-986205, an optimized indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, is well tolerated with potent pharmacodynamic (PD) activity, alone and in combination with nivolumab (nivo)

Quick efficacy seeking trial (QuEST1): a novel combination immunotherapy study designed for rapid clinical signal assessment metastatic castration-resistant prostate cancer

Androgen-targeted therapy-induced epithelial mesenchymal plasticity and neuroendocrine transdifferentiation in prostate cancer: an opportunity for intervention

The human T-box mesodermal transcription factor Brachyury is a candidate target for T-cell-mediated cancer immunotherapy

T-box transcription factor brachyury is associated with prostate cancer progression and aggressiveness

Prostate cancer: brachyury-a biomarker for progression and prognosis?

A novel bifunctional anti-PD-L1/TGF-beta Trap fusion protein (M7824) efficiently reverts mesenchymalization of human lung cancer cells

Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-beta

Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFbeta, in Advanced Solid Tumors

Focal irradiation and systemic TGFbeta blockade in metastatic breast cancer

IL-15 superagonist/IL-15RalphaSushi-Fc fusion complex

ALT-803) markedly enhances specific subpopulations of NK and memory CD8+ T cells, and mediates potent anti-tumor activity against murine breast and colon carcinomas

Calreticulin arms NK cells against leukemia

Ten years of anti-vascular endothelial growth factor therapy

First-in-Human Phase 1 Study of INCMGA00012 in patients with advanced solid tumors: interim results of the cohort expansion phase

Pembrolizumab: living up to expectations

Combinatorial immunotherapy with checkpoint blockers solves the problem of metastatic melanoma-An exclamation sign with a question mark

Combination of immunogenic oncolytic adenovirus ONCOS-102 with anti-PD-1 pembrolizumab exhibits synergistic antitumor effect in humanized A2058 melanoma huNOG mouse model

Granzyme B production distinguishes recently activated CD8(+) memory cells from resting memory cells

The ratio of CD8 +/FOXP3 T lymphocytes infiltrating breast tissues predicts the relapse of ductal carcinoma in situ

An immunosurveillance mechanism controls cancer cell ploidy

Regulatory T cells in cancer immunosuppression -implications for anticancer therapy

The immune contexture in cancer prognosis and treatment

Immunosurveillance in esophageal carcinoma: the decisive impact of regulatory T cells

Negative prognostic impact of regulatory T cell infiltration in surgically resected esophageal cancer post-radiochemotherapy

Pembrolizumab as neoadjuvant therapy before radical cystectomy in patients with muscle-invasive urothelial bladder carcinoma (PURE-01): an open-label, single-arm, phase II Study

Re: pembrolizumab as neoadjuvant therapy before radical cystectomy in patients with muscle-invasive urothelial bladder carcinoma (PURE-01): an open-label, single-arm, phase II study

Neoadjuvant Immunotherapy in muscle-invasive bladder cancer: time to change clinical practice?

Pembrolizumab as second-line therapy for advanced urothelial carcinoma

Role of indoleamine-2,3-dioxygenase inhibitors in salvage therapy for non-muscle invasive bladder cancer

Phase I/II trial of capecitabine and oxaliplatin in combination with bevacizumab and imatinib in patients with metastatic colorectal cancer: AIO KRK 0205

Trial Watch: immunogenic cell death inducers for anticancer chemotherapy

Trial Watch: chemotherapy with immunogenic cell death inducers

Trial watch: chemotherapy-induced immunogenic cell death in immuno-oncology

COVID-19 outbreak: an overview

Coronavirus infections: epidemiological, clinical and immunological features and hypotheses

The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak

Predictive role of plasmatic biomarkers in advanced non-small cell lung cancer treated by nivolumab

Lymphocyte-activation gene 3 (LAG3): the next immune checkpoint receptor

LAG3: the biological processes that motivate targeting this immune checkpoint molecule in human cancer

The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy

Characterization of a novel anti-human lymphocyte activation gene 3 (LAG-3) antibody for cancer immunotherapy

Nivolumab gets FDA nod for bladder cancer

Approved checkpoint inhibitors in bladder cancer: which drug should be used when?

Nivolumab for the treatment of bladder cancer

A phase II, randomized study of nivolumab (nivo) or nivo plus BMS-986205 with or without intravesical Bacillus Calmette-Guerin (BCG) in BCG-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC): checkMate 9UT

A phase I clinical trial of PSMA-directed/TGFβ-insensitive CAR-T cells in metastatic castration-resistant prostate cancer

Trial Watch: toll-like receptor agonists in cancer immunotherapy

Pharmacological modulation of nucleic acid sensors -therapeutic potential and persisting obstacles

The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4

Simultaneous blocking of human toll-like receptors 2 and 4 suppresses myeloid dendritic cell activation induced by mycobacterium bovis bacillus calmette-guerin peptidoglycan

Trial watch: experimental Toll-like receptor agonists for cancer therapy

Percutaneous BCG enhances innate effector antitumor cytotoxicity during treatment of bladder cancer: a translational clinical trial

Combined assessment of peritumoral Th1/Th2 polarization and peripheral immunity as a new biomarker in the prediction of BCG response in patients with high-risk NMIBC

Results of the phase I open label clinical trial SAKK 06/14 assessing safety of intravesical instillation of VPM1002BC, a recombinant mycobacterium Bacillus Calmette Guerin (BCG), in patients with non-muscle invasive bladder cancer and previous failure of conventional BCG therapy

Mitochondrial damage causes inflammation via cGAS-STING signaling in acute kidney injury

Cisplatin-induced immune modulation in ovarian cancer mouse models with distinct inflammation profiles

Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer

Pooled analysis of clinical outcomes with neoadjuvant cisplatin and gemcitabine chemotherapy for muscle invasive bladder cancer

Metabolic vulnerability of cisplatin-resistant cancers

Gemcitabine alters the proteasome composition and immunopeptidome of tumour cells

Low dose gemcitabine increases the cytotoxicity of human Vgamma9Vdelta2 T cells in bladder cancer cells in vitro and in an orthotopic xenograft model

ENERGIZE: a Phase III study of neoadjuvant chemotherapy alone or with nivolumab with/without linrodostat mesylate for muscle-invasive bladder cancer

Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden

Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma

Epigenetic priming of both tumor and NK cells augments antibody-dependent cellular cytotoxicity elicited by the anti-PD-L1 antibody avelumab against multiple carcinoma cell types

Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial

Immunotherapy for urothelial carcinoma: current evidence and future directions

Adding indoximod to hypofractionated radiotherapy with anti-PD-1 checkpoint blockade enhances early NK and CD8(+) T-cell-dependent tumor activity

Molecular pathways: targeting IDO1 and other tryptophan dioxygenases for cancer immunotherapy

Effect of combined anti-PD-1 and temozolomide therapy in glioblastoma

Survival gain in glioblastoma patients treated with dendritic cell immunotherapy is associated with increased NK but not CD8+T cell activation in the presence of adjuvant temozolomide

Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma

Cyclophosphamide induces type I interferon and augments the number of CD44(hi) T lymphocytes in mice: implications for strategies of chemoimmunotherapy of cancer

Cyclophosphamide synergizes with type I interferons through systemic dendritic cell reactivation and induction of immunogenic tumor apoptosis

High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy

Outcome of newly diagnosed high risk medulloblastoma treated with carboplatin, vincristine, cyclophosphamide and etoposide

Phase 2 study of concurrent radiotherapy and temozolomide followed by temozolomide and lomustine in the treatment of children with high-grade glioma: a report of the Children's Oncology Group ACNS0423 study

Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951

Lomustine and bevacizumab in progressive glioblastoma

Updates in the clinical development of epacadostat and other indoleamine 2,3-dioxygenase 1 inhibitors (IDO1) for human cancers

Discovery of cyanopyridine scaffold as novel indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors through virtual screening and preliminary hit optimisation

Apatinib promotes autophagy and apoptosis through VEGFR2/ STAT3/BCL-2 signaling in osteosarcoma

Apatinib: a review in advanced gastric cancer and other advanced cancers

Anti-PD-1 antibody SHR-1210 combined with apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric junction cancer: an open-label, dose escalation and expansion study

Apatinib-induced protective autophagy and apoptosis through the AKT-mTOR pathway in anaplastic thyroid cancer

LG is supported by a Breakthrough Level