Abstract
RMX1002 (grapiprant) is a selective E-type prostanoid receptor 4 (EP4) antagonist and a promising candidate for cancer therapy, potentially enhancing anti-tumor immune responses. This study aimed to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of RMX1002 as monotherapy and in combination with anti-PD-1 antibody toripalimab for advanced solid tumors. This multicenter, phase I trial enrolled patients with histologically or cytologically confirmed advanced solid tumors. This study included three phases: Ia (dose-escalation of RMX1002 monotherapy from 200 to 650 mg BID), Ib (dose-escalation from 500 to 650 mg BID in combination with toripalimab), and Ic (dose-expansion of 500 mg BID with toripalimab). Safety, pharmacokinetics, pharmacodynamics, and efficacy were assessed. A total of 45 patients were enrolled (17 in phase Ia, 12 in phase Ib, and 16 in phase Ic). No dose-limiting toxicity was reported, and the MTD was not reached. Overall, 21 patients experienced RMX1002-related adverse events with CTCAE grade ≥ 3. Pharmacokinetics revealed rapid absorption of RMX1002 with the maximum concentration (Cmax) reached within 2 to 5 h, and dose-dependent increases in Cmax and area under the concentration-time curve. The increase in urinary metabolite of PGE2 suggested the inhibition of EP4 signaling pathway. The best response was stable disease, reported in 64.7%, 28.6%, and 18.8% of patients in phase Ia, Ib, and Ic, respectively. RMX1002 was well tolerated and showed a best response of stable disease. RMX1002 500 mg BID with toripalimab 240 mg every 3 weeks is the recommended dose for future trials.
Supplementary Information
The online version contains supplementary material available at 10.1007/s10637-025-01512-z.
Keywords: RMX1002, Grapiprant, Prostaglandin E2, EP4, Immunotherapy, Solid tumors
Introduction
Prostaglandin E2 (PGE2) is critical for tumor progression and metastasis [1–3]. Within the tumor microenvironment, PGE2 compromises natural killer (NK) cell activity, diminishes chemokine production, and suppresses chemokine receptor expression on conventional dendritic cells type 1 (cDC1) [4]. PGE2 also inhibits function of CD8 + T cells [5]. Consequently, targeting the PGE2 signaling pathway emerges as a promising strategy in anti-tumor agent development. The inhibition of pivotal components within this pathway, including cyclooxygenase-2 (COX-2) and the E-prostanoid receptor 4 (EP4) [5], is anticipated to yield therapeutic benefits [6]. Thus, anti-tumor strategies targeting downstream elements of the PGE2 signaling cascade emerge as a viable and promising therapeutic strategy.
The E-type prostanoid receptor 4 (EP4), identified as a downstream G protein-coupled receptor of PGE2, is primarily expressed on the cell membrane of gastrointestinal epithelial cells, myeloid cells, vascular smooth muscle cells, T lymphocytes, and tumor cells. EP4 also regulates various cytokines, such as IL-8, IL-10, IL-12, CXCL10, CCL5, and CXCL2, which have been revealed to play critical role in cancer development and progression [7, 8]. It has emerged as a critical contributor to PGE 2-mediated enhancement of tumor survival pathways, and targeting EP4 has demonstrated promising in vivo anti-tumor potential in various types of cancer, including but not limited to breast [9, 10], lung [11], and colon cancers [12, 13]. Clinical trials of EP4 antagonists, such as E7046 (AN0025) [14, 15] and ONO-4578 (BMS-986310) [16], have revealed the safety profile and underscored their potential as anti-tumor agents. Despite these advances, the clinical translation of EP4 inhibitors in oncology necessitates further exploration and development. On the other hand, targeting the pathway of EP4 has been considered promising in further enhancing the efficacy of cancer immunotherapy, since tumors in nonresponders to immunotherapy can evade the immune surveillance system through mechanisms related with inflammation [17, 18]. However, the combination of inhibiting EP4 and immunotherapy has been less investigated.
RMX1002 (grapiprant) is a highly selective antagonist of the EP4 receptor. A preclinical study in CT26 cell allograft murine model has reported that RMX1002 reduces expression of Foxp3 and TGF-β in tumor tissues when compared with control mice and had potent antitumor activity. PGE2’s ability to suppress NK cell activity and impede dendritic cell (DC) infiltration within the tumor milieu complicates the presentation of tumor neoantigens and subsequent activation of CD8 + T cells [19]. Consequently, EP4 blockade is posited to enhance the efficacy of immune checkpoint inhibitors (ICIs), yielding a synergistic effect as suggested by preliminary research [20] and preclinical studies involving RMX1002 (unpublished data).
This study is a phase I trial designed to assess the safety and primary anti-tumor activity of RMX1002 as monotherapy and in combination with toripalimab, a PD-1 blockade, in patients with advanced solid tumors (ChiCTR1900026031).
Method
Study design
This is a multi-center, open label, phase I study of RMX1002 alone and in combination with toripalimab in advanced solid tumors (ChiCTR1900026031). This study was conducted across 3 centers in China from May, 2019 to Jul, 2023. The phase I study is divided into three phases: phase Ia, the dose-escalation of RMX1002 monotherapy; phase Ib, the dose-escalation of RMX1002 in combination with toripalimab; and phase Ic, dose-expansion of RMX1002 with toripalimab. In phase Ia, participants were orally administered RMX1002 twice daily (BID) according to the pharmacokinetics (PK) parameters observed in healthy Chinese subjects. The initial dose was determined at 200 mg BID based on the PK profile and safety data of RMX1002 from preclinical studies. Dosing increments proceeded through 200, 300, 400, 500, and 650 mg RMX1002 BID, adhering to a “3 + 3” dose-escalation protocol, except for the first dose level (n = 1). Advancement to subsequent dose levels depended on the incidence of dose-limiting toxicities (DLTs) within the first 21 days of treatment, with escalation permitted if ≤ 1 participant per cohort experienced DLT and halted if ≥ 2 participants had DLT. Phase Ib employed a “rolling six design” for evaluating two doses of RMX1002 (500 and 650 mg BID) in combination with toripalimab (240 mg, administered once every three weeks (Q3W)). Escalation ceased if ≥ 2 DLTs were observed within any dose group. Following the findings from the initial phases, 500 mg BID of RMX1002 was selected for the dose-expansion in phase Ic. Patients in phase Ib and phase Ic were intravenously infused toripalimab 240 mg every 3 weeks (Q3w). Toripalimab was infused for at least 60 min the first time. If tolerated, the infusion was shortened to 30 min for all subsequent administrations. Treatment continued until disease progression, intolerable toxicity, death, patient withdrawal, or study conclusion, whichever occurred first. Maximum treatment duration of toripalimab spanned two years in phases Ib/Ic. Patients in phase Ib/Ic parts with progressive disease were allowed to continue treatment if investigators believed they benefited from the therapy. Efficacy was assessed via imaging studies. Adverse events (AEs) were monitored throughout the study. PK and PD evaluations were conducted for all participants.
In phase Ia/Ib, the primary endpoints included the maximum tolerated dose (MTD), recommended dose for combination (RDC), safety and tolerance for RMX1002 alone and RMX1002 in combination with toripalimab. The secondary endpoints were to assess the PK and preliminary efficacy. In phase Ic, the primary endpoint was the anti-tumor activity of RMX1002 in combination with toripalimab. The secondary endpoints included safety, tolerance and PK characteristics.
This study was registered in center for drug evaluation, NMPA of China with registered ID: CTR20190801 (phase Ia) and CTR20201261(phase Ib/Ic), and Chinese Clinical Trial Registry (ChiCTR) with registered ID: ChiCTR1900026031. The trial was conducted in adherence to the principles outlined in the Declaration of Helsinki and the guidelines of Good Clinical Practice (GCP). Ethical approval for the protocol was obtained from the ethics committees of Beijing Cancer Hospital, along with each of the participating centers, under the approval numbers 2018L02782, 2018L02783, and 2018L02784. Prior to the commencement of any procedures, all participating patients provided their written informed consent.
Patients
Participants with histologically or cytologically confirmed recurrent or metastatic solid tumors were enrolled. Eligible patients were aged 18 years or older, had one or more measurable lesions according to RECIST 1.1 and adequate organ function, were refractory or intolerant to standard therapy or had no standard therapy, and had an ECOG performance status score of 0 or 1, a life expectancy of at least 3 months. Additionally, for patients included in phase Ib/Ic undergoing combined immunotherapy, patients with colorectal cancer should be confirmed as microsatellite stable (MSS), and those with breast cancer should be confirmed negative for HER2, ER, and PR by histology. Major exclusion criteria included allergy to RMX1002 or toripalimab, previous administration of EP4 inhibitors, consumption of NSAIDs within 14 days prior to commencement of the study treatment, or any systemic anti-tumor therapy within the preceding 28 days. The detailed inclusion and exclusion criteria are delineated in Table S1.
Assessments
MTD was defined as the highest dose at which no more than one out of six subjects experienced a DLT. DLT was assessed during the first treatment cycle of 21 days. For phase Ia, DLT encompassed conditions such as grade ≥ 4 anemia necessitating transfusion, febrile neutropenia, any other grade ≥ 3 hematological toxicity, and any grade ≥ 3 non-hematological toxicity. Phase Ib expanded DLT criteria to include both immune-related and non-immune-related toxicities. Table S2 provides a detailed list of the toxicities classified as DLT. AEs were categorized according to the Medical Dictionary for Regulatory Activities (MedDRA) and graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The study recorded treatment-emergent adverse events (TEAEs), RMX1002 treatment-related adverse events (TRAEs), serious adverse events (SAEs), and immune-related adverse events (irAEs).
Blood samples were collected for pharmacokinetic assessments before morning dose at cycle 1 day 1 (C1D1), C1D7, C1D14, C2D1, C3D1, C4D1, C6D1, and C8D1. Additional samples were collected within 12 h post-morning dose on C1D1 and C1D14 for RMX1002 concentration analysis and PK parameter calculation. The pharmacodynamic parameter, urine PGE-M (a metabolite of PGE2), was measured at baseline and after the morning dose at C1D1, C1D14, and C4D21.
A baseline tumor assessment was performed within 28 days before starting therapy. Tumor assessments were conducted with imaging scans, such as CT or MRI scans. Imaging assessments were performed at screening, every 6 weeks (± 7 days) in 48 weeks after the first infusion, and every 9 weeks (± 7 days) thereafter until disease progression, the start of new anti-tumor therapies, withdrawal of consent, loss to follow-up or study completion, whichever occurring earlier. Imaging assessments were done by investigators. The assessment of tumor response adhered to RECIST 1.1 criteria, and the efficacy endpoints included objective response rate (ORR), disease control rate (DCR), time to response (TTR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). A survival follow-up will be conducted every 2 months after discontinuation of study drugs to collect survival information and anti-cancer treatment information after discontinuation of study drugs.
Statistical analysis
The determination of the sample size was based on the structured design principles of the study: the “3 + 3” dose escalation in phase Ia, the “rolling six design” in phase Ib, and the dose-expansion in phase Ic. The number of patients to be enrolled was dependent upon the observed safety and pharmacokinetic profile. The full analysis set (FAS) encompasses all subjects who were successfully screened and subsequently administered at least one dose of the study drug. The safety set (SS) comprises participants from the FAS who have undergone at least one post-treatment safety evaluation.
Descriptive statistics were used to summarize patient data. The Kaplan-Meier method was employed for the analysis of time-to-event variables. PK parameters were calculated using Phoenix WinNonlin version 8.3, whereas all other statistical analyses were executed with SAS version 9.4.
Results
Baseline patients characteristics
As delineated in Fig. 1, out of 68 initially screened patients, 45 were ultimately enrolled in the study with 17 in phase Ia, 12 in phase Ib, and 16 in phase Ic (Fig. 1). The median age of participants across the three phases was 57, 56.5 and 54.5 years, respectively. Colorectal cancer was the most common type of cancer in phase Ia (52.9%) and Ib (100%), while phase Ic included various types of cancer encompassing esophageal cancer (18.8%), head and neck cancer (25%), breast cancer (31.2%) and cervical carcinoma (25%). There were 12 (70.6%), 8 (66.7%) and 15 (93.8%) patients with ECOG performance status of 1 in three phases, respectively. All patients (100%) presented with cancer metastases. As shown in Table 1, most patients in Ib (83.3%) had liver metastases; more than half patients in phase Ia (52.9%) and Ib (58.3%) had lung metastases; while 62.5% patients showed metastases of distant lymph nodes. All patients had received at least one line of prior systemic therapies. Three (17.6%) patients in phase Ia and 11 (68.8%) in phase Ic had received previous PD-1/PD-L1 blockade therapy. More detailed baseline characteristics are shown in Table 1.
Fig. 1.
Study flowchart. FAS, full analysis set; SS, safety set; DLT, dose-limiting toxicity; PK, pharmacokinetics; PD; pharmacodynamics
Table 1.
Baseline characteristics of patients
| Variables | Ia (N = 17) |
Ib (N = 12) |
Ic (N = 16) |
|||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 200 mg BID (N = 1) |
300 mg BID (N = 3) |
400 mg BID (N = 4) |
500 mg BID (N = 3) |
650 mg BID (N = 6) |
All (N = 17) |
500 mg BID (N = 7) |
650 mg BID (N = 5) |
All (N = 12) |
500 mg BID (N = 16) |
|
| Median age (range) | 50 (50–50) | 61 (54–66) | 67 (52–68) | 50 (42–57) | 52.5 (43–70) | 57 (42–70) | 57 (19–68) | 56 (31–68) | 56.5 (19–68) | 54.5 (31–69) |
| Gender, n (%) | ||||||||||
| Male | 1 (100%) | 3 (100%) | 3 (75.0%) | 0 | 3 (50.0%) | 10 (58.8%) | 3 (42.9%) | 4 (80.0%) | 7 (58.3%) | 5 (31.3%) |
| Female | 0 | 0 | 1 (25.0%) | 3 (100%) | 3 (50.0%) | 7 (41.2%) | 4 (57.1%) | 1 (20.0%) | 5 (41.7%) | 11 (68.8%) |
| Tumor type, n (%) | ||||||||||
| Colorectal cancer | 1 (100%) | 2 (66.7%) | 2 (50.0%) | 2 (66.7%) | 2 (33.3%) | 9 (52.9%) | 7 (100%) | 5 (100%) | 12 (100%) | 0 |
| Esophageal cancer | 0 | 1 (33.3%) | 1 (25.0%) | 0 | 0 | 2 (11.8%) | 0 | 0 | 0 | 3 (18.8%) |
| Head and neck cancer | 0 | 0 | 1 (25.0%) | 0 | 0 | 1 (5.9%) | 0 | 0 | 0 | 4 (25%) |
| Laryngeal cancer | 0 | 0 | 0 | 0 | 1 (16.7%) | 1 (5.9%) | 0 | 0 | 0 | 0 |
| Thyroid carcinoma showing thymus-like differentiation | 0 | 0 | 0 | 0 | 1 (16.7%) | 1 (5.9%) | 0 | 0 | 0 | 0 |
| Poorly differentiated squamous cell carcinoma of the anterior mediastinum | 0 | 0 | 0 | 0 | 1 (16.7%) | 1 (5.9%) | 0 | 0 | 0 | 0 |
| Vaginal cancer | 0 | 0 | 0 | 0 | 1 (16.7%) | 1 (5.9%) | 0 | 0 | 0 | 0 |
| Breast cancer | 0 | 0 | 0 | 1 (33.3%) | 0 | 1 (5.9%) | 0 | 0 | 0 | 5 (31.2%) |
| Cervical carcinoma | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 4 (25%) |
| ECOG performance status, n (%) | ||||||||||
| 0 | 0 | 2 (66.7%) | 1 (25.0%) | 0 | 2 (33.3%) | 5 (29.4%) | 2 (28.6%) | 2 (40.0%) | 4 (33.3%) | 1 (6.3%) |
| 1 | 1 (100%) | 1 (33.3%) | 3 (75.0%) | 3 (100%) | 4 (66.7%) | 12 (70.6%) | 5 (71.4%) | 3 (60.0%) | 8 (66.7%) | 15 (93.8%) |
| Metastases, n (%) | ||||||||||
| Any location | 1 (100%) | 3 (100%) | 4 (100%) | 3 (100%) | 6 (100%) | 17 (100%) | 7 (100%) | 5 (100%) | 12 (100%) | 16 (100%) |
| Liver | 1 (100%) | 2 (66.7%) | 2 (50.0%) | 1 (33.3%) | 1 (16.7%) | 7 (41.2%) | 5 (71.4%) | 5 (100%) | 10 (83.3%) | 2 (12.5%) |
| Lung | 0 | 1 (33.3%) | 4 (100%) | 2 (66.7%) | 2 (33.3%) | 9 (52.9%) | 3 (42.9%) | 4 (80.0%) | 7 (58.3%) | 5 (31.3%) |
| Regional lymph nodes | 1 (100%) | 0 | 1 (25.0%) | 1 (33.3%) | 3 (50.0%) | 6 (35.3%) | 1 (14.3%) | 0 | 1 (8.3%) | 4 (25.0%) |
| Distant lymph nodes | 0 | 2 (66.7%) | 1 (25.0%) | 1 (33.3%) | 2 (33.3%) | 6 (35.3%) | 5 (71.4%) | 4 (80.0%) | 9 (75.0%) | 10 (62.5%) |
| Bone | 0 | 0 | 0 | 1 (33.3%) | 1 (16.7%) | 2 (11.8%) | 1 (14.3%) | 1 (20.0%) | 2 (16.7%) | 1 (6.3%) |
| Pleura | 0 | 0 | 0 | 0 | 1 (16.7%) | 1 (5.9%) | 1 (14.3%) | 0 | 1 (8.3%) | 3 (18.8%) |
| Other | 1 (100%) | 1 (33.3%) | 2 (50.0%) | 3 (100%) | 2 (33.3%) | 9 (52.9%) | 2 (28.6%) | 5 (100%) | 7 (58.3%) | 9 (56.3%) |
| Number of previous lines of systemic treatment, n (%) | 1 (100%) | 3 (100%) | 4 (100%) | 3 (100%) | 6 (100%) | 17 (100%) | 7 (100%) | 5 (100%) | 12 (100%) | 16 (100%) |
| 1st line | 0 | 1 (33.3%) | 1 (25.0%) | 0 | 0 | 2 (11.8%) | 0 | 0 | 0 | 1 (6.3%) |
| 2nd line | 0 | 1 (33.3%) | 0 | 1 (33.3%) | 1 (16.7%) | 3 (17.6%) | 3 (42.9%) | 5 (100%) | 8 (66.7%) | 5 (31.3%) |
| 3rd line | 1 (100%) | 0 | 1 (25.0%) | 1 (33.3%) | 2 (33.3%) | 5 (29.4%) | 3 (42.9%) | 0 | 3 (25.0%) | 4 (25.0%) |
| ≥4th line | 0 | 1 (33.3%) | 2 (50.0%) | 1 (33.3%) | 3 (50.0%) | 7 (41.2%) | 0 | 0 | 0 | 6 (37.5%) |
BID, twice daily; ECOG, Eastern Cooperative Oncology Group
Safety
All participants (n = 45) had received at least one dose of RMX1002, and were included in the SS. The safety profile was shown in Table 2, Table S3 (TEAE profile) and Table S4 (TRAE profile). No DLTs were observed across all dose groups and MTD was not reached in phases Ia and Ib. In phase Ia, the median treatment duration was 2 cycles, spanning from 1 to 21 cycles. All 17 patients (100%) experienced TEAEs and TRAEs. There were eight instances (47.1%) of grade ≥ 3 TEAEs, while each of the 200, 400, 500, and 650 mg BID dose groups reporting one grade ≥ 3 TRAE respectively. Anemia (58.8%), pyrexia (35.3%), hypoalbuminemia (35.3%), leukopenia (29.4%), and increased aspartate aminotransferase (29.4%) were the most common TEAEs. Three participants experienced SAEs: one in the 200 mg cohort (intestinal obstruction) and two in the 400 mg cohort (femoral neck fracture and acute kidney injury), none of which were considered related to RMX1002. Notably, no TEAEs prompted discontinuation of the study drug, participant withdrawal from the study, or resulted in mortality.
Table 2.
Summary of adverse events
| Patients with adverse events, n (%) | Ia (N = 17) |
Ib (N = 12) |
Ic (N = 16) |
|||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 200 mg BID (N = 1) |
300 mg BID (N = 3) |
400 mg BID (N = 4) |
500 mg BID (N = 3) |
650 mg BID (N = 6) |
All (N = 17) |
500 mg BID (N = 7) |
650 mg BID (N = 5) |
All (N = 12) |
500 mg BID (N = 16) |
|
| TEAE | 1 (100%) | 3 (100%) | 4 (100%) | 3 (100%) | 6 (100%) | 17 (100%) | 7 (100%) | 5 (100%) | 12 (100%) | 16 (100%) |
| Grade ≥ 3 TEAE | 1 (100%) | 0 | 3 (75.0%) | 2 (66.7%) | 2 (33.3%) | 8 (47.1%) | 4 (57.1%) | 3 (60.0%) | 7 (58.3%) | 12 (75.0%) |
| TRAE | 1 (100%) | 3 (100%) | 4 (100%) | 3 (100%) | 6 (100%) | 17 (100%) | 7 (100%) | 5 (100%) | 12 (100%) | 16 (100%) |
| Grade ≥ 3 TRAE | 1 (100%) | 0 | 1 (25.0%) | 1 (33.3%) | 1 (16.7%) | 4 (23.5%) | 4 (57.1%) | 3 (60.0%) | 7 (58.3%) | 10 (62.5%) |
| SAE | 1 (100%) | 0 | 2 (50.0%) | 0 | 0 | 3 (17.6%) | 2 (28.6%) | 2 (40.0%) | 4 (33.3%) | 8 (50.0%) |
| Treatment-related SAE | 0 | 0 | 0 | 0 | 0 | 0 | 1 (14.3%) | 1 (20.0%) | 2 (16.7%) | 5 (31.3%) |
| irAE | NE | NE | NE | NE | NE | NE | 5 (71.4%) | 4 (80.0%) | 9 (75.0%) | 6 (37.5%) |
| Grade ≥ 3 irAE | NE | NE | NE | NE | NE | NE | 1 (14.3%) | 1 (20.0%) | 2 (16.7%) | 2 (12.5%) |
| TEAEs leading to RMX1002 discontinuation | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (20.0%) | 1 (8.3%) | 0 |
| TEAEs leading to withdrawal | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| TEAEs leading to death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 5 (31.3%) |
BID, twice daily; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event; SAE, serious adverse event; irAE, immune-related adverse event; NE, not evaluable
In the context of combination therapy during phases Ib and Ic, all patients (100%) experienced TEAEs and TRAEs. Elevated bilirubin and protein in urine (n = 8 for both TEAEs, 66.7%), and anemia (n = 13, 81.3%) were the most common observed TRAEs in phase Ib and Ic, respectively. Specifically, there were 17 patients (60.7%) suffering grade ≥ 3 TRAEs (phase Ib, n = 7; phase Ic, n = 10). Nine (32.1%) patients suffered CRS (4 in phase Ib and 5 in phase Ic). Notably, there were no withdrawals due to TRAEs/TEAEs in phases Ib/Ic. Five deaths were reported related to TEAEs in phase Ic, encompassing disseminated intravascular coagulation (DIC), respiratory distress, a congenital familial hereditary disorder (tracheoesophageal fistula), and two cases of death from unknown cause. Three deaths were considered related to treatment: one due to DIC and two from unknown causes in patients with advanced cancer. Additionally, three cases of CRS classified as SAEs were observed. These cases involved fever, rash, and elevated cytokine levels requiring hospitalization and were successfully managed with corticosteroids, tocilizumab, and supportive care. Detailed descriptions of these cases are provided in Table S5.
PK
The PK profile of RMX1002 is illustrated in Table S6 and Fig. 2. During phase Ia, RMX1002 was absorbed with the plasma maximum concentration (Cmax) reached within 2 to 3 h post-administration across all dose levels, except for the 400 mg cohort, which peaked around 4 h. The plasma concentrations then declined with a half-life ranging from 2.2 to 3.7 h. Notably, the Cmax and area under the concentration-time curve (AUC) showed a more than dose-proportional increase for both single and multiple dosing regimens.
Fig. 2.
The monitored concentrations of RMX1002 at single and multiple doses. Concentration-time curve of RMX1002 in (A) liner scale and (B) semi-logarithmic scale after single dose administration in phase Ia. Concentration-time curve of RMX1002 in (C) liner scale and (D) semi-logarithmic scale after multiple doses administration in phase Ia. Concentration-time curve of RMX1002 in (E) liner scale and (F) semi-logarithmic scale after single dose administration in combination with toripalimab in phases Ib and Ic. Concentration-time curve of RMX1002 in (G) liner scale and (H) semi-logarithmic scale after multiple doses administration in combination with toripalimab in phases Ib and Ic
In the combination therapy phases (Ib/Ic), Cmax were consistently observed within 4 h, with a comparable half-life of approximately 2 to 3 h. Notably, after single-dose, the combination therapy resulted in lower Cmax and AUC values for RMX1002 than those observed during monotherapy for 500 mg and 600 mg dose levels. Nonetheless, upon reaching steady-state conditions after multiple doses, the Cmax, ss and AUC0 − t, ss for the 500 mg BID combination therapy aligned closely with those seen in monotherapy.
Regarding drug accumulation, the PK data did not indicate significant accumulation of RMX1002. In the 400 mg BID monotherapy and the 650 mg BID combination therapy cohorts, the geometric mean ratio of calculated AUC from time zero to infinity (AUC0−∞) for multiple doses relative to single doses demonstrated a 90% CI lower limit slightly above 100% for these groups. For other dosage cohorts, the 90% CI lower limits were all beneath 100%.
Pharmacodynamics
As shown in Figure S1, in phase Ia, the urinary PGE-M levels in most dose cohorts initially increased, peaking at C1D21, and then declined over time. Phases Ib and Ic exhibited a consistently increasing trend in urinary PGE-M concentrations throughout the study duration. The overall increase in PGE-M levels in urine underscores the effect of RMX1002 in inhibiting the EP4 signaling pathway.
Dose determination
In phase Ia, MTD was not reached after finishing all designed dose escalation. The incidence of any grade TRAEs and ≥ 3 grade TRAEs were similar from the dose level of 200 mg BID to 650 mg BID. Based on the PK data, the Cmax and AUC showed increased potential with the dose escalation. Thus, the dose levels of 500 mg and 650 mg BID were chosen to explored in phase 1b. In phase 1b, the safety profile was acceptable in both dose levels of 500 mg and 650 mg BID. While, stable disease cases were only observed at dose level of 500 mg BID. So that, 500 mg BID was determined as REC to further explored in phase Ic.
Efficacy
Up to the last follow-up (Jul. 2023), the median follow-up duration was 4.6 months. Thirty-eight of 45 patients (84.4%) had finished efficacy assessment. Seven patients (15.6%) withdrew the study before the first efficacy assessment for clinical disease progression, TRAEs or personal reasons (phase Ia, n = 1; phase Ic, n = 6). In both RMX1002 monotherapy cohort (phase Ia) and RMX1002 plus toripalimab cohort (phase Ib/Ic), no objective response was observed (Table 3 and Figure S2).
Table 3.
Efficacy of RMX1002 as monotherapy or in combination with toripalimab
| Ia (N = 17) |
Ib (N = 12) |
Ic (N = 16) |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Best response | 200 mg BID (N = 1) |
300 mg BID (N = 3) |
400 mg BID (N = 4) |
500 mg BID (N = 3) |
650 mg BID (N = 6) |
All (N = 17) |
500 mg BID (N = 7) |
650 mg BID (N = 5) |
All (N = 12) |
500 mg BID (N = 16) |
| CR | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| PR | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| SD | 1 (100%) | 2 (66.7%) | 2 (50.0%) | 2 (66.7%) | 4 (66.7%) | 11 (64.7%) | 2 (28.6%) | 0 | 2 (16.7%) | 3 (18.8%) |
| PD | 0 | 1 (33.3%) | 1 (25.0%) | 1 (33.3%) | 2 (33.3%) | 5 (29.4%) | 5 (71.4%) | 5 (100%) | 10 (83.3%) | 7 (43.8%) |
| NE | 0 | 0 | 1 (25.0%) | 0 | 0 | 1 (5.9%) | 0 | 0 | 0 | 6 (37.5%) |
| ORR | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 95% CI | 0%, 97.5% | 0%, 70.8% | 0%, 60.2% | 0%, 70.8% | 0%, 45.9% | 0%, 19.5% | 0%, 41.0% | 0%, 52.2% | 0%, 26.5% | 0%, 20.6% |
| DCR | 1 (100%) | 2 (66.7%) | 2 (50.0%) | 2 (66.7%) | 4 (66.7%) | 11 (64.7%) | 2 (28.6%) | 0 | 2 (16.7%) | 3 (18.8%) |
| 95% CI | 2.5%, 100% | 9.4%, 99.2% | 6.8%, 93.2% | 9.4%, 99.2% | 22.3%, 95.7% | 38.3, 85.8% | 3.7%, 71.0% | 0%, 52.2% | 2.1%, 48.4% | 4.0%, 45.6% |
BID, twice daily; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluable; ORR, objective response rate; CI, confidence interval; DCR, disease control rate
In phase Ia, 11 patients (64.7%) achieved stable disease (SD) (200 mg BID, n = 1; 300/400/500 mg BID, n = 2 each; 650 mg BID, n = 4), resulting in a DCR of 64.7% (95% confidence interval (CI), 38.3–85.8%). And 5 patients suffered progression disease (PD) (300/400/500 mg BID, n = 1 each; 650 mg BID, n = 2). The median PFS was 2.07 months. Of note, one patient with head and neck cancer who receiving RMX1002 400 mg BID achieved SD over 450 days (Figure S2A). Furthermore, tumor shrinkage was observed in another patient in the 500 mg BID cohort after 8 treatment cycles (Figure S3). The first target lesion (lung metastasis 1) decreased from a baseline of 1.58 cm to 1.35 cm, the second target lesion (lung metastasis 2) decreased from 1.08 cm to 0.93 cm, and the third target lesion (breast metastasis) decreased from 3.35 cm to 2.87 cm. This patient achieved SD and remained for 257 days until PD occurred (Figure S2A). In phase Ib and Ic, two and three patients who received RMX1002 (500 mg BID) plus toripalimab experienced SD, with a DCR of 16.7% (95%CI, 2.1–48.4%) and 18.8% (95%CI, 4.0-45.6%), respectively. The median PFS was 1.2 and 1.3 months for patients in phase Ib and Ic, respectively. Three spider plots (Figures S2D, S2E, and S2F) illustrate tumor shrinkage and SD durations across phases Ia, Ib, and Ic.
Discussion
This phase I dose-escalation and expansion trial of RMX1002, evaluated both as a monotherapy and in combination with immunotherapy in advanced-stage tumors. No DLTs were observed across the dosage range of 200 to 650 mg BID, which underscores safety and tolerability of RMX1002 monotherapy. Within this dosage range, patients achieving SD indicated RMX1002’s potential efficacy in advanced tumors. In light of the safety, preliminary efficacy, PK and pharmacodynamics profiles of RMX1002, the RP2D of RMX1002 was determined to be 500 mg BID.
The PK profile of RMX1002 demonstrated a relatively rapid absorption, with were slightly slower compared with the time to maximum concentration (Tmax) observed in healthy volunteers (approximately 1 to 1.5 h). Despite this, RMX1002 maintained a consistent Tmax across various doses, indicating stable absorption pattern at different dose levels. PK parameters, such as the AUC and Cmax, showed a more than dose-proportional increase, suggesting the importance of monitoring for potential AEs with higher doses. However, the absence of DLTs and the overall mild and manageable nature of AEs indicated that the increased drug concentrations within the explored dose range might not significantly elevate the risk of toxicities. Given the half-life of RMX1002, a twice-daily dosing regimen is deemed appropriate, aligning with the theoretical need for sustained inhibition of the EP4 signaling pathway to achieve optimal anti-tumor efficacy. Notably, the drug’s parameters including Cmax and Tmax, exhibited consistency over multiple administrations, reinforcing confidence in the drug’s safety for extended use. Furthermore, the absence of significant drug accumulation over time further affirms RMX1002’s safety profile.
The pharmacodynamics measurement through urinary PGE-M levels, underscored RMX1002’s inhibitory impact on the EP4 signaling pathway. Urinary PGE-M, serving as a direct quantifier of PGE2 [21], reflects the rapid metabolism of PGE2 to PGE-M, followed by its urinary excretion [22]. This increasing pattern, diverging from the expected decrease in PGE2 following COX-2 inhibition, suggests that RMX1002’s mechanism may induce a shift in PGE2 metabolism and excretion by preventing its interaction with the EP4 receptor. This initial increase in PGE-M levels tends to normalize beyond 21 days, hinting at a dynamic balance within metabolism of PGE2 influenced by RMX1002 administration. Considering the widespread use of immunotherapy in advanced-stage cancers, this study further delineates RMX1002’s PK and pharmacodynamics profiles under combination therapy setting. Despite the potential pharmacological interference with the concurrent use of immunotherapy, RMX1002 maintained stable and consistent PK and pharmacodynamics characteristics, as evidenced by the concentration-time and urinary PGE-M concentration-time curves. These findings suggest RMX1002’s robust PK characteristics, rapid absorption, dose-dependent increases in drug concentration, and sustained pharmacodynamics response over prolonged treatment. Moreover, the drug’s performance remains unaffected in combination therapy. However, the implications of these results necessitate cautious consideration regarding dose optimization and the combination of RMX1002 with other treatments to maximize therapeutic efficacy while minimizing potential risks.
In the preliminary study involving healthy volunteers, RMX1002 was characterized by a favorable safety profile, a finding that was corroborated in the phase Ia phase of this trial with advanced cancer patients, where only three SAEs were reported and all were determined to be unrelated to RMX1002. TEAEs in healthy subjects predominantly manifested as abnormal laboratory parameters, whereas in cancer patients, TEAEs extended to clinical symptoms such as fever, fatigue, cough, rash, and peripheral edema. These AEs may be related to the prolonged and repeated administration of the drug, compounded by the underlying conditions inherent to advanced cancers. However, the combination of RMX1002 with toripalimab during phases Ib/Ic led to the observation of CRS. Given the CRS incidents has not been observed in preclinical studies [23], clinical studies of RMX1002 among Chinese healthy volunteers (CTR20180240) and clinical evaluations of RMX1002 for pain therapy with ~ 1,000 subjects, the emergence of CRS may represent a novel safety signal in combination therapy setting. CRS, while rare, has been recognized as an adverse effect of immunotherapy [24–26], characterized by an extensive immune-inflammatory response triggered by T-cell activation against cancer cells [27]. The emergence of CRS might suggest that RMX1002 possesses the capacity to potentiate immune reactions. On the other hand, two cases of CRS in this study were considered SAEs, and both CRS cases achieved recovery through pharmacological interventions (tocilizumab, steroids, etc.) and non-pharmacological measures (suspension of study drug). Therefore, CRS is rather manageable. Nevertheless, the further research on RMX1002 in combination with immunotherapy might pay attention to immune status indicators to discern and manage any potential AEs.
The anti-tumor activity of RMX1002 as observed in this study did not demonstrate objective response among participants with the best response being SD, aligning with the outcomes from clinical trial of E7046 in advanced tumors [14]. Given the study’s focus on advanced cancer, the challenge of achieving significant tumor reduction with EP4 inhibition alone is considerable. Thus, the emphasis was appropriately placed on SD. Notably, a patient with head and neck cancer, presenting with lung and distant lymph node metastases within the 400 mg BID dose cohort, achieved SD for an impressive duration of 14 months before experiencing disease progression. Additionally, nearly two-thirds of patients (64.7%) in phase Ia achieved SD, which was numerically higher than that in other EP4 inhibitor studies, where E7046 [14] and ONO-4578 [16] reported SD rates of 23% and 30%, respectively. Immunotherapy, pivotal in treating various advanced tumors where curative options are unavailable [28], faces challenges with monotherapy, including limited tumor response rates and resistance development over time [29]. This underscores the clinical need for additional treatments to bolster immunotherapy outcomes. RMX1002 potentially enhances immune responses to tumor cells by antagonizing PGE2 and may synergize with immunotherapy to prevent immune escape of tumor cells. AAT-008, sharing similar active components, showcased immunostimulatory effects in preclinical models [30], reinforcing the rationale for combining RMX1002 with immunotherapy. In this study, the combination therapy phases (Ib/Ic) at the RP2D of 500 mg BID yielded DCRs of 28.6% and 18.8%, respectively. While no objective response was observed, the stage IV patients enrolled in this study, characterized by extensive metastases and prior systemic treatment failures, present a particularly challenge for achieving response. Besides, the majority of patients included in combined therapy phases were those with colorectal cancer, thus this might suggest that colorectal cancer may not be sufficiently sensitive to the combination of RMX1002 with immunotherapy. Notably, one patient with head and neck cancer who received RMX1002 monotherapy (400 mg BID) achieved SD and maintained over 450 days. Therefore, further exploration into other types of tumors, or the combination of RMX1002 with other treatment modalities such as chemotherapy may also be warranted in the future.
The higher SD rate observed in phase Ia compared to phases Ib and Ic can be attributed to several factors. First, patients in phase Ia experienced fewer AEs, resulting in longer treatment durations (average 4.7 cycles) compared to 2.7 cycles in phase Ib and 1.7 cycles in phase Ic. This prolonged exposure to RMX1002 may have contributed to the better SD rate in monotherapy. Second, the majority of patients in Phase Ia had colorectal cancer, and a considerable proportion of these patients achieved SD. Given the significant advances in colorectal cancer’s response to immunotherapy in recent years, we included only colorectal cancer patients in Phase Ib. However, the SD rate was not as favorable, likely due to the impact of the higher AE burden in the combination therapy. Therefore, we did not include colorectal cancer patients in Phase Ic, but instead a mix of tumor types (esophageal, head and neck, breast, and cervical cancers). Despite this, the SD rate in phase Ic remained lower than that of phase Ia, further reflecting the influence of increased AEs and the heterogeneous responses among different cancer types. These findings underscore the need to optimize patient selection and manage AEs more effectively to maximize treatment benefit.
Despite the valuable insights gained from our study, several limitations should be acknowledged. As an early-phase clinical trial, our investigation into RMX1002’s antitumor activity provides preliminary insights that warrant further exploration. Further investigation of RMX1002’s efficacy is necessary, particularly in combination therapy settings and with biomarker-driven patient selection. This will help identify populations that might present more significant responses. While we included a PD analysis of urinary PGE-M levels to evaluate the impact of RMX1002 on the PGE2 pathway, this approach primarily reflects pathway inhibition and does not directly assess immune responses, such as T-cell activation or chemokine modulation. Future studies should incorporate these immune-related indicators to provide a more comprehensive representation of RMX1002’s pharmacodynamic effects and their contribution to antitumor mechanisms.
RMX1002 emerges as a promising EP4 inhibitor, showcasing an acceptable safety and tolerability profile in patients with advanced cancer, with overall manageable AEs. While the study presents RMX1002 as a potential therapeutic agent with modest anti-tumor activity, further comprehensive research is warranted to substantiate its efficacy. The potential for RMX1002 to synergize with immunotherapy positions it as a potential candidate for systemic anti-cancer treatment. Exploring the combination of RMX1002 with additional therapies (not limited to immunotherapy) is warranted, while the efficacy of RMX1002 in colorectal cancer awaits further investigation. This study provides a foundation for future research, emphasizing the need for a more detailed exploration of RMX1002’s role in cancer treatment.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Acknowledgements
None.
Author contributions
D.L., J.G., J.Z., Y.S., H.W., T.L., L.Z., M.L. and L.S. wrote the manuscript; D.L., L.Z. and L.S. designed the research; D.L., J.G., J.Z., Y.S., H.W., T.L., L.Z., M.L., X.H. and L.S. performed the research; D.L., J.G., J.Z., Y.S., H.W., T.L. and L.S. analyzed the data; L.S. contributed new reagents/analytical tools.
Funding
The study was supported by Ningbo Newbay Pharmaceutical Technology Co., Ltd.
Data availability
The data underlying this article are available in the article and in its online supplementary material.
Declarations
Ethical approval and consent to participate
The trial was conducted in adherence to the principles outlined in the Declaration of Helsinki and the guidelines of Good Clinical Practice (GCP). Ethical approval for the protocol was obtained from the ethics committees of Beijing Cancer Hospital, along with each of the participating centers, under the approval numbers 2018L02782, 2018L02783, and 2018L02784. Prior to the commencement of any procedures, all participating patients provided their written informed consent.
Patient consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Dan Liu, Jifang Gong and Jian Zhang are co-first authors.
Contributor Information
Xichun Hu, Email: xchu2009@hotmail.com.
Lin Shen, Email: shenlin@bjmu.edu.cn.
References
- 1.Finetti F, Travelli C, Ercoli J et al (2020) Prostaglandin E2 and Cancer: insight into Tumor Progression and Immunity. Biology (Basel) 9. 10.3390/biology9120434 [DOI] [PMC free article] [PubMed]
- 2.Cheng H, Huang H, Guo Z, Chang Y, Li Z (2021) Role of prostaglandin E2 in tissue repair and regeneration. Theranostics 11:8836–8854. 10.7150/thno.63396 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Niringiyumukiza JD, Cai H, Xiang W (2018) Prostaglandin E2 involvement in mammalian female fertility: ovulation, fertilization, embryo development and early implantation. Reprod Biol Endocrinol 16:43. 10.1186/s12958-018-0359-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Bottcher JP, Bonavita E, Chakravarty P et al (2018) NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment promoting Cancer Immune Control. Cell 172:1022–1037e14. 10.1016/j.cell.2018.01.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Jin K, Qian C, Lin J, Liu B (2023) Cyclooxygenase-2-Prostaglandin E2 pathway: a key player in tumor-associated immune cells. Front Oncol 13:1099811. 10.3389/fonc.2023.1099811 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Harris RE (2009) Cyclooxygenase-2 (cox-2) blockade in the chemoprevention of cancers of the colon, breast, prostate, and lung. Inflammopharmacology 17:55–67. 10.1007/s10787-009-8049-8 [DOI] [PubMed] [Google Scholar]
- 7.Cui G, Wang Z, Liu H, Pang Z (2022) Cytokine-mediated crosstalk between cancer stem cells and their inflammatory niche from the colorectal precancerous adenoma stage to the cancerous stage: mechanisms and clinical implications. Front Immunol 13:1057181. 10.3389/fimmu.2022.1057181 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Konya V, Marsche G, Schuligoi R, Heinemann A (2013) E-type prostanoid receptor 4 (EP4) in disease and therapy. Pharmacol Ther 138:485–502. 10.1016/j.pharmthera.2013.03.006 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.De Paz Linares GA, Opperman RM, Majumder M, Lala PK (2021) Prostaglandin E2 receptor 4 (EP4) as a therapeutic target to impede breast Cancer-Associated Angiogenesis and Lymphangiogenesis. Cancers (Basel) 13. 10.3390/cancers13050942 [DOI] [PMC free article] [PubMed]
- 10.Tonisen F, Perrin L, Bayarmagnai B et al (2017) EP4 receptor promotes invadopodia and invasion in human breast cancer. Eur J Cell Biol 96:218–226. 10.1016/j.ejcb.2016.12.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Wang J, Zhang L, Kang D, Yang D, Tang Y (2018) Activation of PGE2/EP2 and PGE2/EP4 signaling pathways positively regulate the level of PD-1 in infiltrating CD8(+) T cells in patients with lung cancer. Oncol Lett 15:552–558. 10.3892/ol.2017.7279 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Mashimo M, Shimizu A, Mori A et al (2022) PARP14 regulates EP4 receptor expression in human colon cancer HCA-7 cells. Biochem Biophys Res Commun 623:133–139. 10.1016/j.bbrc.2022.07.055 [DOI] [PubMed] [Google Scholar]
- 13.Karpisheh V, Joshi N, Zekiy AO et al (2020) EP4 receptor as a novel promising therapeutic target in colon cancer. Pathol Res Pract 216:153247. 10.1016/j.prp.2020.153247 [DOI] [PubMed] [Google Scholar]
- 14.Hong DS, Parikh A, Shapiro GI et al (2020) First-in-human phase I study of immunomodulatory E7046, an antagonist of PGE(2)-receptor E-type 4 (EP4), in patients with advanced cancers. J Immunother Cancer 8. 10.1136/jitc-2019-000222 [DOI] [PMC free article] [PubMed]
- 15.Wyrwicz L, Saunders M, Hall M et al (2023) AN0025, a novel antagonist of PGE2-receptor E-type 4 (EP4), in combination with total neoadjuvant treatment of advanced rectal cancer. Radiother Oncol 185:109669. 10.1016/j.radonc.2023.109669 [DOI] [PubMed] [Google Scholar]
- 16.Iwasa S, Koyama T, Nishino M et al (2023) First-in-human study of ONO-4578, an antagonist of prostaglandin E(2) receptor 4, alone and with nivolumab in solid tumors. Cancer Sci 114:211–220. 10.1111/cas.15574 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Gao YJ, Li SR, Huang Y (2023) An inflammation-related gene landscape predicts prognosis and response to immunotherapy in virus-associated hepatocellular carcinoma. Front Oncol 13:1118152. 10.3389/fonc.2023.1118152 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Li X, Wang Y, Zhai Z et al (2023) Predicting response to immunotherapy in gastric cancer via assessing perineural invasion-mediated inflammation in tumor microenvironment. J Exp Clin Cancer Res 42:206. 10.1186/s13046-023-02730-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Take Y, Koizumi S, Nagahisa A (2020) Prostaglandin E receptor 4 antagonist in Cancer Immunotherapy: mechanisms of action. Front Immunol 11:324. 10.3389/fimmu.2020.00324 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Cheng Z, Wang Y, Zhang Y et al (2023) Discovery of 2H-Indazole-3-carboxamide derivatives as Novel Potent Prostanoid EP4 receptor antagonists for Colorectal Cancer Immunotherapy. J Med Chem 66:6218–6238. 10.1021/acs.jmedchem.2c02058 [DOI] [PubMed] [Google Scholar]
- 21.Kiely M, Milne GL, Minas TZ et al (2021) Urinary PGE-M in men with prostate Cancer. Cancers (Basel) 13. 10.3390/cancers13164073 [DOI] [PMC free article] [PubMed]
- 22.Johnson JC, Schmidt CR, Shrubsole MJ et al (2006) Urine PGE-M: a metabolite of prostaglandin E2 as a potential biomarker of advanced colorectal neoplasia. Clin Gastroenterol Hepatol 4:1358–1365. 10.1016/j.cgh.2006.07.015 [DOI] [PubMed] [Google Scholar]
- 23.Sartini I, Giorgi M (2021) Grapiprant: a snapshot of the current knowledge. J Vet Pharmacol Ther 44:679–688. 10.1111/jvp.12983 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Morris EC, Neelapu SS, Giavridis T, Sadelain M (2022) Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. Nat Rev Immunol 22:85–96. 10.1038/s41577-021-00547-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Shah D, Soper B, Shopland L (2023) Cytokine release syndrome and cancer immunotherapies - historical challenges and promising futures. Front Immunol 14:1190379. 10.3389/fimmu.2023.1190379 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Zhou Y, Zheng GH, Li N et al (2023) Fatal cytokine-release syndrome in a patient receiving toripalimab: a case report. Immunotherapy 15:641–645. 10.2217/imt-2022-0289 [DOI] [PubMed] [Google Scholar]
- 27.Zhang Y, Guan XY, Jiang P (2020) Cytokine and chemokine signals of T-Cell exclusion in tumors. Front Immunol 11:594609. 10.3389/fimmu.2020.594609 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Ling SP, Ming LC, Dhaliwal JS et al (2022) Role of Immunotherapy in the treatment of Cancer: a systematic review. Cancers (Basel) 14. 10.3390/cancers14215205 [DOI] [PMC free article] [PubMed]
- 29.Blach J, Wojas-Krawczyk K, Nicos M, Krawczyk P (2021) Failure of immunotherapy-the Molecular and Immunological Origin of Immunotherapy Resistance in Lung Cancer. Int J Mol Sci 22. 10.3390/ijms22169030 [DOI] [PMC free article] [PubMed]
- 30.Manabe Y, Takahashi Y, Sugie C et al (2023) Biological effects of prostaglandin E2-EP4 antagonist (AAT-008) in murine colon cancer in vivo: enhancement of immune response to radiotherapy and potential as a radiosensitizer. Transl Cancer Res 12:351–358. 10.21037/tcr-22-1857 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data underlying this article are available in the article and in its online supplementary material.