Trophoblast Cell Surface Antigen Research Articles

Sacituzumab Govitecan Demonstrates Efficacy across Tumor Trop-2 Expression Levels in Patients with Advanced Urothelial Cancer.

Human trophoblast cell surface antigen 2 (Trop-2) is a protein highly expressed in urothelial cancer (UC). Sacituzumab govitecan (SG) is a Trop-2-directed antibody drug conjugate with a hydrolysable linker and a potent SN-38 payload. This study explored Trop-2 expression in tumors treated with SG in cohorts 1 to 3 (C1-3) from the TROPHY-U-01 study and evaluated whether efficacy was associated with Trop-2 expression. TROPHY-U-01 (NCT03547973) is an open-label phase II study that assessed the efficacy and safety of SG (alone or in combinations) in patients with unresectable locally advanced or metastatic UC (mUC). Archival tumor samples collected at enrollment for C1-3 were analyzed for Trop-2 membrane expression by considering histological scores (H-scores; scale 0-300) and the percentage of membrane positive tumor cells at low magnification (4×). The association of Trop-2 with clinical endpoints [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)] was evaluated. In C1-3, tissue was collected from 158 (82%) of 192 treated patients, and 146 (76%) had evaluable Trop-2 data. Trop-2 was highly expressed in tumor samples. The median [interquartile range (IQR)] Trop-2 H-score was 215 (180-246), and the median (IQR) percentage of membrane positive tumor cells was 91% (80-98). Trop-2 expression at any level was observed in 98% of patients. Furthermore, ORR, PFS, and OS benefits were observed across all Trop-2 expression levels. Trop-2 protein is highly expressed in UC, as confirmed by examining tumors from patients enrolled in the TROPHY-U-01 trial. The results indicate that SG demonstrates efficacy in mUC across Trop-2 expression levels.

Efficacy and Safety of Sacituzumab Govitecan in Patients With Advanced Solid Tumors (TROPiCS-03): Analysis in Patients With Advanced Endometrial Cancer.

Patients with advanced endometrial cancer (EC) who progress on or after platinum-based therapy and immunotherapy have poor prognosis. We report efficacy and safety of sacituzumab govitecan (SG), a trophoblast cell-surface antigen 2 (Trop-2)-directed antibody-drug conjugate, in patients with advanced EC. TROPiCS-03 (ClinicalTrials.gov identifier: NCT03964727) is a multicohort, open-label, phase II basket study in patients with metastatic solid tumors. Eligible patients in the EC cohort received SG 10 mg/kg once on days 1 and 8 every 3 weeks. Primary end point was objective response rate (ORR) by investigator's assessment per RECIST v1.1. Secondary end points included clinical benefit rate (CBR; complete and partial response, and stable disease ≥6 months), duration of response (DOR), and progression-free survival (PFS) per investigator assessment, overall survival, and safety. Trop-2 expression of archival or baseline tumor specimens was analyzed by immunohistochemistry. At data extraction date, 41 patients were enrolled. Median follow-up was 5.8 months (range, 0.7-19.3); median previous therapies was three (range, 1-6); and 85% of patients received previous chemotherapy and immunotherapy. ORR was 22% (95% CI, 11 to 38); CBR was 32% (95% CI, 18 to 48). Median DOR was 8.8 months (95% CI, 2.8 to not estimable); median PFS was 4.8 months (95% CI, 2.8 to 9.8). Trop-2 exploratory analysis was conducted retrospectively for 39 patients. Tumor Trop-2 protein was highly expressed in EC, showing limited correlation with efficacy. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 73% of patients. Study drug discontinuation due to TRAEs was 5%. Two deaths occurred, deemed unrelated to SG. Findings from TROPiCS-03 showed encouraging efficacy of SG with a manageable toxicity profile in a heavily pretreated population with advanced EC. Safety findings were consistent with the known SG safety profile.

Unveiling the placental secrets: Exploring histopathological changes and TROP2 expression in intrahepatic cholestasis of pregnancy

IntroductionGestational cholestasis, also known as intrahepatic cholestasis of pregnancy (ICP) or obstetric cholestasis, is a liver disease that can manifest in late pregnancy. Trophoblast cell surface antigen (TROP2) is a type I transmembrane glycoprotein identified in placental trophoblast cells that plays a critical role in trophoblast invasion of the decidua upon implantation into the placenta. Our study aims to investigate the role of TROP2 in pregnancy cholestasis. Materials and methodsStudy groups: Group 1 (control group) (n = 10): consists of healthy normal pregnant women without any disease, Group 2 (cholestasis group) (n = 10): consists of pregnant women diagnosed with cholestasis. After routine histological follow-up, hematoxylin and eosin staining and TROP2 immunostaining were performed and scored. ResultsIn the cholestasis group, in contrast to the control group, thrombus structures were observed in the intervillous space. In the cholestasis group compared to the control group, villus mesenchymal connective tissue cells, capillary endothelium and trophoblasts around the villus showed significantly stronger anti-TROP2 staining (p < 0.05). DiscussionCholestasis, a condition that may manifest during pregnancy, may be associated not only with observable pathological changes in placental tissues at the light microscopic level, but also with an increase in TROP2 expression. Given the critical role of TROP2 in trophoblast invasion during placental implantation, we hypothesize that TROP2 may serve as a key marker of the cholestatic processes occurring during pregnancy.

Antibody-Drug Conjugates: The New Treatment Approaches for Ovarian Cancer.

Ovarian cancer (OC), accounting for approximately 200,000 deaths worldwide annually, is a heterogeneous disease showing major differences in terms of its incidence, tumor behavior, and outcomes across histological subtypes. In OC, primary chemotherapy, paclitaxel carboplatin, bevacizumab, and PARP inhibitors have shown prolonged progression-free survival and a favorable overall response rate compared to conventional treatments. However, treatment options for platinum-resistant recurrence cases are limited, with no effective therapies that significantly prolong the prognosis. Recently, mirvetuximab soravtansine, an alpha-folate receptor (FRα)-targeted antibody-drug conjugate (ADC), was approved by the US Food and Drug Administration for patients with FRα-positive recurrent epithelial OC (EOC). This approval was based on a Phase II study, which demonstrated its efficacy in such patients. ADCs comprise an antibody, a linker, and a payload, representing new concept agents without precedence. Advanced clinical studies are developing ADCs for patients with OC, targeting solid tumors such as gynecologic cancer. Ongoing clinical trials are evaluating ADCs targeting FRα and human epidermal growth factor receptor 2, trophoblast cell surface antigen-2, sodium-dependent phosphate transport protein 2B, and cadherin-6 in Phase II/III studies. In this review, we summarize the existing evidence supporting the use of ADCs in OC, discuss ongoing clinical trials and preclinical studies, and explore the potential of these innovative agents to address the challenges in OC treatment.

Trophoblast cell surface antigen-2: a promising new biomarker and potential therapeutic target in penile squamous cell carcinoma.

To evaluate the potential utility of antibody-drug conjugates targeting trophoblast cell surface antigen-2 (TROP-2) in patients with primary penile squamous cell carcinoma (PSCC), patients with recurrence (REC cohort), and patient-matched distant metastases (MET cohort), and to assess the potential use of TROP-2 as a predictive non-invasive biomarker in PSCC. A cohort comprising a PRIM (n = 37), REC (n = 5) and MET subcohort (n = 7), with MET including lymph node and lung metastases, was analysed using quantitative real-time PCR, ELISA and immunohistochemical staining with evaluation of H-score. TROP-2 mRNA and serum protein levels were significantly increased in primary and recurrent PSCC compared to cancer-free controls (both P < 0.001). Immunohistochemical analysis revealed that most of the PRIM cohort (n = 34/37, median H-score 260, interquartile range [IQR] 210-300), as well as all patients in the REC (median [IQR] H-score 200 [165-290]) and MET cohorts (median [IQR] H-score 280 [260-300]) exhibited moderate to strong membranous TROP-2 expression. Additionally, The H-score (membranous TROP-2 expression) was positively correlated with TROP-2 mRNA (ρ = 0.69, P < 0.0001, R2 = 0.70) and protein levels (ρ = 0.86, P < 0.0001, R2 = 0.59), indicating its potential as a non-invasive biomarker in PSCC. In summary, our results support further studies on TROP-2 as a diagnostic and therapeutic target in primary, recurrent and metastatic PSCC.

Trophoblast cell-surface antigen 2 is a biomarker and potential therapeutic target in human colon cancer.

e15514 Background: Trophoblast cell-surface antigen 2 (TROP2), a transmembrane glycoprotein in epithelial cells, is implicated in malignant progression, notably in breast cancer therapy. However, the clinicopathologic aspects of TROP2 in colorectal cancer (CRC) are unclear. This study aims to explore the association between TROP2 expression and clinicopathological features in CRC and investigate the inhibitory effects of the anti-TROP2 antibody-SN-38 conjugate (ADC-TROP2) on colon cancer cells. Methods: A retrospective analysis of 1296 CRC patients who underwent colorectomy at Renji Hospital, Shanghai Jiaotong University School of Medicine, was conducted. Immunohistochemistry determined the expressions of TROP2, HER2, and PD-L1 in colon cancer tissues. Statistical analyses, including the chi-square test and Cox proportional hazards model, assessed associations. Sacituzumab Govitecan (ADC-TROP2 drug) cytotoxicity on human cancer cells was determined using the MTT method. Results: TROP2 was predominantly expressed at the cell membrane of cancer tissues, with 50% of cases TROP2-positive. The overexpression of TROP2 (staining extension 2+ or 3+) were found in 356 (27.5%) cases. The clinicopathological features of all 1296 patients based on the TROP2 expression in their cancer cells were summarized in Table 1. Compared to TROP2 negativity expression, the high TROP2 expression was significantly associated with the advantaged tumor stage (III/IV, P = 0.022), high tumor invasion depth (T3/T4, P = 0.002), lymph node metastasis (N1/N2, p = 0.026), HER-2 expression (2+/3+, p = 0.013) ,PD-L1 CPS (CPS≤5,P = 0.007). Sacituzumab Govitecan exhibited stronger inhibition in TROP2-positive human CRC cells in TROP2-negative CRC cells compared to TROP2-negative cells and the control SN-38 agent. Conclusions: TROP2 expression positive in 50% of CRC cases is associated with with advantaged tumor stage, high tumor invasion depth, lymph node metastasis. Sacituzumab Govitecan demonstrates potent targeting of TROP2-positive CRC cells, suggesting TROP2 as a potential biomarker for clinical prognosis and therapeutic targeting in colon cancer. [Table: see text]

Sacituzumab govitecan in patients with advanced or metastatic radioactive-iodine refractory thyroid carcinoma: The phase 2 SETHY, GETNE-T2318 trial.

TPS6130 Background: Current treatment options for advanced or metastatic differentiated thyroid carcinoma (DTC) with vascular endothelial growth factor inhibitors provide clinical benefit, despite the fact that most patients will acquire treatment resistance, whereas, advanced or metastatic anaplastic thyroid carcinoma (ATC) still lacks effective treatment options. Trophoblast cell surface antigen 2 (TROP-2) is highly expressed at the membrane of DTC and ATC, while it is rarely expressed in normal tissues. Moreover, TROP-2 is associated with tumor aggressiveness and poor prognosis. Targeting TROP-2 with sacituzumab govitecan, an antibody-drug conjugate with a SN-38 payload, showed efficacy in other cancer types such as triple negative or HER positive breast cancer or urothelial cancer and may be an effective treatment for thyroid carcinoma. SETHY is the first clinical trial with antibody-drug conjugates in thyroid cancer. Methods: The SETHY trial is a single-arm, multicohort, prospective, phase 2 trial of sacituzumab govitecan in patients with advanced or metastatic radioactive-iodine refractory thyroid cancer being recruited in 10 hospitals in Spain. Patients are ≥ 18 years, ECOG 0-1, should have recovered from any prior toxicity and have an adequate organ function. Patients will be included in two cohorts: DTC after progression (PD) to 1-3 prior systemic therapies (cohort 1) or ATC in 1st-line treatment or after failure of any systemic therapy (Cohort 2). Prior topoisomerase 1 inhibitors are not permitted. All patients will receive sacituzumab govitecan (10 mg/kg intravenously) on Days 1 and 8 of every 21-days cycle, until PD, death, study withdrawal, or unacceptable toxicity. Computed tomography (CT) or magnetic resonance imaging (MRI) scans and blood monitoring of tumor markers are performed every 12 weeks (Q12W) until PD. The primary endpoint is objective response rate (ORR) according to RECIST v1.1. Secondary endpoints include disease control rate, duration of response, progression-free survival, overall survival, safety, and quality of life (assessed through EORTC QLQ-C30 at baseline and Q12W until PD). Archival tumor samples will be collected at screening for retrospective central evaluation of TROP-2 expression levels and ancillary studies. The study uses a Simmon-II design considering a ORR of 5% as null hypothesis and an alternative ORR of 20% (α=0.1 one sided, β=0.2). In total, the study requires a total of 21 patients per cohort; 12 in the 1st stage and, if at least one response is reported, 9 additional in the 2nd stage. The study is approved and open to patient selection in Spain. Clinical trial identification: EU CT: 2023-504898-20-00 / NCT06235216 Clinical trial information: NCT06235216 .

Sacituzumab tirumotecan (SKB264/MK-2870) in patients (pts) with previously treated locally recurrent or metastatic triple-negative breast cancer (TNBC): Results from the phase III OptiTROP-Breast01 study.

104 Background: TROP2 (trophoblast cell surface antigen 2) is highly expressed in TNBC and is associated with worse survival. Sacituzumab tirumotecan (SKB264/MK-2870) is a TROP2 ADC developed with a novel linker to conjugate the payload, a belotecan-derivative topoisomerase I inhibitor with a drug-to-antibody-ratio (DAR) of 7.4. The hydrolytically linker permits both extracellular pH-sensitive cleavage and intracellular enzymatic cleavage to release the membrane permeable payload enabling the “bystander effect”. Here, we report the results from a phase Ⅲ study of sacituzumab tirumotecan in pts with advanced TNBC (OptiTROP-Breast01, NCT05347134). Methods: In this randomized phase Ⅲ trial, SKB264 was compared with physician's choice of chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine) in pts with locally recurrent or metastatic TNBC who had received two or more prior therapies including at least one for metastatic setting. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR). The TROP2 expression was determined by immunohistochemistry (IHC) using the semi-quantitative H-score method. Results: Pts were randomly assigned to receive SKB264 (n = 130) or chemotherapy (n = 133). The median age was 51 years; 87% had visceral metastases; 26% received prior PD-1/PD-L1 inhibitors; 48% received three or more prior lines of chemotherapy for advanced disease. The primary endpoint of PFS was met based on interim analysis (data cutoff: Jun 21, 2023) with a 69% reduction in risk of progression or death (HR 0.31; 95% CI, 0.22 to 0.45; P &lt;0.00001). The median PFS assessed by BICR was 5.7 months (95% CI, 4.3 to 7.2) with SKB264 and 2.3 months (95% CI, 1.6 to 2.7) with chemotherapy; PFS at 6 months was 43.4% vs 11.1%. In the subset of pts with TROP2 H-score &gt; 200, the median PFS was 5.8 months with SKB264 and 1.9 months with chemotherapy (HR 0.28; 95% CI, 0.17 to 0.48). At the first planned interim analysis for overall survival (OS) (data cutoff: Nov 30, 2023) with median follow-up of 10.4 months, OS was statistically significant in favor of SKB264 (HR 0.53; 95% CI, 0.36 to 0.78; P =0.0005); the median OS was not reached (95% CI, 11.2 to NE) with SKB264 and 9.4 months (95% CI, 8.5 to 11.7) with chemotherapy. The objective response rate assessed by BICR was 43.8% with SKB264 and 12.8% with chemotherapy. Most common grade ≥ 3 treatment-related adverse events (SKB264 vs chemotherapy) were neutrophil count decreased (32.3% vs 47.0%), anemia (27.7% vs 6.1%) and white blood cell count decreased (25.4% vs 36.4%). Conclusions: Sacituzumab tirumotecan monotherapy demonstrated statistically significant and clinically meaningful PFS and OS benefit over chemotherapy, with a manageable safety profile in pts with heavily pretreated advanced TNBC and limited treatment options. Clinical trial information: NCT05347134 .

Dose escalation and expansion results from the phase I study of F0024, a trophoblast cell-surface antigen 2 (TROP2) antibody-drug conjugate (ADC), in patients (pts) with advanced solid tumors.

e13131 Background: F0024 is an antibody-drug conjugate (ADC) targeting Trop-2, an intracellular calcium signaling transducer overexpressed on many epithelial tumors, for delivery of SN-38, the active metabolite of irinotecan. We assessed its safety and efficacy in patients with advanced solid tumors, mainly in triple negative breast cancer (TNBC). Methods: PTs with unresectable solid tumors refractory to/relapsed from standard treatment received F0024 on days 1 and 8 of 21-day treatment cycles. Primary objectives include maximum tolerated dose (MTD) identification, safety, and tolerability and secondary objectives include efficacy, pharmacokinetics, and incidence of anti-drug antibodies against F0024. Pts were eligible regardless of TROP2 level. Results: As of October 8, 2023, 62 pts were treated with≥1 dose of F0024. 21 pts were treated during dose escalation at 2.5 (n = 1), 5.0 (n = 3), 7.5 (n = 3), 10 (n = 4), 12 (n = 8), and 15 (n = 2) mg/kg and 41 pts with TNBC were treated in dose expansion at 10.0 (n = 30) and 12.0 (n = 11) mg/kg. 32 pts (51.6%) discontinued (20 (32.2%) due to disease progression per RECIST v1.1). Treatment emergent adverse events (TEAEs) regardless of causality were reported in 61 of 62 pts (98.4%; 34 pts [54.8%] experienced ≥grade 3, 9 pts [14.5%] had serious adverse events). Treatment related adverse events (TRAEs) were reported in 61 of 62 pts (98.4%; 32 pts [51.6%] experienced ≥grade 3, 4 pts [6.5%] had serious adverse events). The most common grade 3 TRAE were neutropenia (45.2%), leukopenia (33.9%), febrile neutropenia (4.8%), anemia (4.8%), and maculo-papular rash (4.8%). A total of 17 responses have been observed at the dose of 5.0 mg/kg or greater. 34 TNBC pts were dosed at 10 and 19 were dosed at 12 mg/kg with exposure to a median of 11.5 (1.0-26.0) and 4.0 (1.0-21.0) doses. 11 partial responses were achieved in 29 efficacy-evaluable TNBC pts at 10 mg/kg leading to an overall response rate (ORR) of 37.9% (95% CI 20.7% - 57.7%). The disease control rate of 10 mg/kg is 79.3% (95% CI 60.3%-92.0%). 5 escalation pts and 25 expansion pts remain on trial. Updated trial details/results will be presented. Conclusions: In this first-in-human study of F0024, treatment was generally well tolerated and MTD was not yet reached up to 12 mg/kg. F0024 demonstrated encouraging preliminary antitumor activity in heavily pretreated TNBC pts, especially in 10 and 12 mg/kg. Clinical trial information: NCT05174637 .

ESG401, a trophoblast cell-surface antigen 2 (TROP2) antibody drug conjugate (ADC), for the treatment of first-line metastatic triple negative breast cancer (mTNBC).

e13132 Background: ESG401, a novel ADC comprising a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to the Topoisomerase I Inhibitor SN-38, with the Drug-Antibody Ratio at 8, by a stable cleavable linker, exhibited preliminary efficacy and tolerability in the Phase Ia trial (Ma, ASCO 2023). This report summarizes current results from the first-line mTNBC cohort of the Phase Ib trial. Methods: Patients (pts) aged ≥18 years with confirmed local advanced/unresectable or metastatic TNBC, without prior metastatic treatment, received ESG401 (16 mg/kg IV on Day 1,8, and 15, with a 28-day cycle) until unacceptable toxicity, progressive disease, or consent withdrawal. Results: As of the cutoff date (Jan 30th, 2024), 23 pts in the cohort received ≥1 dose of ESG401. Median age was 52 years (range: 33-73), 34.8% were ECOG 0, 26.1% were de novo stage IV, 73.9% had visceral disease (8.7% brain, 34.8% liver, 52.2% lung), 43.5% received radiotherapy, and 73.9% received chemotherapy (73.9% Taxanes, 69.6% Anthracycline, 4.3% Platinum)as prior treatments for early-stage disease. Among 14 Efficacy Evaluable (EE) pts, the ORR was 78.6%, including one (7.1%) patient who achieved a complete response. DCR was 100%, and CBR was 85.7%. Eight pts (57.1%) achieved confirmed Partial Response (PR). As of the cutoff date, 14 pts (63.6%) remained on treatment, with the longest on-treatment duration being 8.0 mons. Two (2) pts in this cohort had brain metastases. One pt achieved a complete intracranial response, and the overall response evaluation was PR. The evaluation time for the other pt has not yet been reached. Across the entire Phase Ia/1b trials, including 15 EE pts with brain metastases, the best overall intracranial response rate was 33%, with an intracranial disease control rate of 73%. The response of the intracranial tumor lesion is correlated with the response of the non-CNS lesion. The safety profile of ESG401 remained consistent with previous reports, showing no new or unexpected safety signals. The most common TRAEs were leukopenia (65.2%), neutropenia (69.6%), anemia (43.5%), fatigue (21.7%), nausea (43.5%), and vomiting (34.8%). The most common TRAEs≥ Grade 3 were neutropenia (43.5%). There was no ≥ Grade 3 diarrhea. No interstitial lung disease (ILD) has been reported so far for the entire PhIa/b trials containing 139 pts. Conclusions: ESG401 demonstrates promising antitumor activity in the first-line mTNBC pts, with efficacy comparable to the combination therapy reported by the BEGONIA Study. Additionally, the efficacy of ESG401 in brain metas in the first-line mTNBC pts is in alignment with our previous observations made in the late-line mTNBC and HR+/HER2- BC pts. These results warrant further clinical investigation of ESG401. Clinical trial information: NCT04892342 .

The role of TROP-2 in the progression and target therapy in penile squamous cell carcinoma.

e17023 Background: Penile squamous cell carcinoma(PSCC) is a devastating malignancy of urogenitary system. However, current chemotherapy treatments including TIP regimen has showed limited effects but strong side effects in advanced PSCC. Trophoblast cell-surface antigen-2 (Trop-2) is a novel target for Antibody-drug conjugates (ADC) drugs and is proved to be effective in several human cancers, but its role in PSCC has not been clearly certified. Methods: 198 PSCC tumor tissue specimens and clinicopathological data were collected. TROP-2 expression was detected by IHC experiments and the correlation between TROP-2 expression and clinicopathological data of patients was analyzed through statistical methods. Then a series of in vivo and in vitro experiments were conducted to investigate the mechanism that how TROP-2 promote PSCC cell proliferation. Results: IHC results showed that TROP-2 was highly expressed in 60.2% of tumor specimens, and statistical analysis revealed a positive association of TROP-2 expression with advanced pT, pN stages and extranodal extension (ENE), as well as poor prognosis. Knockdown of TROP-2 expression inhibited the proliferation of PSCC cells both in vivo and in vitro. Further experiments identified that TROP-2 promoted PSCC cell proliferation via AKT-mediated PKCα signaling pathway. TROP-2 ADC drugs could inhibited PSCC cell proliferation both in vitro and in vivo. Conclusions: TROP-2 promotes PSCC cell proliferation, and TROP-2 targeted ADC-drug is a promising agent for PSCC treatment in future.

Phase I/II study of TROP2 CAR engineered IL15-transduced cord blood-derived NK cells delivered intraperitoneally for the management of platinum resistant ovarian cancer, mesonephric-like adenocarcinoma, and pancreatic cancer.

TPS5626 Background: Novel treatments are needed for patients with ovarian, pancreatic, and mesonephric-like adenocarcinoma (MLA) that has recurred or progressed after initial treatment, as current standard of care therapies in these settings result in low response rates. Chimeric antigen receptor-transduced natural killer (CAR-NK) cells have emerged as a therapeutic alternative to CAR-T cells, with decreased toxicity and enhanced feasibility as an “off-the-shelf” therapy. TROP2, or trophoblast cell-surface antigen 2, is a transmembrane calcium-signal transducer that is overexpressed in many cancer types and associated with poor clinical outcomes. Recent studies have demonstrated TROP2 as a promising target for adoptive cell therapy in breast and gastric cancers. An intraperitoneal route of adoptive cell therapy delivery may provide superior disease control and decreased toxicity in these target cancers with predisposition for intra-abdominal/peritoneal involvement. Pre-clinical studies have established the efficacy and safety of TROP2 CAR NK cells in ovarian and pancreatic cancers. Methods: This is a phase I/II study of the intraperitoneal delivery of TROP2-CAR/IL-15 transduced cord blood (CB)-NK cells for recurrent/progressive ovarian cancer, pancreatic cancer, and MLA (NCT05922930). Subjects must have disease present in the peritoneal cavity or retroperitoneal lymph nodes and tumors must demonstrate at least 1+ TROP2 expression by immunohistochemistry. The primary endpoints are toxicity rates and defining the recommended phase II dose (RP2D). Key secondary endpoints include treatment efficacy, circulating tumor DNA levels, serial characterization of the immune microenvironment, and patient-reported outcomes. There are four possible dose levels ranging from 8.0x106 to 4.0x109 cells. We will enroll patients from the three disease cohorts using the Bayesian optimal interval (BOIN) design to find the maximum tolerated dose and RP2D, with a maximum sample size of 21. Once the R2PD is chosen, we will enroll up to 10 patients within each disease cohort to further evaluate safety and efficacy. Subjects enrolled will be admitted to the hospital, receive lymphodepleting chemotherapy (fludarabine 30 mg/m2 and cyclophosphamide 300mg/m2) on days -5 to -3, and will receive a single dose of cryopreserved and thawed intraperitoneal TROP2-CAR/IL15-transduced CB-NK cells on day 0. The dose-limiting toxicity window will be from day 0 until day 28. Severity of adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5. The first patient on this trial was treated in January 2024. Clinical trial information: NCT0592293 .

Preliminary exploration of Trop2 ADC in combination with immune checkpoint inhibitors in the different molecular subtypes of invasive breast carcinoma.

e12558 Background: Human trophoblastic cell surface antigen 2 (Trop2) is a transmembrane protein overexpressed in breast cancer tissues. However, it is present at minimal levels in adult somatic tissues, making it an ideal target for treatment with antibody-drug conjugates (ADCs). Sacituzumab govitecan, an anti-Trop2 ADC, has been approved for the treatment of triple-negative breast cancer and urothelial cancer. Recent studies have demonstrated that human cytotoxic T lymphocytes can recognize Trop2. Accordingly, we aimed to assess the role of Trop2 in the tumor immune activity of different subtypes of breast cancer, and laying the foundation for further studies on the efficacy of the combination of Trop2 ADC and immune checkpoint inhibitors in breast cancer. Methods: We retrospectively retrieved tissues from 152 invasive breast carcinoma of no special type and 111 benign breast tumor tissues and undergoing surgical resection at our institution from 2018 to 2023. Immunohistochemistry was used to detect Trop2 and PD-L1 expression and lymphatic invasion in patients, and their correlations with clinicopathological factors were analyzed. Trop2 expression was evaluated using the H-score. The median as the cut-off value, a score of 0–240 indicated low expression, and 240–300 indicated high expression. Cases with CPS ≥ 1% were considered positive for PD-L1. Results: The expression was Trop2 in breast cancer tissues than in benign tumor tissues (P&lt;0.0001). Immune infiltration analysis suggested that Trop2 expression was correlated with immune cell infiltration and the abundance (P&lt;0.001). Kaplan–Meier plotter analysis demonstrated that high Trop2 expression was related to poor prognosis in patients with triple-negative breast cancer (overall survival: HR=1.53, P=0.029; relapse-free survival: HR=1.26, P=0.045). In contrast, Trop2 expression was not significantly associated with prognosis in other breast cancer subtypes. However, there was no statistically significant correlation found between PD-L1 expression and Trop-2 expression in breast cancer. Conclusions: The findings suggest that Trop2 correlates with poor prognosis and immune cell infiltration in breast cancer. This indicates the role of Trop2 as a potential prognostic biomarker, laying the foundation for further research focusing on the immune regulatory role of Trop2. [Table: see text]

SMART: A phase II study of sacituzumab govitecan (SG) with or without atezolizumab immunotherapy in rare genitourinary (GU) tumors such as small cell, adenocarcinoma, and squamous cell bladder/urinary tract cancer, renal medullary carcinoma (RMC) and penile cancer.

TPS4627 Background: Rare tumors of the GU tract often exhibit aggressive clinical behavior, yet lack effective standard of care treatment options. SG is an antibody-drug conjugate (ADC) targeting trophoblastic cell surface antigen 2 (Trop2) with a payload of SN-38, a topoisomerase inhibitor. SG monotherapy gained accelerated approval in pts with metastatic urothelial carcinoma (mUC) post platinum and immune-checkpoint inhibitor (ICI) therapy based on the TROPHY-U-01 trial (Tagawa S et al., JCO 2021). Atezolizumab is an anti-PD-L1 ICI approved for use in multiple solid tumors. SMART will evaluate the efficacy and safety of SG monotherapy or SG plus atezolizumab in select rare GU tumors. Methods: SMART is an open-label, non-randomized, Phase 2 trial. Pts must have locally advanced (unresectable) or metastatic GU tumors of the following histologies: small cell carcinoma, squamous cell carcinoma, or primary adenocarcinoma of the bladder or urinary tract, RMC, or squamous cell carcinoma of the penis. Pts may be treatment-naïve or have received any number of prior therapies; pts with small cell carcinoma must have received a platinum-based regimen. Pts treated with a PD-1/PD-L1 ICI will be assigned to Cohort A/Treatment Arm 1 and will receive SG monotherapy (10mg/kg IV, D1 and D8 of 21 day cycles). Pts without prior ICI treatment will be assigned to Cohort B/Treatment Arm 2 and will receive SG (10mg/kg IV, D1 and D8 of 21 day cycles) with concomitant atezolizumab (1200mg IV, D1 of 21 day cycles). Treatment will continue until disease progression (max duration of treatment 5 years) or intolerable side effects. The primary endpoint is objective response rate (ORR) (RECIST v1.1) for each Cohort, with restaging every 3 cycles. Secondary endpoints include safety, clinical benefit rate (CR+PR+SD), median PFS/OS for each Cohort, and ORR for each histology. Exploratory analyses include determination of baseline tumor mutation and transcriptional profile, Trop2 expression, ctDNA/CTCs, peripheral blood immune subsets and cytokine profile correlation with response, and correlation of UGT1A1 allele genotype with response and safety. This study utilizes a Simon minimax two-stage design, with enrollment of up to 43 evaluable pts (accrual ceiling of 60 pts). Cohort A will enroll 11 pts in Stage 1; if 1 or more of the first 11 pts has a response (unacceptably low rate of 5%, p0=0.05; alpha 0.10, beta=0.20), accrual will continue into Stage 2 up to 18 evaluable pts. Cohort B will enroll 16 evaluable pts in Stage 1; if 2 or more pts have a response (unacceptably low rate of 10%, p0=0.10; alpha 0.10, beta=0.10), accrual will continue in Stage 2 up to a total of 25 evaluable pts. This study is open at the NIH Clinical Center (CC); enrollment may open at 1-2 additional centers. Clinical trial information: NCT06161532 .

Trophoblast Cell Surface Antigen 2 Expression in Thymic Carcinoma: Brief Report

IntroductionTrophoblast cell surface antigen 2 (TROP2) is a transmembrane glycoprotein overexpressed in various cancer types. Although TROP2-targeting therapy is currently attracting attention, little is known about TROP2 expression in thymic carcinoma. MethodsTROP2 gene expression in thymic epithelial tumors was analyzed using RNA-sequencing (RNA-seq) data for 122 cases obtained from The Cancer Genome Atlas. Immunohistochemistry (IHC) staining with anti-TROP2 antibody (SP295) was performed in 26 cases of thymic carcinoma tissues surgically resected at Juntendo University. ResultsRNA-seq data analysis from The Cancer Genome Atlas revealed that TACSTD2 (gene encoding TROP2) expression was significantly higher in thymic carcinoma than in thymoma (adjusted p = 6.64e-05). There was also a trend of increasing expression in the order of thymoma type B1, B2, B3, and thymic carcinoma. As for IHC in thymic carcinoma, TROP2 expression was localized to the membrane of cancer cells. Intensity 0, 1, and 2 was observed in six (23.1%), 11 (42.3%), and nine (34.6%) cases, respectively, leading to TROP2 positivity in 20 cases (76.9%). The median proportion of TROP2-positive tumor cells and the median H-score were 25.0% (range: 0%–100%) and 25.0 (range: 0–200), respectively. No relevant factors were identified in the analysis of TROP2 expression and patient background. Although not significant, high TROP2 expression (H-score ≥ 50) tended to be associated with shorter survival. ConclusionsTROP2 expression in thymic carcinoma was confirmed by both RNA-seq and IHC, with high expression observed in IHC for intensity (76.9%) and proportion. TROP2 could be a potential target in thymic carcinoma.

Assessment of TROP2, CEACAM5 and DLL3 in metastatic prostate cancer: Expression landscape and molecular correlates

Therapeutic approaches targeting proteins on the surface of cancer cells have emerged as an important strategy for precision oncology. To capitalize on the potential impact of drugs targeting surface proteins, detailed knowledge about the expression patterns of the target proteins in tumor tissues is required. In castration-resistant prostate cancer (CRPC), agents targeting prostate-specific membrane antigen (PSMA) have demonstrated clinical activity. However, PSMA expression is lost in a significant number of CRPC tumors. The identification of additional cell surface targets is necessary to develop new therapeutic approaches. Here, we performed a comprehensive analysis of the expression heterogeneity and co-expression patterns of trophoblast cell-surface antigen 2 (TROP2), delta-like ligand 3 (DLL3), and carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) in CRPC samples from a rapid autopsy cohort. We show that DLL3 and CEACAM5 exhibit the highest expression in neuroendocrine prostate cancer (NEPC), while TROP2 is expressed across different CRPC molecular subtypes, except for NEPC. We further demonstrated that AR alterations were associated with higher expression of PSMA and TROP2. Conversely, PSMA and TROP2 expression was lower in RB1-altered tumors. In addition to genomic alterations, we show a tight correlation between epigenetic states, particularly histone H3 lysine 27 methylation (H3K27me3) at the transcriptional start site and gene body of TACSTD2 (encoding TROP2), DLL3, and CEACAM5, and their respective protein expression in CRPC patient-derived xenografts. Collectively, these findings provide insights into patterns and determinants of expression of TROP2, DLL3, and CEACAM5 with implications for the clinical development of cell surface targeting agents in CRPC.

Progress and Innovative Combination Therapies in Trop-2-Targeted ADCs.

Precise targeting has become the main direction of anti-cancer drug development. Trophoblast cell surface antigen 2 (Trop-2) is highly expressed in different solid tumors but rarely in normal tissues, rendering it an attractive target. Trop-2-targeted antibody-drug conjugates (ADCs) have displayed promising efficacy in treating diverse solid tumors, especially breast cancer and urothelial carcinoma. However, their clinical application is still limited by insufficient efficacy, excessive toxicity, and the lack of biological markers related to effectiveness. This review summarizes the clinical trials and combination therapy strategies for Trop-2-targeted ADCs, discusses the current challenges, and provides new insights for future advancements.

Assessment of immunohistochemical expression of trophoblast cell surface antigen 2 (Trop 2) in oral squamous cell carcinoma and its clinicopathological correlation

Trophoblast cell surface antigen 2 (Trop 2) is a transmembrane glycoprotein that is involved in a variety of oncogenic cell signaling pathways. Its heterogeneous expression in normal and cancerous tissues makes it a diagnostic and prognostic marker for various malignancies, including Oral Squamous Cell Carcinoma (OSCC). To assess the immunohistochemical expression of Trop 2 in OSCC and evaluate its clinicopathological correlation. Histopathologically diagnosed 40 cases of OSCC and their respective clinical records were retrieved and subsequent clinical staging and histopathological grading was done. Formalin fixed parrafin embedded sections were subjected to immunohistochemistry with anti Trop 2 antibody using standard DAB technique. The immunohistochemical expression of Trop 2 was evaluated using immunostaining intensity and mean integrated score followed by its comparison with age, gender, anatomical site, clinical stages and histopathological grades of OSCCTrop 2 expression was positive in 97.5% of cases. There was a statistically significant difference (p value&amp;#60;0.001) between immunostaining intensity and integrated score of Trop 2 among various histopathological grades of OSCC. As grade of OSCC increased, integrated score decreased. Trop 2 is one of the biomarkers that may serve as a useful tool to detect the changes undergoing at the molecular level which have prognostic or therapeutic significance.

Trophoblast Cell Surface Antigen 2 (Trop2) Is Expressed in Cases of EBV-Positive Diffuse Large B-Cell Lymphoma Emerging from Angioimmunoblastic T-Cell Lymphoma

Trophoblast Cell Surface Antigen 2 (Trop2) Is Expressed in Cases of EBV-Positive Diffuse Large B-Cell Lymphoma Emerging from Angioimmunoblastic T-Cell Lymphoma

Antibody-Drug Conjugate Sacituzumab Govitecan Enables a Sequential TOP1/PARP Inhibitor Therapy Strategy in Patients with Breast Cancer.

The antibody-drug conjugate (ADC) sacituzumab govitecan (SG) comprises the topoisomerase 1 (TOP1) inhibitor (TOP1i) SN-38, coupled to a monoclonal antibody targeting trophoblast cell surface antigen 2 (TROP-2). Poly(ADP-ribose) polymerase (PARP) inhibition may synergize with TOP1i and SG, but previous studies combining systemic PARP and TOP1 inhibitors failed due to dose-limiting myelosuppression. Here, we assess the proof-of-mechanism and clinical feasibility for SG and talazoparib (TZP) employing an innovative sequential dosing schedule. In vitro models tested pharmacodynamic endpoints, and in a phase 1b clinical trial (NCT04039230), 30 patients with metastatic triple-negative breast cancer (mTNBC) received SG and TZP in a concurrent (N = 7) or sequential (N = 23) schedule. Outcome measures included safety, tolerability, preliminary efficacy, and establishment of a recommended phase 2 dose. We hypothesized that tumor-selective delivery of TOP1i via SG would reduce nontumor toxicity and create a temporal window, enabling sequential dosing of SG and PARP inhibition. In vitro, sequential SG followed by TZP delayed TOP1 cleavage complex clearance, increased DNA damage, and promoted apoptosis. In the clinical trial, sequential SG/TZP successfully met primary objectives and demonstrated median progression-free survival (PFS) of 7.6 months without dose-limiting toxicities (DLT), while concurrent dosing yielded 2.3 months PFS and multiple DLTs including severe myelosuppression. While SG dosed concurrently with TZP is not tolerated clinically due to an insufficient therapeutic window, sequential dosing of SG followed by TZP proved a viable strategy. These findings support further clinical development of the combination and suggest that ADC-based therapy may facilitate novel, mechanism-based dosing strategies.