P1, N=45, Recruiting, Epsilogen Ltd | Not yet recruiting --> Recruiting

P1, N=143, Recruiting, Coherent Biopharma (Suzhou) Co., Ltd. | Phase classification: P1a/1b --> P1 | Trial completion date: Mar 2024 --> Sep 2024 | Trial primary completion date: Sep 2023 --> Sep 2024

P1, N=170, Recruiting, Coherent Biopharma (Suzhou) Co., Ltd. | Trial primary completion date: Dec 2023 --> Oct 2024

P1, N=45, Not yet recruiting, Epsilogen Ltd

TPIV200 was well tolerated but was not associated with improved PFS. Additional studies are required to uncover potential synergies using multiepitope vaccines targeting FRα. Trial Registration NLM/NCBI Registry, NCT02978222, https://clinicaltrials.gov/search?term=NCT02978222.

The results showed that CBP-1018 was eliminated immediately after injection and MMAE reached the maximum exposure at approximately 2 h after infusion. The maximum concentration of MMAE did not exceed 20.0 ng/mL, suggesting that the off-target toxicity of CBP-1018 injection was controllable.

P1, N=51, Active, not recruiting, Instil Bio | Phase classification: P1a/1b --> P1

Describing CBP-1008: a FR/ TRPV6 targeted drug conjugate in Phase II pivotal studies of advanced ovarian cancer treatment; Exploring CBP-1018: a FR/ PSMA targeted drug conjugate in Phase Ib for prostate cancer therapy; Highlighting CBP-1019: TOP1i payload drug conjugate for unmet medical needs

The safety profile is tolerable and maximum tolerated dose has not been reached, with evidence of anti-tumour activity observed in a patient with ovarian cancer. These results demonstrate the potential of IgE therapy for cancer.

Multiple SD and PSA decrease were observed at DLs of 0.08-0.14 mg/kg, conferred a promising preliminary antitumor activity in pts with mCRPC despite of COVID-19's impacts. MTD was not reached and dose-escalation to establish the RP2D is continuing.

A 2nd generation FOLR1-CAR T cell was created by fusing the ScFv from farletuzumab (anti-FOLR1 monoclonal antibody) with a 4-1BB costimulatory and CD3z cytotoxicity domain... FOLR1-CAR T cells appear to have in vivo activity against U2OS cell line and support further testing of safety and feasibility in an early phase clinical trial for relapsed/refractory OS. >

Adding farletuzumab to standard chemotherapy does not improve PFS in patients with OC who were platinum-sensitive in first relapse with low CA-125 levels. Folate receptor-α expression was not measured in this study. (Clinical Trial Registry NCT02289950).

AFVT-2101 was well-tolerated with no test article-related adverse effects on clinical observations, bodyweight, clinical chemistry, hematology, coagulation, anatomic pathology, or immunotoxicity parameters. The no observed adverse effect level (NOAEL) was determined to be 150 mg/kg under the conditions of the study.The safety profile is being further evaluated in an ongoing pivotal 4-week GLP study incorporating standard toxicology endpoints, safety pharmacology (CNS, CV, and respiratory), gross and anatomic pathology, as well as cytokine, immunophenotyping, receptor occupancy, TK, and ADA analyses.In conclusion, AFVT-2101 is well-tolerated in NHPs with a pharmacokinetic and safety profile consistent with its intended clinical application.

The clinical development of antibody drug conjugates (ADCs) in ovarian cancer began in 2008 with farletuzumab, a humanized monoclonal antibody, and vintafolide, an antigen drug conjugate, both targeting alpha folate receptor...In September 2021, the FDA approved tisotumab vedotin (TV) in recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. This was followed in November 2022, by the approval of mirvetuximab soravtansine (MIRV) for adult patients with folate receptor alpha (FRα) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens...We also outline new concepts in the field of ADCs, including promising targets such as NaPi2 and novel drug delivery platforms such as dolaflexin with a scaffold-linker. Finally, we briefly present challenges in the clinical management of ADC toxicities and the emerging role of ADC combination therapies, including chemotherapy, anti-angiogenic and immunotherapeutic agents.

P1a/1b, N=51, Active, not recruiting, Instil Bio | Recruiting --> Active, not recruiting

P3, N=1100, Terminated, Morphotek | Completed --> Terminated; Lack of efficacy

P1a/1b, N=51, Recruiting, Instil Bio | Not yet recruiting --> Recruiting

P1a/1b, N=51, Not yet recruiting, Instil Bio

When combined with TCR-specific binding, CoStAR significantly enhanced T-cell proliferation, persistence, and antitumor activity in vivo vs TCR alone, resulting in tumor control and prolonged survival. Effects were not observed with CoStAR alone, underscoring that signaling through CoStAR alone does not induce T-cell effector function. The sustained proliferation of anti-FOLR1 CoStAR T cells without exogenous IL-2 support in vitro and in vivo supports a clinical TIL regimen free of high-dose IL-2.

The novel anti-FOLR1 CoStAR molecule improves T-cell effector function through dual CD28- and CD40-mediated costimulation upon targeted engagement of tumor-expressed FOLR1. Anti-FOLR1 CoStAR TIL manufacturing is feasible in tumors associated with FOLR1 expression, including ovarian, lung, and renal. A first-in-human clinical study of ITIL-306, an anti-FOLR1 CoStAR TIL product, is planned.

Within the FRα+/TRPV6+ tumors, tumor growth inhibition well correlates with IHC score of FRα (R2=0.89).It is indicated that clinical trials in selected indications using biomarkers assay to screening patients will expedite the clinical development of CBP-1008. Initial clinical response has been observed in our Phase I trial.

We generated a FOLR1-directed CAR using anti-FOLR1 binder (Farletuzumab), IgG4 intermediate spacer and 41-BB/CD3zeta signaling domains... We tested the target specificity of FOLR1-directed CAR T cells against FOLR1-positive (CBF/GLIS-CB, WSU-AML, Kasumi-1 FOLR1+ ) and FOLR1-negative (Kasumi-1) cells. CD8 FOLR1 CAR T cells demonstrated cytolytic activity against FOLR1 positive but not FOLR1 negative cells ( Figure 1B ). Furthermore, both CD8 and CD4 FOLR1 CAR T cells produced higher levels of IL-2, IFN-

Background MORAb-202 is an ADC consisting of a FRα-targeting antibody (farletuzumab) paired with a cathepsin B-cleavable linker and an eribulin payload. The major toxicity observed with MORAb-202 treatment was hematologic toxicity. Conclusion These findings suggest MORAb-202 may be a promising ADC for TNBC and warrants further clinical investigation in this setting.

Finally, we confirmed that the level of core-fucosylation on FOLR1 especially at the glycosite Asn-201 positively regulated the cellular uptake capacity of folates, and enhanced uptake of folates could promote the EMT of HCC cells. Based on the results, we proposed a potential pathway for HGF or TGF-β1-induced EMT of HCC cells: HGF or TGF-β1 treatment of HCC cells can increase the expression of glycosyltransferase FUT8 to up-regulate the core-fucosylation of N-glycans on glycoproteins including the FOLR1; core-fucosylation on FOLR1 can then enhance the folate uptake capacity to finally promote the EMT progress of HCC cells.

P2, N=80, Completed, Marker Therapeutics, Inc. | Active, not recruiting --> Completed

The ADC could be a more reasonable choice than mAb as a targeting agent for the FOLRα-expressing tumor.

The antibody-drug conjugate (ADC) MORAb-202, consisting of farletuzumab paired with a cathepsin B-cleavable linker and eribulin, targets folate receptor alpha (FRA), which is frequently overexpressed in various tumor types. Toxicology studies (Q3Wx2) in non-human primates suggested that the major observed toxicity of MORAb-202 is hematologic toxicity. Overall, these findings support the concept that MORAb-202 represents a promising investigational ADC for the treatment of TNBC patients.

P2, N=80, Active, not recruiting, Marker Therapeutics, Inc. | Trial completion date: Dec 2021 --> Aug 2021 | Trial primary completion date: Dec 2021 --> Aug 2021

Her induction included cytarabine, daunorubicin, etoposide, gemtuzumab ozogamicin, and repeated intrathecal cytarabine until her CSF had cleared on three consecutive occasions...Her second course included epigenetic modification with decitabine and vorinostat, gemtuzumab ozogamicin, fludarabine, high-dose cytarabine, and idarubicin... AMKL with GLIS2 fusion and RAM phenotype is exceptionally difficult to treat with conventional therapy. Innovative solutions are desperately needed for this grave disease. Assessing Bcl-2 status and incorporating venetoclax and liposomal daunorubicin- cytarabine into initial therapeutic planning should be strongly considered in these patients.

Anti-c-Met and anti-AXL CAR NK or T cells could be effective in glioblastoma cells.

This innovative class of therapeutics showed encouraging early signs of clinical efficacy in PROC particularly mirvetuximab soravtansine that has been successfully introduced into three randomized and controlled phase III studies. In this review, the evidence from clinical trials supporting the development of ADCs targeting folate receptor alpha, sodium-dependent phosphate transporter 2B, dipeptidase 3, mesothelin, mucin 16, and tissue factor using various cytotoxic payloads in PROC is reviewed.

This finding requires replication in larger cohorts. In addition, OCCC could be tested for ERBB2 amplification for inclusion in gynecological basket trials targeting this alteration.

These results suggest the driving role of FOLR1 in HCC resistance to sorafenib, which may be exerted through FOLR1-induced autophagy. Therefore, this study may provide new insights into understanding the mechanism of sorafenib resistance.

High adherence to the MDP may counteract the genetic predisposition associated with one-carbon metabolism on breast cancer risk in postmenopausal women.

Our study can provide a deep insight into molecular mechanisms of PEM resistance in NSCLC and contribute to the development of more effective therapeutic schedules. SIGNIFICANCE: Our study can provide deeper insight into molecular mechanisms of PEM resistance in NSCLC and contribute to the development of more effective therapeutic schedules.

In orthotopic xenograft mouse models, FOLR1-expressing T47D tumors and non-FOLR1-expressing MCF7 tumors were suppressed upon MORAb-202 administration. The novel anti-FOLR1 antibody-eribulin conjugate MORAb-202 has potential antitumor effects in breast cancer.

An OR-gated CAR-T cell strategy against CA125 and MSLN would target the majority of tumor cells in most cases. Antigen expression and T-cell infiltration patterns are favorable for this strategy in primary and recurrent disease.

Despite frequent DLL3 expression in NEC, a potential therapeutic benefit of DLL3-targeted drugs remains uncertain given the recent failure of the Rova-T therapeutic trial in small cell lung carcinomas. Small cohorts of NEC enriched in PIK3CA/PTEN/AKT and programmed cell death protein 1/PD-L1 alterations indicate therapeutic roles for their respective inhibitors.

P2, N=96, Completed, M.D. Anderson Cancer Center | N=42 --> 96

The ability of this tracer to quantify CD8 T-cell tumor infiltrates was evaluated in preclinical studies following single-agent treatment with FOLR1-T-cell bispecific (TCB) antibody and combination therapy of CEA-TCB (RG7802) and CEA-targeted 4-1BB agonist CEA-4-1BBL...Taken together, the anti-CD8-minibody 89Zr-Df-IAB22M2C revealed a high sensitivity for the detection of intratumoral CD8+ T cell infiltrates upon either single or combination treatment with T cell bispecific antibody-based fusion proteins. These results provide further evidence that the anti-CD8 tracer, which is currently in Clinical Phase II, is a promising monitoring tool for intratumoral CD8+ T cells in patients treated with CIT.

Future expansion of this methodology into other cellular therapies (CAR NK or BiTE) and the examination of new data sources could reveal additional targets with robust expression in AML. Demonstration of cell surface expression of these targets, and appropriate preclinical evidence of efficacy, could lay the groundwork for quickly moving these therapies to clinical trials in AML.