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A subset of mammalian genes exhibits genomic imprinting, whereby one parental allele is preferentially expressed. Differential DNA methylation at imprinted loci serves both to mark the parental origin of the alleles and to regulate their expression. In mouse, the imprinted gene Rasgrf1 is associated with a paternally methylated imprinting control region which functions as an enhancer blocker in its unmethylated state. Because Rasgrf1 is imprinted in a tissue-specific manner, we investigated the methylation pattern in monoallelic and biallelic tissues to determine if methylation of this region is required for both imprinted and non-imprinted expression. Our analysis indicates that DNA methylation is restricted to the paternal allele in both monoallelic and biallelic tissues of somatic and extraembryonic lineages. Therefore, methylation serves to mark the paternal Rasgrf1 allele throughout development, but additional factors are required for appropriate tissue-specific regulation of expression at this locus.

5544 Background: SIRPα-Fc-CD40L is a hexameric, bi-functional fusion protein consisting of SIRPα linked to CD40L via an inert Fc linker. This molecule competitively inhibits CD47 to enhance tumor cell phagocytosis and activates CD40 to increase antigen processing and cross-presentation by antigen presenting cells (APCs) to CD8 T cells, thus bridging innate and adaptive immunity. Methods: This first-in-human, Phase 1 dose escalation study evaluated SL-172154 in patients (pts) with advanced platinum resistant ovarian, fallopian tube and primary peritoneal cancers (PROC). SL-172154 was administered intravenously across 5 dose levels (0.1, 0.3, 1.0, 3.0, 10mg/kg). Dose escalation followed a modified toxicity probability interval 2 design. Objectives included evaluation of safety, dose-limiting toxicity (DLT), recommended phase 2 dose, pharmacokinetic and pharmacodynamic (PD) parameters, and antitumor activity per RECIST 1.1. Results: As of 3 Jan 2023, 27 pts (median age 66 years [range 33-85]; median of 4 prior systemic therapies [range 2-9]) with ovarian (70%), fallopian tube (15%) or primary peritoneal (15%) cancer were dosed. Treatment-emergent AEs (>15%) regardless of grade (G) included infusion related reaction (IRR) (67%), fatigue (44%), nausea (33%), back pain (26%), constipation, diarrhea (both 22%), decreased appetite and pruritus (both 19%). There was one DLT of G3 ALT increased at 10mg/kg requiring dose interruption for resolution. A maximum tolerated dose was not reached. G3/4 treatment-related AEs (>1pt) were AST increased (G3) and lymphopenia (G4), each in 2 pts (7%); all were fully resolved with no dose modifications. There were no fatal AEs, no AEs that led to drug discontinuation and no events of cytokine release syndrome. The frequency of IRR events increased with increasing dose, and slowing the rate of infusion was utilized for mitigation. SL-172154 Cmax and AUC increased with dose with greater than proportional exposure noted at 3 and 10mg/kg potentially due to target saturation. These findings were supported by dose-dependent target engagement of CD47 and CD40 on CD4 T cells and B cells respectively, approaching 100% by 3 mg/kg. Rapid dose-dependent egress of CD40+ B cells was maximal at ≥3mg/kg. SL-172154 induced dose-dependent responses in IL-12, CXCL-8, CXCL-10, IL-10, CCL2, CCL20, and CCL22, which also approached a plateau at ≥3mg/kg. Analysis of peripheral and tumor immunophenotypes and anti-drug antibodies in response to SL-172154 is ongoing and will be presented. Best response was stable disease in 6/27 response evaluable (22%) pts. Conclusions: SL-172154 is well tolerated in heavily pretreated PROC pts. IRRs were readily manageable. Maximal CD47 and CD40 target engagement and CD40-dependent PD effects were observed with ≥3mg/kg SL-172154. 3mg/kg is a safe, tolerable, and pharmacologically active dose for evaluation in combination studies in pts with PROC. Clinical trial information: NCT04406623 .

Objectives: Patients with epithelial ovarian cancer (EOC) recurring between 6 and 12 months after primary platinum chemotherapy have worse prognosis than those recurring in >12 months. Artificially prolonging the platinum-free interval (PFI) with cytotoxic chemotherapy was tested in MITO-8 with poor outcomes. This study aimed to determine the impact of using non-platinum or targeted therapy in 2nd line treatment of EOC patients recurring 6-12 months after completion of primary platinum-based chemotherapy.Methods: A multi-institutional retrospective review of 177 patients with recurrent EOC and PFI of 6-12 months following primary chemotherapy was performed comparing platinum versus nonplatinum chemotherapy or targeted therapy for 2nd line treatment. PFI1 was defined as the date of last chemotherapy to date of recurrence. PFS2/3 were defined as start of 2nd or 3rd line chemotherapy to start of subsequent line. Results:Of 177 patients, the majority of patients were Caucasian, had serous histology, and underwent primary cytoreductive surgery. Median PFI1 was 8.2 months (95% CI 8-9 months). Second line platinum was omitted in 28% of patients. Bevacizumab was used in 2nd line in 16% of patients; 19% received other targeted therapies. Median PFS2 for platinum chemotherapy was