Neuroblastoma is treated with aggressive multimodal therapy, yet more than 50% of patients experience relapse. We recently showed that relapsed neuroblastomas frequently harbor mutations leading to ...hyperactivated ERK signaling and sensitivity to MEK inhibition therapy. Here we sought to define a synergistic therapeutic partner to potentiate MEK inhibition.
We first surveyed 22 genetically annotated human neuroblastoma-derived cell lines (from 20 unique patients) for sensitivity to the MEK inhibitor binimetinib. After noting an inverse correlation with sensitivity to ribociclib (CDK4/6 inhibitor), we studied the combinatorial effect of these two agents using proliferation assays, cell-cycle analysis, Ki67 immunostaining, time-lapse microscopy, and xenograft studies.
Sensitivity to binimetinib and ribociclib was inversely related (
= -0.58,
= 0.009).
amplification status and expression were associated with ribociclib sensitivity and binimetinib resistance, whereas increased MAPK signaling was the main determinant of binimetinib sensitivity and ribociclib resistance. Treatment with both compounds resulted in synergistic or additive cellular growth inhibition in all lines tested and significant inhibition of tumor growth in three of four xenograft models of neuroblastoma. The augmented growth inhibition was attributed to diminished cell-cycle progression that was reversible upon removal of drugs.
Here we demonstrate that combined binimetinib and ribociclib treatment shows therapeutic synergy across a broad panel of high-risk neuroblastoma preclinical models. These data support testing this combination therapy in relapsed high-risk neuroblastoma patients, with focus on cases with hyperactivated RAS-MAPK signaling.
.
The cyclin-dependent kinase (CDK) 4/6 inhibitor, ribociclib (LEE011), displayed preclinical activity in neuroblastoma and malignant rhabdoid tumor (MRT) models. In this phase I study, the maximum ...tolerated dose (MTD) and recommended phase II dose (RP2D), safety, pharmacokinetics (PK), and preliminary activity of single-agent ribociclib were investigated in pediatric patients with neuroblastoma, MRT, or other cyclin D-CDK4/6-INK4-retinoblastoma pathway-altered tumors.
Patients (aged 1-21 years) received escalating once-daily oral doses of ribociclib (3-weeks-on/1-week-off). Dose escalation was guided by a Bayesian logistic regression model with overdose control and real-time PK.
Thirty-two patients (median age, 5.5 years) received ribociclib 280, 350, or 470 mg/m
Three patients had dose-limiting toxicities of grade 3 fatigue (280 mg/m
;
= 1) or grade 4 thrombocytopenia (470 mg/m
;
= 2). Most common treatment-related adverse events (AE) were hematologic: neutropenia (72% all-grade/63% grade 3/4), leukopenia (63%/38%), anemia (44%/3%), thrombocytopenia (44%/28%), and lymphopenia (38%/19%), followed by vomiting (38%/0%), fatigue (25%/3%), nausea (25%/0%), and QTc prolongation (22%/0%). Ribociclib exposure was dose-dependent at 350 and 470 mg/m
equivalent to 600 (RP2D)-900 mg in adults, with high interpatient variability. Best overall response was stable disease (SD) in nine patients (seven with neuroblastoma, two with primary CNS MRT); five patients achieved SD for more than 6, 6, 8, 12, and 13 cycles, respectively.
Ribociclib demonstrated acceptable safety and PK in pediatric patients. MTD (470 mg/m
) and RP2D (350 mg/m
) were equivalent to those in adults. Observations of prolonged SD support further investigation of ribociclib combined with other agents in neuroblastoma and MRT.
.
Summary
Background
The CXCR4 chemokine receptor promotes tumor survival through mechanisms that include suppressing antitumor immune responses. Mavorixafor (X4P-001) is an oral, selective, allosteric ...CXCR4 inhibitor that decreases the recruitment of immunosuppressive cells into the tumor microenvironment and increases activated cytotoxic Tcell infiltration.
Methods
Patients with metastatic clear cell renal cell carcinoma (ccRCC) unresponsive to nivolumab monotherapy received oral mavorixafor 400 mg daily plus 240 mg intravenous nivolumab every 2 weeks.
Results
Nine patients were enrolled, median age 65 years. At baseline 4 had progressive disease (PD) and 5 had stable disease (SD). One of 5 patients with SD at study entry on prior nivolumab monotherapy had a partial response (PR) on combination treatment; all 4 patients with PD at study entry had a best response of SD with the combination treatment (median duration: 6.7 months; range: 3.7–14.7). Four patients discontinued therapy due to treatment-related adverse events (AEs). Grade ≥ 3 drug-related AEs were elevated alanine and aspartate aminotransferase (2 patients each); and autoimmune hepatitis, chronic kidney disease, increased lipase, maculopapular rash, and mucosal inflammation (1 patient each). A robust increase in levels of chemokine (C-X-C motif) ligand 9 CXCL9 on mavorixafor appeared to correlate with clinical benefit.
Conclusions
The CXCR4 inhibition mediated by mavorixafor, in combination with PD-1 blockade to enhance antitumor immune responses in patients unresponsive to checkpoint inhibitor monotherapy, is worthy of further study. Mavorixafor and nivolumab combination therapy in patients with advanced ccRCC demonstrated potential antitumor activity and a manageable safety profile.
Trial registration: ClinicalTrials.gov identifier: NCT02923531. Date of registration: October 04, 2016.
Ewing sarcoma is an aggressive bone and soft tissue tumor in children and adolescents, with treatment remaining a clinical challenge. This disease is mediated by somatic chromosomal translocations of ...the EWS gene and a gene encoding an ETS transcription factor, most commonly, FLI1. While direct targeting of aberrant transcription factors remains a pharmacological challenge, identification of dependencies incurred by EWS/FLI1 expression would offer a new therapeutic avenue. We used a combination of super-enhancer profiling, near-whole genome shRNA-based and small-molecule screening to identify cyclin D1 and CDK4 as Ewing sarcoma-selective dependencies. We revealed that super-enhancers mark Ewing sarcoma specific expression signatures and EWS/FLI1 target genes in human Ewing sarcoma cell lines. Particularly, a super-enhancer regulates cyclin D1 and promotes its expression in Ewing sarcoma. We demonstrated that Ewing sarcoma cells require CDK4 and cyclin D1 for survival and anchorage-independent growth. Additionally, pharmacologic inhibition of CDK4 with selective CDK4/6 inhibitors led to cytostasis and cell death of Ewing sarcoma cell lines in vitro and growth delay in an in vivo Ewing sarcoma xenograft model. These results demonstrated a dependency in Ewing sarcoma on CDK4 and cyclin D1 and support exploration of CDK4/6 inhibitors as a therapeutic approach for patients with this disease.
The aims of this multicenter study were to evaluate the response rate, progression-free survival, and toxicity of the combination of bortezomib, bendamustine, and rituximab in patients with ...follicular lymphoma whose disease was relapsed or refractory to prior treatment.
Patients received five 35-day cycles of bortezomib, bendamustine, and rituximab: bortezomib administered intravenously (IV) at a dose of 1.6 mg/m(2) on days 1, 8, 15, and 22, cycles one to five; bendamustine 50, 70, or 90 mg/m(2) IV over a 60-minute infusion on days 1 and 2, cycles one to five; and rituximab 375 mg/m(2) on days 1, 8, 15, and 22 of cycle one and day 1 of subsequent cycles. Patients were assessed using the International Workshop Response Criteria, with the primary end point of 60% complete response rate.
Seventy-three patients were enrolled. During the dose-escalation phase, the maximum-tolerated dose for bendamustine was not reached; the 90 mg/m(2) dose level was expanded for the efficacy assessment, and a total of 63 patients received bendamustine 90 mg/m(2). In these 63 patients, the overall response rate was 88% (including 53% complete response). Median duration of response was 11.7 months (95% CI, 9.2 to 13.3). Median progression-free survival was 14.9 months (95% CI, 11.1 to 23.7). Toxicities were manageable; myelosuppression was the main toxicity (25% and 14% of patients experienced grade 3 to 4 neutropenia and grade 3 to 4 thrombocytopenia, respectively). Transient grade 3 to 4 neuropathy occurred in 11% of patients.
The combination of bortezomib, bendamustine, and rituximab is highly active in patients with follicular lymphoma who have received previous treatment.
BackgroundPARP7 is a mono-ART that is upregulated in response to cellular stress (e.g., viral infection, cigarette smoke), and suppresses the Type I interferon (IFN) response following cytosolic ...nucleic acid sensing. RBN-2397 is a first-in-class PARP7 inhibitor, inducing cancer cell autonomous and immune stimulatory effects in preclinical models through enhanced Type I IFN signaling in cancer cells. Moreover, RBN-2397 induces CD8 T cell-dependent tumor-specific immune memory in an immunocompetent mouse cancer model.1 RBN-2397 is currently being tested in an ongoing Phase I clinical study (NCT04053673).2 Here we aimed to compare biomarker results from preclinical models and patient samples.MethodsIn preclinical models, interferon-stimulated gene (ISG) expression was assessed by qPCR, NanoString, or ELISA. Plasma CXCL10 from patients was measured by MSD while ISG expression in PBMCs was measured by NanoString. Baseline and on-treatment patient tumor biopsies were analyzed by NanoString, CD8/GZMB IHC, and MIBI-TOF to characterize immune changes in the tumor microenvironment.ResultsRBN-2397 potently restored tumoral Type I IFN signaling in preclinical models as demonstrated by increases in ISGs, namely CXCL10, which were not observed in non-tumor tissue (e.g. spleen, PBMCs). In peripheral blood from patients treated with RBN-2397, neither plasma nor PBMC CXCL10 increased more than 2-fold over baseline. Expression of 42 ISGs was not consistently induced in a dose-dependent manner in PBMCs. However, in tumor types of interest (e.g. cancers of the upper aerodigestive tract), CXCL10 expression increased 1.5 to 8-fold, with similar effects observed for a subset of ISGs in 5 evaluable paired biopsy samples.Confirming preclinical studies 1, up to 8-fold increases in CD8 T cell infiltration along with induction of granzyme B expression were observed in 4 of 5 paired patient tumor biopsies by immunohistochemistry. Using the MIBI-TOF technology, we observed up to 50-fold increases in intratumoral activated T cells as well as monocytes and M1 macrophages, most strikingly in two NSCLC patients.ConclusionsInhibition of PARP7 with RBN-2397 restores tumor-intrinsic Type I IFN signaling in preclinical models leading to enhanced adaptive immunity, resulting in CD8 T cell-dependent durable tumor regressions. These observations are mirrored in samples from patients treated with RBN-2397 in that pharmacodynamic effects of RBN-2397 were preferentially observed in tumor tissue relative to the periphery, including an increase in immune infiltration into the tumor microenvironment. These data provide evidence for induction of an adaptive immune response and confirm the tumor-intrinsic, immunomodulatory mechanism of action of RBN-2397 in patients.ReferencesGozgit, et al. PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity. Cancer Cell 2021; In press.Falchook, et al. A first-in-human phase 1 study of a novel PARP7 inhibitor RBN-2397 in patients with advanced solid tumors. ASCO 2021; oral presentation.
We studied the efficacy and safety of an investigational enoxaparin regimen, 1.5 mg/kg once daily, as a bridge to warfarin for the outpatient treatment of acute venous thromboembolism. We undertook a ...case-control design. We enrolled 40 acute venous thromboembolism cases prospectively and matched them by age, gender, and location of venous thromboembolism to 80 previously treated controls. All controls had received enoxaparin 1 mg/kg twice daily. The primary end point was recurrent venous thromboembolism. We followed the cases for 30 days. We discontinued enoxaparin after we achieved the target international normalized ratio between 2.0 and 3.0. One case (2.9%) and three controls (3.8%) had recurrent venous thromboembolic events (P = 1.00). There were no major bleeding complications in the case group, compared to 3 (3.8%) in the control group (P = .55). Once daily enoxaparin, 1.5 mg/kg, as a bridge to warfarin was as effective with a similar safety profile as twice daily enoxaparin, 1mg/kg, for initial treatment of acute venous thromboembolism in the outpatient setting. This case-control study provides the rationale for undertaking a randomized controlled trial comparing enoxaparin 1.5 mg/kg once daily versus enoxaparin 1.0 mg/kg twice daily as a bridge to warfarin in outpatients with acute venous thromboembolism.
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