Mammalian Target Of Rapamycin Inhibitors Research Articles

Sarcopenia Susceptibility in Kidney Transplant Recipients: A Cross-Sectional Study Investigating the Impact of the Mammalian Target of Rapamycin Inhibitors

Sarcopenia Susceptibility in Kidney Transplant Recipients: A Cross-Sectional Study Investigating the Impact of the Mammalian Target of Rapamycin Inhibitors

Therapeutic Drug Monitoring for Sirolimus in Children with Vascular Anomalies: What Can We Learn from a Retrospective Study.

Objectives: Sirolimus (SRL), a mammalian target of rapamycin inhibitor, has been widely used to treat patients with vascular anomalies (VAs). The objectives of this study were to summarize the routine blood SRL monitoring data for VAs children, to investigate the factors contributing to the variable blood SRL concentrations and to evaluate the efficacy and safety of SRL therapy. Methods: VAs patients with routine blood SRL monitoring from July 2017 to April 2022 at the Department of Burns and Plastic Surgery, Children's Hospital of Nanjing Medical University were retrospectively collected. Clinical data were obtained from the hospital information system. Results: In total, 67 children (35 females) were enrolled. The therapeutic drug monitoring data showed that the range of measured blood trough concentrations (Ctrough) was 3.6-46.8 ng/mL. At the initial measurements, only 33% of patients were in the target concentration range (10-15 ng/mL). But this proportion became 54% at the last measurements. The whole blood-Ctrough-to-daily dose (Ctrough/Dose) ratio was significantly associated with age and body weight (BW). The patients' laboratory results did not change significantly after SRL treatment. Although the incidence of adverse events was relatively high (44.8%), most of them were mild and tolerable. 70.3% patients had total responses to SRL, whereas 29.7% children exhibited stable disease or progressive disease. No significant differences were found in Ctrough between the total response group and non-response group. Conclusions: This retrospective study revealed a high variability in SRL blood concentrations in Chinese children with VAs. Of note, pediatric patients with older age and a higher BW had a lower Ctrough/Dose ratio. It is a concern whether the range of 10-15 ng/mL is feasible for Chinese children based only on our study. Further studies recruiting more patients are required to redefine the target reference range for children with VAs.

DYRK1B blockade promotes tumoricidal macrophage activity in pancreatic cancer

ObjectiveHighly malignant pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant immunosuppressive and fibrotic tumour microenvironment (TME). Future therapeutic attempts will therefore demand the targeting of tumours and stromal compartments...

Amyotrophic lateral sclerosis as a disease model of sarcopenia

Abstract Sarcopenia, the progressive decline of muscle mass and function, has traditionally been viewed as an age-related process leading to a broad range of adverse outcomes. However, it has been widely reported that sarcopenia can occur earlier in life in association with various conditions (i.e. disease-related sarcopenia), including neuromuscular disorders. As early as 2010, the European Working Group on Sarcopenia in Older People included neurodegenerative diseases characterised by motor neuron loss among the mechanisms underlying sarcopenia. Despite some differences in pathogenetic mechanisms, both amyotrophic lateral sclerosis (ALS) and age-related sarcopenia share common characteristics, such as the loss of motor units and muscle fibre atrophy, oxidative stress, mitochondrial dysfunction and inflammation. The histology of older muscle shows fibre size heterogeneity, fibre grouping and a loss of satellite cells, similar to what is observed in ALS patients. Regrettably, the sarcopenic process in ALS patients has been largely overlooked, and literature on the condition in this patient group is very scarce. Some instruments used for the assessment of sarcopenia in older people could also be applied to ALS patients. At this time, there is no approved specific pharmacological treatment to reverse damage to motor neurons or cure ALS, just as there is none for sarcopenia. However, some agents targeting the muscle, like myostatin and mammalian target of rapamycin inhibitors, are under investigation both in the sarcopenia and ALS context. The development of new therapeutic agents targeting the skeletal muscle may indeed be beneficial to both ALS patients and older people with sarcopenia.

Characteristics and Outcomes of Fetal Cardiac Rhabdomyoma With or Without mTOR Inhibitors, a Systematic Review and Meta-Analysis.

To investigate the characteristics and outcomes of fetal cardiac rhabdomyoma with or without prenatal use of mammalian target of rapamycin inhibitor (mTORi). We systematically searched PubMed, Scopus, and Web of Science until June 2023. Studies reporting on pregnancies with fetal cardiac rhabdomyoma were included. A meta-analysis of proportions was conducted only on studies that included three or more cases. A systematic review included 61 studies reporting on 400 fetuses with cardiac rhabdomyoma, of which 52 studies (389 fetuses) had expectant management and 9 studies (11 fetuses) were managed with mTORi. The meta-analysis included 26 studies reporting on 354 fetuses. Prenatally, 14% (95% CI 4-36) had pericardial effusion, 13% (95% CI 6-27) had arrhythmia, 16% (95% CI 7-31) had outflow tract obstruction, and 10% (95% CI 4-21) had hydrops. Fetal demise occurred in 12% (95% CI 5-30). Before delivery, tumor size reduction was noted in 13%, and after birth in 58%. Following birth, 8% (95% CI 3-14) had neonatal death and 9% (95% 4-17) required cardiac surgery. 60% (95% CI 41-79) of cases were diagnosed with tuberous sclerosis. Seizures were reported only in cases with a tuberous sclerosis diagnosis (41/71 infants). For the 9 studies reporting all together on 11 fetuses with tuberous sclerosis receiving prenatal mTORi, they showed improvement in the size of cardiac rhabdomyoma as well as outflow obstruction and none had fetal demise or neonatal death, and none required postnatal cardiac surgery. We report on the natural history of prenatal cardiac rhabdomyoma, including characteristics, progression, and survival. We report 11 fetuses with tuberous sclerosis and cardiac rhabdomyoma receiving prenatal mTORi, showing promising results.

Neratinib Alone or in Combination with Immune Checkpoint Inhibitors with or without Mammalian Target of Rapamycin Inhibitors in Patients with Fibrolamellar Carcinoma

<b><i>Introduction:</i></b> Fibrolamellar carcinoma (FLC) displays upregulation of several oncogenes, including <i>HER2</i>, and multiple immune-suppressive mechanisms. We investigated the efficacy and safety of the pan-HER tyrosine kinase inhibitor neratinib as monotherapy (SUMMIT phase 2 basket study) or with immune checkpoint and/or mammalian target of rapamycin (mTOR) inhibitors (compassionate-use program) in patients with FLC. <b><i>Methods:</i></b> Patients received neratinib 240 mg/day orally in SUMMIT, or as doublet or triplet combinations with pembrolizumab 2 mg/kg intravenously every 3 weeks, nivolumab 240 mg intravenously every 2 weeks, everolimus 7.5 mg/day orally, or sunitinib 37.5 mg/day orally under compassionate use. The primary endpoint in SUMMIT was objective response rate; safety was a secondary endpoint. <b><i>Results:</i></b> Fifteen patients with FLC received neratinib monotherapy in SUMMIT. The objective response rate was 5% (95% confidence interval [CI]: 0–21.8) and the disease control rate was 13.3% (95% CI: 1.7–40.5). Upon progression, five had added immune checkpoint inhibitors with or without everolimus or sunitinib. Two additional patients received neratinib-based combinations outside of SUMMIT, for a total of 17 neratinib-treated patients. One patient who received neratinib plus pembrolizumab had a confirmed partial response, one treated with neratinib plus everolimus had stable disease lasting 6 months, and one who received neratinib plus pembrolizumab plus sunitinib had stable disease lasting 16 months. Grade 3/4 adverse events with neratinib monotherapy occurred in 10 (66.7%)/2 (13.3%) patients, respectively. Grade 3 adverse events with neratinib-based combinations were hyperglycemia (<i>n</i> = 1; neratinib plus pembrolizumab), hepatic failure, and anaphylaxis (<i>n</i> = 1 each, neratinib plus pembrolizumab plus everolimus). There were no grade 4 adverse events with combination therapy. <b><i>Conclusion:</i></b> In patients with FLC, single-agent neratinib had limited efficacy, but clinical benefit was observed with neratinib in combination with immunotherapy and/or mTOR-targeted agents.

Topical calcineurin and mammalian target of rapamycin inhibitors in inflammatory dermatoses: Current challenges and nanotechnology‑based prospects (Review).

Topical therapy remains a critical component in the management of immune‑mediated inflammatory dermatoses such as psoriasis and atopic dermatitis. In this field, macrolactam immunomodulators, including calcineurin and mammalian target of rapamycin inhibitors, can offer steroid‑free therapeutic alternatives. Despite their potential for skin‑selective treatment compared with topical corticosteroids, the physicochemical properties of these compounds, such as high lipophilicity and large molecular size, do not meet the criteria for efficient penetration into the skin, especially with conventional topical vehicles. Thus, more sophisticated approaches are needed to address the pharmacokinetic limitations of traditional formulations. In this regard, interest has increasingly focused on nanoparticulate systems to optimize penetration kinetics and enhance the efficacy and safety of topical calcineurin and mTOR inhibitors in inflamed skin. Several types of nanovectors have been explored as topical carriers to deliver tacrolimus in both psoriatic and atopic skin, while preclinical data on nanocarrier‑based delivery of topical sirolimus in inflamed skin are also emerging. Given the promising preliminary outcomes and the complexities of drug delivery across inflamed skin, further research is required to translate these nanotherapeutics into clinical settings for inflammatory skin diseases. The present review outlined the dermatokinetic profiles of topical calcineurin and mTOR inhibitors, particularly tacrolimus, pimecrolimus and sirolimus, focusing on their penetration kinetics in psoriatic and atopic skin. It also summarizes the potential anti‑inflammatory benefits of topical sirolimus and explores novel preclinical studies investigating dermally applied nanovehicles to evaluate and optimize the skin delivery, efficacy and safety of these 'hard‑to‑formulate' macromolecules in the context of psoriasis and atopic dermatitis.

Long-Term Outcome after Early Mammalian Target of Rapamycin Inhibitor-Based Immunosuppression in Kidney Transplant Recipients.

Background: The use of mammalian target of rapamycin inhibitors (mTORis) in kidney transplantation increases the risk of donor-specific human leukocyte antigen (HLA) antibody formation and rejection. Here, we investigated the long-term consequences of early mTORi treatment compared to calcineurin inhibitor (CNI) treatment. Methods: In this retrospective single-center analysis, key outcome parameters were compared between patients participating in randomized controlled immunosuppression trials between 1998 and 2011, with complete follow-up until 2018. The outcomes of eligible patients on a CNI-based regimen (n = 384) were compared with those of patients randomized to a CNI-free mTORi-based regimen (n = 81) and 76 patients randomized to a combination of CNI and mTORi treatments. All data were analyzed according to the intention-to-treat (ITT) principle. Results: Deviation from randomized immunosuppression for clinical reasons occurred significantly more often and much earlier in both mTORi-containing regimens than in the CNI treatment. Overall patient survival, graft survival, and death-censored graft survival did not differ between the treatment groups. Donor-specific HLA antibody formation and BPARs were significantly more common in both mTORi regimens than in the CNI-based immunosuppression. Conclusions: The tolerability and efficacy of the mTORi treatment in kidney graft recipients are inferior to those of CNI-based immunosuppression, while the long-term patient and graft survival rates were similar.

Long-term follow-up of the randomized, prospective Scandinavian heart transplant everolimus de novo study with early calcineurin inhibitors avoidance (SCHEDULE) trial

IntroductionEarly substitution of calcineurin inhibitor (CNI) with mammalian target of rapamycin inhibitors has been shown to improve kidney function and reduce intimal hyperplasia in heart transplant (HTx) recipients but data on long-term outcome of such a regime are still sparse. MethodsIn the SCHEDULE trial, 115 de novo HTx recipients were randomized to a) everolimus with reduced exposure of CNI followed by CNI withdrawal at week 7-11 post-transplant or b) standard-exposure with CNI. Both groups received mycophenolate mofetil and corticosteroids. Herein we report on the 10-12 year long-term follow-up of the study. ResultsA total of 78 patients attended the follow-up visit at a median time of 11 years post-transplant. In the everolimus intention to treat (ITT) group 87.5% (35/40 patients) still received everolimus and in the CNI ITT group 86.8 % (33/38) still received CNI. Estimated glomerular filtration rate (eGFR) (least square mean (95% CI)) at the 10-12 years visit was 82.7 (74.2-91.1) ml/min/1.73m2 and 61.0 (52.3-69.7) ml/min/1.73m2 in the everolimus and CNI group, respectively (p<0.001). Graft function measured by ejection fraction, ECG, NT-proBNP and drug safety were comparable between groups. During the study period there was a total of 28 deaths, but there was no difference in survival between the everolimus and the CNI group (aHR 0.61 (95% CI 0.29-1.30) p=0.20). For the composite endpoint of death, re-transplantation, myocardial infarction, PCI, dialysis, kidney transplantation or cancer no between group differences were found (aHR 1.0 (95% CI 0.57-1.77) p=0.99). ConclusionsDe novo HTx patients randomized to everolimus and low dose CNI followed by CNI free therapy sustained significantly better long-term kidney function than patients randomized to standard therapy. The graft function at 10-12 years was similar in both groups and there was no difference in survival.

Evolving trends in immunosuppression use and cytomegalovirus infection risk over the past decade in kidney transplantation.

The goal was to determine trends in immunosuppression use and its impact on cytomegalovirus (CMV) outcomes over the past 10 years. This was a single-center longitudinal cohort study of adult kidney recipients transplanted between Jan 2012 and June 2021. Baseline and follow-up data were gathered via chart abstraction and analyzed using univariate and multivariate analyses. Of 2392 kidney transplants conducted, 131 patients did not meet inclusion criteria. The mean age was 52 years, 41% were female, 57% were black, and 19% were CMV high-risk. The use of rabbit anti-thymocyte globulin (RATG) induction (odds ratio [OR] 1.6, 1.3-2.1), tacrolimus (FK) level >8ng/mL (OR 1.1, 1.09-1.11), CMV D+/R- rates (OR 1.06, 1.02-1.10), white blood cell count <3000 (OR 1.22, 1.18-1.26) and valganciclovir prophylaxis (OR 1.7, 1.6-1.9) have significantly increased over the past 10 years. Rejection rates (OR 0.86, 0.82-0.91) and BK viremia >2000 (OR 0.91, 0.91-0.98) have decreased. RATG induction (adjusted hazard ratio [aHR] 1.35, 1.2-1.5), FK >8ng/mL (aHR 3.5, 3.2-3.9), Belatacept conversion (aHR 2.5, 2.1-3.1), and rejection (aHR 1.8, 1.6-2.0) were significant risk factors for developing CMV infection, while mycophenolate mofetil <1500mg (aHR 0.52, 0.47-0.59), mammalian target of rapamycin inhibitor (mTORi) conversion (0.77, 0.56-0.89), cyclosporine-A conversion (aHR 0.68, 0.56-0.84) were associated with lower risk of CMV infection. Increasing use of potent immunosuppression coupled with higher CMV D+/R- F rates may be driving higher rates of CMV infection. Cyclosporine and mTORi conversion appears to be protective against CMV. A more individualized immunosuppression regimen based on infection risk merits consideration.

Pharmacodynamic Effect of mTOR Inhibition-based Immunosuppressive Therapy on T- and B-cell Subsets After Renal Transplantation.

The mammalian target of rapamycin inhibitor (mTORi) therapy after kidney transplantation is solely monitored pharmacokinetically, not necessarily reflecting PI3K-Akt-mTOR pathway blockade efficacy leading to potential under-or overimmunosuppression. In this cross-sectional study, phosphoflow cytometry was used to determine the efficacy of mTOR inhibition in peripheral T- and B-lymphocyte subsets by assessing p70S6 kinase (p70S6K) phosphorylation in renal transplant recipients upon treatment with a combination of either mTORi and calcineurin inhibitors (n = 18), or mTORi with mycophenolic acid (n = 9). Nine dialysis patients with end-stage renal disease and 17 healthy age-matched volunteers served as controls. mTORi treatment reduced p70S6K phosphorylation in CD4+, CD8+ T, and CD19+ B cells compared with healthy controls (HCs). Subpopulation analysis of CD4+ T cells and CD19+ B cells revealed a significant reduction of p70S6K phosphorylation in CD4+CD45RA-CD25- Th cells (P < 0.05), CD24hiCD38hi transitional B cells (P < 0.001), CD24+CD38- memory B cells (P < 0.001), and CD24intCD38int-naive B cells (P < 0.05) upon mTORi treatment, whereas CD4+CD45RA-CD25++CD127- regulatory T cells and CD24-CD38hi plasmablasts were not affected. Compared with mTORi + mycophenolic acid therapy, mTORi + calcineurin inhibitor treatment exhibited an even stronger inhibition of p70S6K phosphorylation in CD4+CD45RA-CD25- Th cells and CD8+ T cells. However, trough levels of mTORi did not correlate with p70S6K phosphorylation. mTORi selectively inhibited p70S6K phosphorylation in select lymphocyte subtypes. Assessing p70S6K phosphorylation by phosphoflow cytometry may serve as an approach to understand cell subset specific effects of mTORi providing detailed pharmacodynamic information for individualizing immunosuppression.

Vitamin D in tuberous sclerosis complex-associated tumors

Mammalian target of rapamycin inhibitors (mTORi) have been used to treat pediatric tuberous sclerosis complex (TSC)-associated tumors, particularly in cases with contraindications to surgery or difficulties in complete tumor resection. However, some patients experience side effects and tumor regression after discontinuation of the treatment. Therefore, there is an urgent need to develop drugs that can be used in combination with mTORi to increase their efficacy and minimize their side effects. 1,25-Dihydroxyvitamin D3 (1,25-D), which has anticancer properties, may be a promising candidate for adjuvant or alternative therapy because TSC and cancer cells share common mechanisms, including angiogenesis, cell growth, and proliferation. Vitamin D receptor-mediated signaling can be epigenetically modified and plays an important role in susceptibility to 1,25-D. Therefore, vitamin D signaling may be a promising drug target, and in vitro studies are required to evaluate the efficacy of 1,25-D in TSC-associated tumors, brain development, and core symptoms of psychiatric disorders.

A Systematic Review of Laser Treatment for Angiofibromas in Tuberous Sclerosis.

While mammalian target of rapamycin inhibitors have revolutionized the management of angiofibroma in tuberous sclerosis complex (TS), physical modalities such as laser are still indicated for recalcitrant lesions. The authors performed a systematic review of the efficacy and safety of laser treatment for TS-related facial angiofibroma. The electronic databases such as MEDLINE, Embase, PubMed, Cochrane Central Register of Controlled Trials, and Web of Science were searched from inception to October 10, 2023, for eligible records. Forty-seven articles met the inclusion criteria, representing a total of 217 patients with TS-related facial angiofibroma who received laser treatment. Several lasers have been trialed in patients including carbon dioxide ( n = 95, 43.7%), pulsed dye ( n = 21, 9.7%), argon ( n = 16, 7.4%), neodymium-doped: yttrium aluminum garnet ( n = 12, 5.5%), copper vapor ( n = 9, 4.1%), potassium titanyl phosphate ( n = 7, 3.2%), erbium: yttrium aluminum garnet ( n = 2, 0.9%), lasers and various combination therapies ( n = 55, 25.3%). Potassium titanyl phosphate, pulsed dye, and neodymium-dopsed:yttrium aluminum garnet lasers are better suited to manage the vascular components of angiofibroma while ablative lasers such as erbium: yttrium aluminum garnet and carbon dioxide lasers may present better options for lesions with a prominent fibrous component. While several lasers have been trialed with broadly favorable results, the low level of evidence precludes definitive conclusions, and no single laser appears superior.

Focal Cortical Dysplasia: Diagnosis, Classification, and Treatment Options

AbstractFocal cortical dysplasias (FCDs) include a spectrum of anomalies of cortical development that consist in one or more areas with altered lamination and in some cases, neurons of abnormal morphology. Clinically, these structural anomalies led to arise of epilepsy, which is more often a focal, drug-resistant type with onset in pediatric or adolescent age. Occasionally, other symptoms have been reported in patients with FCDs, such as headache, movement disorders, and cognitive impairment. According to International League against Epilepsy scheme of 2011, three main subtypes of FCD can be distinguished, based of anatomopathological feature, radiological signs, and clinical expression. Magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography, and neurophysiology are the cornerstones of diagnosis, although their negativity cannot exclude FCD in symptomatic patients, especially in FCD type I which often is elusive. In MRI, the main finding is the irregularity of the cortical–subcortical signal, specifically reduction of cortical thickness and absence of clear demarcation between gray and white matters, which is strongly diagnostic for FCD. Epilepsy related to FCD is difficult to manage and until now there is not a clear direction for treatment's rules. FCD shows poor response to antiepileptic drugs (AEDs), and there is no evidence of some AED that has proved more efficacy than others in patients with FCDs. Considering genetical and pathophysiological recent acquisitions, mammalian target of rapamycin inhibitors may play a fundamental role in future treatment of FCDs, but nowadays, surgery still remains the main weapon, with 50% of patients who undergo neurosurgery.

Research progress on the prevention and treatment of chemotherapy-induced ovarian damage.

Chemotherapy is a main treatment option for malignant tumors, but it may cause various adverse effects, including dysfunction of female endocrine system and fertility. Chemotherapy-induced ovarian damage has been concerned with ovarian preservation but also the prevention and treatment of ovarian dysfunction. In this article, the mechanisms of ovarian injury caused by chemotherapy, including apoptosis of the follicle and supporting cells, follicle "burn out", ovarian stromal and microvascular damage; and influencing factors, including age at diagnosis, initial low pre-treatment anti-Müllerian hormone levels, toxicity, dose and regimen of chemotherapy drugs are reviewed based on the latest research results and clinical practice. The article also discusses measures and frontier therapies for the prevention and treatment of ovarian injury, including the application of gonadotropin releasing hormone agonists or antagonists, tyrosine kinase inhibitors, antioxidants, sphingosine-1-phosphate, ceramide-1-phosphate, mammalian target of rapamycin inhibitors, granulocyte-colony stimulating factor, stem cell therapy and artificial ovaries.

Immunosuppression in liver transplant oncology: position paper of the Italian Board of Experts in Liver Transplantation (I-BELT).

Liver transplant oncology (TO) represents an area of increasing clinical and scientific interest including a heterogeneous group of clinical-pathological settings. Immunosuppressive management after LT is a key factor relevantly impacting result. However, disease-related guidance is still lacking, and many open questions remain in the field. Based on such a substantial lack of solid evidences, the Italian Board of Experts in Liver Transplantation (I-BELT) (a working group including representatives of all national transplant centers), unprecedently promoted a methodologically sound consensus conference on the topic, based on the GRADE approach. The group final recommendations are herein presented and commented. The 18 PICOs and Statements and their levels of evidence and grades of recommendation are reported and grouped into seven areas: (1) risk stratification by histopathological and bio-molecular parameters and role of mTORi post-LT; (2) steroids and HCC recurrence; (3) management of immunosuppression when HCC recurs after LT; (4) mTORi monotherapy; (5) machine perfusion and HCC recurrence after LT; (6) physiopathology of tumor-infiltrating lymphocytes and immunosuppression, the role of inflammation; (7) immunotherapy in liver transplanted patients. The interest in mammalian targets of rapamycin inhibitors (mTORi), for steroid avoidance and the need for a reduction to CNI exposure emerged from the consensus process. A selected list of unmet needs prompting further investigations have also been developed. The so far heterogeneous and granular approach to immunosuppression in oncologic patients deserves greater efforts for a more standardized therapeutic response to the different clinical scenarios. This consensus process makes a first unprecedented step in this direction, to be developed on a larger scale.

Abstract PO3-04-12: SUMIT-BC: Phase 2 randomized study of fulvestrant with or without the cyclin-dependent kinase 7 inhibitor (CDK7i) samuraciclib in advanced hormone receptor positive (HR+) breast cancer after CDK4/6i

Abstract Background: CDK7 has 3 critical roles in cancer: enhanced transcription of oncogenes and upregulation of anti-apoptotic genes, acceleration of the cell cycle through phosphorylation of other CDKs and driving estrogen receptor (ER) resistance to hormonal therapy. Inhibition of CDK7 is therefore a potential novel anti-cancer therapeutic strategy. In an initial single-arm evaluation samuraciclib (CT7001), a once daily (QD) oral CDK7 inhibitor has demonstrated a favourable safety profile and clinical activity in combination with fulvestrant, a selective estrogen receptor degrader (SERD), in patients with HR+/HER2- advanced breast cancer who have previously been treated with a CDK4/6 inhibitor. There was evidence of enhanced benefit in patients with no detectable TP53 mutation from baseline circulating tumor DNA (ctDNA) analysis and in patients without baseline liver metastases [1]. Samuraciclib is associated with low grade gastrointestinal (GI) adverse events such as nausea, vomiting and diarrhea managed with simple prophylaxis and patient counselling. An instant release capsule formulation was used in the initial clinical evaluation of samuraciclib requiring patients to take multiple capsules designed to rapidly release a large amount of material high in the GI tract. In this study a novel single tablet formulation will be administered which may enhance GI tolerability (2). This Phase 2 open-label randomised study will evaluate the efficacy, safety, pharmacokinetics and Quality of Life (QoL) impact of samuraciclib in combination with fulvestrant in comparison to a fulvestrant monotherapy control arm. Consistent with the principles of the current Project OPTIMUS initiative, 2 dose levels of samuraciclib will be evaluated [3]. All patients will undergo baseline ctDNA evaluation of TP53 mutation status to permit a prospective evaluation of its patient selection biomarker potential. Trial Design: Eligible patients will provide written informed consent, be aged 18 years or older, have histologically or cytologically confirmed ER+/HER2- advanced or metastatic breast cancer not amenable to resection or radiotherapy of curative intent, have received an aromatase inhibitor in combination with a CDK4/6 inhibitor in either the adjuvant or advanced setting, be receiving a luteinizing hormone-releasing hormone agonist if pre/perimenopausal and have RECIST v1.1 evaluable disease. Prior SERD, mammalian target of rapamycin inhibitor (mTORi) or chemotherapy for advanced breast cancer are not permitted. All patients will undergo baseline Guardant360 ctDNA analysis to establish their TP53 mutation status among others. 60 patients will be enrolled and will all receive fulvestrant 500mg IM administered on days 1, 15 and 29 and then monthly thereafter. Patients will be randomized 1:1:1 to fulvestrant alone, fulvestrant and samuraciclib 240mg QD or fulvestrant and samuraciclib 360mg QD. Patients will undergo RECIST v1.1 evaluation at baseline every 8-weeks until week 48, followed by every 12-weeks thereafter. The pharmacokinetics of samuraciclib and fulvestrant will be studied though the first 6 months of the study, with highest intensity during month 1. To evaluate Quality of Life (QoL) The Functional Assessment of Cancer Therapy -Breast questionnaire (FACT-B) will be completed. The primary endpoint is clinical benefit response at 24 weeks. Secondary endpoints are tolerability, progression free survival, overall response rate, duration of response, and the pharmacokinetics of fulvestrant and samuraciclib. QoL and correlations between ctDNA detectable TP53 mutations and efficacy/safety finding in this patient population will be reported. The study opened for recruitment in June 2023.

Abstract PO3-04-13: SUMIT-ELA: Phase 1b/2 combination of cyclin-dependent kinase 7 inhibitor (CDK7i) samuraciclib and selective estrogen receptor degrader (SERD) elacestrant in advanced hormone receptor positive (HR+) breast cancer after CDK4/6i

Abstract Background: CDK7 has 3 critical roles in cancer: enhanced transcription of oncogenes and upregulation of anti-apoptotic genes, acceleration of the cell cycle through phosphorylation of other CDKs and driving estrogen receptor (ER) resistance to hormonal therapy. Inhibition of CDK7 is therefore a potential novel anti-cancer therapeutic strategy. Samuraciclib (CT7001), a once daily oral CDK7 inhibitor has demonstrated a favorable safety profile and clinical activity in combination with fulvestrant (SERD) in patients with HR+/HER2- advanced breast cancer who have previously been treated with a CDK4/6 inhibitor [1]. Extended benefit was observed in patients with no TP53-mutation per circulating tumor DNA (ctDNA) analysis detectable at baseline. Limitations in the pharmacokinetic (PK) properties and route of administration (intramuscular only) of fulvestrant mean that oral alternatives are desirable. Recently, the EMERALD phase 3 study of the oral SERD elacestrant demonstrated a significant PFS benefit over standard of care endocrine treatment in the ER+/HER2- advanced or metastatic breast cancer population previously treated with a CDK4/6 inhibitor. [2]. Non-clinical data indicate that the underlying biology driving samuraciclib combination with endocrine therapy translates from fulvestrant to elacestrant, clinical evaluation is warranted [3]. This open-label Phase 1b dose escalation and Phase 2 dose expansion study will evaluate the safety, efficacy and pharmacokinetics of samuraciclib in combination with elacestrant. ctDNA analysis is informative for both elacestrant and samuraciclib, via ESR1-mutation status and TP53-mutation status respectively, and is an integral part of the study design. Trial Design: Eligible patients will provide written informed consent, be aged 18 years or older, have histologically or cytologically confirmed ER+/HER2- advanced or metastatic breast cancer not amenable to resection or radiotherapy of curative intent, have received an aromatase inhibitor in combination with a CDK4/6 inhibitor in either the adjuvant or advanced setting, be receiving a luteinizing hormone-releasing hormone agonist if pre/perimenopausal and have RECIST v1.1 evaluable disease. Prior SERD, mammalian target of rapamycin inhibitor (mTORi) or chemotherapy for advanced breast cancer are not permitted. The study will enrol ~48 patients. All patients will undergo baseline Guardant360 ctDNA analysis to establish their ESR-1 and TP53-mutation status. Patients will undergo RECIST v1.1 evaluation at baseline every 8-weeks until week 48, followed by every 12-weeks thereafter. Initially both samuraciclib and elacestrant will be administered once daily in a dose escalation/de-escalation approach under supervision of the study Safety Review Committee. The primary endpoint in Phase 1b is the identification of tolerable combination dose levels for both samuraciclib and elacestrant and in Phase 2 expansion to quantify the progression free survival benefit of the combination. Secondary endpoints are tolerability, clinical benefit response at 24 weeks, overall response rate, duration of response, best percent change in tumor size, pharmacokinetics and correlations between ctDNA detectable ESR1 and TP53 mutations and efficacy/safety finding in this patient population. The study opened for recruitment in June 2023.

Primary prophylaxis with mTOR inhibitor enhances T cell effector function and prevents heart transplant rejection during talimogene laherparepvec therapy of squamous cell carcinoma

The application of mammalian target of rapamycin inhibition (mTORi) as primary prophylactic therapy to optimize T cell effector function while preserving allograft tolerance remains challenging. Here, we present a comprehensive two-step therapeutic approach in a male patient with metastatic cutaneous squamous cell carcinoma and heart transplantation followed with concomitant longitudinal analysis of systemic immunologic changes. In the first step, calcineurin inhibitor/ mycophenolic acid is replaced by the mTORi everolimus to achieve an improved effector T cell status with increased cytotoxic activity (perforin, granzyme), enhanced proliferation (Ki67) and upregulated activation markers (CD38, CD69). In the second step, talimogene laherparepvec (T-VEC) injection further enhances effector function by switching CD4 and CD8 cells from central memory to effector memory profiles, enhancing Th1 responses, and boosting cytotoxic and proliferative activities. In addition, cytokine release (IL-6, IL-18, sCD25, CCL-2, CCL-4) is enhanced and the frequency of circulating regulatory T cells is increased. Notably, no histologic signs of allograft rejection are observed in consecutive end-myocardial biopsies. These findings provide valuable insights into the dynamics of T cell activation and differentiation and suggest that timely initiation of mTORi-based primary prophylaxis may provide a dual benefit of revitalizing T cell function while maintaining allograft tolerance.

Clinicopathological characteristics of everolimus-associated interstitial lung disease: A single-center consecutive analysis.

Everolimus, a mammalian target of rapamycin inhibitor used as an antineoplastic drug, is associated with a remarkably high incidence of interstitial lung disease (ILD). The clinical and pathological characteristics of ILD caused by everolimus have not been thoroughly investigated; therefore, we aimed to elucidate the features of everolimus-associated ILD. We retrospectively reviewed the medical records of patients who received everolimus for cancer treatment at our hospital. Patient backgrounds were compared between the ILD and non-ILD groups. Chest computed tomography (CT), changes in biomarkers, and lung histopathological features were analyzed for ILD cases. Sixty-six patients were reviewed, and ILD developed in 19. There were no differences in patient demographics between the ILD and non-ILD groups. The severity of ILD was grade 1 (G1) in 9 and grade 2 (G2) in 10 cases. Chest CT showed organizing pneumonia (OP) or a hypersensitive pneumonia pattern. The levels of lactate dehydrogenase, C-reactive protein, Krebs von den lungen-6, and surfactant protein-D (SP-D) at the onset of ILD were significantly higher than those at baseline. Analysis of G1 and G2 ILD subgroups showed a higher SP-D levels in the G2 subgroup. Five patients underwent lung biopsies; all specimens demonstrated alveolitis with lymphocytic infiltration and granulomatous lesions, and some had OP findings. Everolimus-associated ILD is mild and has a favorable prognosis. Patients with symptomatic ILD were more likely to have higher SP-D levels than those with asymptomatic ILD. Granulomatous lesions are an important pathological feature of everolimus-associated ILD.