Oxidative addition of aryl bromides to 12‐electron Rh(PiBu3)2BArF4 (ArF=3,5‐(CF3)2C6H3) forms a variety of products. With p‐tolyl bromides, RhIII dimeric complexes result ...Rh(PiBu3)2(o/p‐MeC6H4)(μ‐Br)2BArF42. Similarly, reaction with p‐ClC6H4Br gives Rh(PiBu3)2(p‐ClC6H4)(μ‐Br)2BArF42. In contrast, the use of o‐BrC6H4Me leads to a product in which toluene has been eliminated and an isobutyl phosphine has undergone CH activation: Rh{PiBu2(CH2CHCH3CH2)}(PiBu3)(μ‐Br)2BArF42. Trapping experiments with ortho‐bromo anisole or ortho‐bromo thioanisole indicate that a possible intermediate for this process is a low‐coordinate RhIII complex that then undergoes CH activation. The anisole and thioanisole complexes have been isolated and their structures show OMe or SMe interactions with the metal centre alongside supporting agostic interactions, Rh(PiBu3)2(C6H4OMe)BrBArF4 (the solid‐state structure of the 5‐methyl substituted analogue is reported) and Rh(PiBu3)2(C6H4SMe)BrBArF4. The anisole‐derived complex proceeds to give Rh{PiBu2(CH2CHCH3CH2)}(PiBu3)(μ‐Br)2BArF42, whereas the thioanisole complex is unreactive. The isolation of Rh(PiBu3)2(C6H4OMe)BrBArF4 and its onward reactivity to give the products of CH activation and aryl elimination suggest that it is implicated on the pathway of a σ‐bond metathesis reaction, a hypothesis strengthened by DFT calculations. Calculations also suggest that CH bond cleavage through phosphine‐assisted deprotonation of a non‐agostic bond is also competitive, although the subsequent protonation of the aryl ligand is too high in energy to account for product formation. CH activation through oxidative addition is also ruled out on the basis of these calculations. These new complexes have been characterised by solution NMR/ESIMS techniques and in the solid‐state by X‐ray crystallography.
Agostic interactions: Oxidative addition of a variety of aryl bromides to the formally 12‐electron RhI complex Rh(PiBu3)2BArF4 forms a number of products depending on the substrate, some of which proceed to give species that have undergone CH activation and aryl elimination (see scheme), suggesting that they are isolated intermediates in a σ‐bond metathesis reaction.
Despite an improving therapeutic landscape, significant challenges remain in treating the majority of patients with advanced ovarian or renal cancer. We identified the cell-cell adhesion molecule ...cadherin-6 (
) as a lineage gene having significant differential expression in ovarian and kidney cancers. HKT288 is an optimized CDH6-targeting DM4-based antibody-drug conjugate (ADC) developed for the treatment of these diseases. Our study provides mechanistic evidence supporting the importance of linker choice for optimal antitumor activity and highlights CDH6 as an antigen for biotherapeutic development. To more robustly predict patient benefit of targeting CDH6, we incorporate a population-based patient-derived xenograft (PDX) clinical trial (PCT) to capture the heterogeneity of response across an unselected cohort of 30 models-a novel preclinical approach in ADC development. HKT288 induces durable tumor regressions of ovarian and renal cancer models
, including 40% of models on the PCT, and features a preclinical safety profile supportive of progression toward clinical evaluation.
We identify CDH6 as a target for biotherapeutics development and demonstrate how an integrated pharmacology strategy that incorporates mechanistic pharmacodynamics and toxicology studies provides a rich dataset for optimizing the therapeutic format. We highlight how a population-based PDX clinical trial and retrospective biomarker analysis can provide correlates of activity and response to guide initial patient selection for first-in-human trials of HKT288.
.
Perinatal and newborn complications are major risk factors for unfavorable fetal and neonatal outcomes. Gestational dating and growth monitoring can be instrumental in the identification and ...management of high-risk pregnancies and births. The INTERGROWTH-21.sup.st Project developed the first global standards for gestational dating and fetal and newborn growth monitoring, supplying a toolkit for clinicians. This study aimed to assess the feasibility and acceptability of the first known implementation study of these standards in a low resource setting. The study was performed in two 12-month phases from March 2016 to March 2018 at Jacaranda Health, a private maternity hospital in peri-urban Nairobi, Kenya. In-depth interviews, focus group discussions and a provider survey were utilized to evaluate providers' experiences during implementation. Client chart data, for pregnant women attending antenatal care and/or delivering at Jacaranda Health along with their newborns, were captured to assess uptake and effect of the standards on clinical decision-making. Facility-level support and provider buy-in proved to be critical factors driving the success of implementing the standards. However, additional support was needed to strengthen capacity to conduct and interpret ultrasounds and maintain motivation among providers. We observed a significant increase in the uptake of obstetric ultrasounds, particularly gestational dating, during the implementation of the standards. Although no significant changes were detected in the identification of high-risk pregnancies, referrals and deliveries by Cesarean section during implementation, we did observe a significant reduction in inductions for post-date. No significant barriers were reported regarding the use of the newborn standards. Over 80% of providers advocated for the standards to remain in place with some enhancements related mainly to training, advocacy and procurement. The findings are timely with increasing global adoption of the standards and the challenging and multi-faceted nature of translating new, evidence-based guidelines into routine clinical practice.
BackgroundIn order to make further gains in preventing newborn deaths, effective interventions are needed. Ultrasounds and newborn anthropometry are proven interventions to identify preterm birth ...complications, the leading cause of newborn deaths. The INTERGROWTH-21st global gestational dating and fetal and newborn growth standards prescribe optimal growth in any population. Jacaranda Health in Kenya was the first low-resource health facility to implement the standards and evaluate their feasibility and acceptability.ObjectiveTo capture patients’ perceptions of ultrasound and newborn care before and during implementation of the INTERGROWTH-21st standards.MethodsThe study was conducted over two years before and during the introduction of the INTERGROWTH-21st standards. Fifty pregnant and/or newly delivered women were selected for in-depth interviews and focus group discussions using convenience and purposive sampling. Interviews were conducted by research assistants using semi-structured guides once in the pre-implementation phase and twice in the implementation phase. Interviews were transcribed, double-coded by two independent researchers and thematically analyzed together. Demographic information was obtained from hospital records.ResultsPatients reported being generally satisfied with ultrasound care when providers communicated effectively. Women reported a priority for ultrasound was that it allowed them to feel reassured. However, a clear need for better pre-screening information emerged consistently from patients. Women noted that factors facilitating their choosing to have an ultrasound included ensuring the well-being of the fetus and learning the sex. Barriers included wait times and financial constraints. Patients were generally satisfied with care using the newborn standards.ConclusionsAs the INTERGROWTH-21st standards are implemented worldwide, understanding ways to facilitate implementation is critical. Increased and standardized communication about ultrasound should be provided before the procedure to increase satisfaction and uptake. Considering patient perspectives when integrating new standards or guidelines into routine clinical care will inform effective strategies in care provision, thus improving maternal and newborn health and survival.
In order to make further gains in preventing newborn deaths, effective interventions are needed. Ultrasounds and newborn anthropometry are proven interventions to identify preterm birth ...complications, the leading cause of newborn deaths. The INTERGROWTH-21
global gestational dating and fetal and newborn growth standards prescribe optimal growth in any population. Jacaranda Health in Kenya was the first low-resource health facility to implement the standards and evaluate their feasibility and acceptability.
To capture patients' perceptions of ultrasound and newborn care before and during implementation of the INTERGROWTH-21
standards.
The study was conducted over two years before and during the introduction of the INTERGROWTH-21
standards. Fifty pregnant and/or newly delivered women were selected for in-depth interviews and focus group discussions using convenience and purposive sampling. Interviews were conducted by research assistants using semi-structured guides once in the pre-implementation phase and twice in the implementation phase. Interviews were transcribed, double-coded by two independent researchers and thematically analyzed together. Demographic information was obtained from hospital records.
Patients reported being generally satisfied with ultrasound care when providers communicated effectively. Women reported a priority for ultrasound was that it allowed them to feel reassured. However, a clear need for better pre-screening information emerged consistently from patients. Women noted that factors facilitating their choosing to have an ultrasound included ensuring the well-being of the fetus and learning the sex. Barriers included wait times and financial constraints. Patients were generally satisfied with care using the newborn standards.
As the INTERGROWTH-21
standards are implemented worldwide, understanding ways to facilitate implementation is critical. Increased and standardized communication about ultrasound should be provided before the procedure to increase satisfaction and uptake. Considering patient perspectives when integrating new standards or guidelines into routine clinical care will inform effective strategies in care provision, thus improving maternal and newborn health and survival.
Background Despite objective responses to immune checkpoint blockade in patients with ovarian cancer (OC), therapies providing durable clinical benefit are lacking.1 An increased density of OC tumor ...infiltrating lymphocytes (TIL), specifically memory T cells with enhanced CD28 signaling, are associated with improved survival2 and immunotherapy response.3Adoptive cell therapy (ACT) utilizing ex vivo expanded TIL has demonstrated durable complete responses in several epithelial malignancies, but has shown limited clinical benefit in OC.4,5 This is due in part to extended manufacturing times and use of TIL products with a differentiated and exhausted phenotype.4,5 Casitas B lineage lymphoma-B (CBL-B) is an E3 ubiquitin ligase that limits T cell activation in the absence of CD28 co-stimulation following T cell receptor engagement. Ex vivo inhibition of CBL-B with the small molecule inhibitor NX-0255 increases the expansion of stem-like TIL with enhanced in vivo tumor cytotoxicity and persistence compared to conventional TIL expanded in IL-2 alone.6,7 Here we present our pre-clinical and early manufacturing experience of drug enhanced TIL therapy (DeTIL-0255) in OC. Methods Tumor tissue from N=21 consenting patients undergoing resection for OC across multiple US clinical sites was fragmented and cultured with IL-2 and NX-0255 under research (N=20) or clinical scale (N=1) manufacturing conditions. Following 22 days of culture, DeTIL-0255 cell products were characterized by multiparameter spectral flow cytometry. Results Even with as low as five input 2x2 mm3 tumor fragments, DeTIL-0255 was reproducibly expanded from primary and metastatic OC lesions with an average fold increase of 184±179 (mean ± SD) following the rapid expansion protocol and Day 22 total viable cell count of 8.0x108±5.3x108 cells (research scale) and 2.5x1010 cells (clinical scale). OC DeTIL-0255 was comprised of T (81.4±10.1%) and NKT (10.5±10.4%) cells with < 4% monocytes, NK, or B cells. OC DeTIL-0255 showed a balanced mixture of CD4 (53.4±28.9%) and CD8 (38.8±27.8%) T cells with heightened expression of the co-stimulatory marker CD226 (CD4: 87.4±12.6%; CD8: 86.0±16.4%), previously shown to predict immunotherapy response 8. In contrast to prior OC TIL products, OC DeTIL-0255 were primarily effector memory (CD4: 59.7±30.6%; CD8: 55.6±29.8%) and central memory cells (CD4: 21.0±23.7%; CD8: 12.4±16.9%) displaying limited T cell exhaustion (CD4: PD-1 26.2±22.8%, LAG-3 15.1±13.5%, CD57 4.4±4.3%; CD8: PD-1 17.7±19.6%, LAG-3 45.4±28.4%, CD57 2.9±2.5%). Conclusions OC DeTIL-0255 demonstrate a favorable phenotype amenable for ACT. A Phase 1 clinical study of DeTIL-0255 in women with recurrent/platinum resistant OC is ongoing (NCT05107739). References Zamarin D, Burger RA, Sill MW, Powell DJ Jr, Lankes HA, Feldman MD, Zivanovic O, Gunderson C, Ko E, Mathews C, Sharma S, Hagemann AR, Khleif S, Aghajanian C. Randomized phase II trial of nivolumab versus nivolumab and ipilimumab for recurrent or persistent ovarian cancer: An NRG oncology study. J Clin Oncol. 2020; 38:1814-1823. Anadon CM, Yu X, Hänggi K, Biswas S, Chaurio RA, Martin A, Payne KK, Mandal G, Innamarato P, Harro CM, Mine JA, Sprenger KB, Cortina C, Powers JJ, Costich TL, Perez BA, Gatenbee CD, Prabhakaran S, Marchion D, Heemskerk MHM, Curiel TJ, Anderson AR, Wenham RM, Rodriguez PC, Conejo-Garcia JR. Ovarian cancer immunogenicity is governed by a narrow subset of progenitor tissue-resident memory T cells. Cancer Cell. 2022;40:545-557. Duraiswamy J, Turrini R, Minasyan A, Barras D, Crespo I, Grimm AJ, Casado J, Genolet R, Benedetti F, Wicky A, Ioannidou K, Castro W, Neal C, Moriot A, Renaud-Tissot S, Anstett V, Fahr N, Tanyi JL, Eiva MA, Jacobson CA, Montone KT, Westergaard MCW, Svane IM, Kandalaft LE, Delorenzi M, Sorger PK, Färkkilä A, Michielin O, Zoete V, Carmona SJ, Foukas PG, Powell DJ Jr, Rusakiewicz S, Doucey MA, Dangaj Laniti D, Coukos G. Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation. Cancer Cell. 2021;39: 1623-1642. Kverneland AH, Pedersen M, Westergaard MCW, Nielsen M, Borch TH, Olsen LR, Aasbjerg G, Santegoets SJ, van der Burg SH, Milne K, Nelson BH, Met Ö, Donia M, Svane IM. Adoptive cell therapy in combination with checkpoint inhibitors in ovarian cancer. Oncotarget. 2020; 11:2092-2105. Pedersen M, Westergaard MCW, Milne K, Nielsen M, Borch TH, Poulsen LG, Hendel HW, Kennedy M, Briggs G, Ledoux S, Nøttrup TJ, Andersen P, Hasselager T, Met Ö, Nelson BH, Donia M, Svane IM. Adoptive cell therapy with tumor-infiltrating lymphocytes in patients with metastatic ovarian cancer: a pilot study. Oncoimmunology. 2018; 7:e1502905. Whelan S, Gosling J, Mani M, Cohen F, Tenn-McClellan A, Powers J, Hansen G, Lotze M, Sands A. NX-0255, a small molecule CBL-B inhibitor, expands and enhances tumor infiltrating lymphocytes (TIL) for use in adoptive cancer immunotherapy. J Immunother Cancer. 2021; 9: 98. Gallotta M, Romo JG, Borodovsky A, Tenn-McClellan A, Stokes J, Gosling J, Hansen GM, Sands A, Rountree R, Guiducci C. Ex-vivo inhibition of CBL-B with a novel small molecule inhibitor, NX-0255, enhances persistence and anti-tumor activity of adoptively transferred CD8+ T cells in mouse tumor models. Cancer Res. 2022; 82:573. Banta KL, Xu X, Chitre AS, Au-Yeung A, Takahashi C, O’Gorman WE, Wu TD, Mittman S, Cubas R, Comps-Agrar L, Fulzele A, Bennett EJ, Grogan JL, Hui E, Chiang EY, Mellman I. Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8+ T cell responses. Immunity. 2022;55:512-526. Ethics Approval All studies were performed in full accordance with the guidelines for good clinical practice and the Declaration of Helsinki and approved by the cited institutional protocol review committee and IRB. Consent Written informed consent was obtained from the patient for use of patient specimens for research and subsequent publication.
PDF
