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Despite some impressive clinical results with immune checkpoint inhibitors, the majority of patients with cancer do not respond to these agents, in part due to immunosuppressive mechanisms in the tumor microenvironment. High levels of adenosine in tumors can suppress immune cell function, and strategies to target the pathway involved in its production have emerged. CD73 is a key enzyme involved in adenosine production. This led us to identify a novel humanized antagonistic CD73 antibody, mAb19, with distinct binding properties. mAb19 potently inhibits the enzymatic activity of CD73 in vitro, resulting in an inhibition of adenosine formation and enhanced T-cell activation. We then investigated the therapeutic potential of combining CD73 antagonism with other immune modulatory and chemotherapeutic agents. Combination of mAb19 with a PD-1 inhibitor increased T-cell activation in vitro. Interestingly, this effect could be further enhanced with an agonist of the adenosine receptor ADORA3. Adenosine levels were found to be elevated upon doxorubicin treatment in vivo, which could be blocked by CD73 inhibition. Combining CD73 antagonism with doxorubicin resulted in superior responses in vivo. Furthermore, a retrospective analysis of rectal cancer patient samples demonstrated an upregulation of the adenosine pathway upon chemoradiation, providing further rationale for combining CD73 inhibition with chemotherapeutic agents. This study demonstrates the ability of a novel CD73 antibody to enhance T-cell function through the potent suppression of adenosine levels. In addition, the data highlight combination opportunities with standard of care therapies as well as with an ADORA3 receptor agonist to treat patients with solid tumors.

Aligning development and climate goals means Africa’s energy systems will be based on clean energy technologies in the long term, but pathways to get there are uncertain and variable across countries. Although current debates about natural gas and renewables in Africa are heated, they largely ignore the substantial context specificity of the starting points, development objectives and uncertainties of each African country’s energy system trajectory. Here we—an interdisciplinary and majority African group of authors—highlight that each country faces a distinct solution space and set of uncertainties for using renewables or fossil fuels to meet its development objectives. For example, Ethiopia is headed for an accelerated green-growth pathway, but Mozambique is at a crossroads of natural gas expansion with implicit large-scale technological, economic, financial and social risks and uncertainties. We provide geopolitical, policy, finance and research recommendations to create firm country-specific evidence to identify adequate energy system pathways for development and to enable their implementation.

Androgen deprivation therapy and second-generation androgen receptor signaling inhibitors such as enzalutamide are standard treatments for advanced/metastatic prostate cancer. Unfortunately, most men develop resistance and relapse; signaling via insulin-like growth factor (IGF) has been implicated in castration-resistant prostate cancer. We evaluated the antitumor activity of xentuzumab (IGF ligand–neutralizing antibody), alone and in combination with enzalutamide, in prostate cancer cell lines (VCaP, DuCaP, MDA PCa 2b, LNCaP, and PC-3) using established in vitro assays, and in vivo, using LuCaP 96CR, a prostate cancer patient-derived xenograft (PDX) model. Xentuzumab + enzalutamide reduced the viability of phosphatase and tensin homolog (PTEN)-expressing VCaP, DuCaP, and MDA PCa 2b cells more than either single agent, and increased antiproliferative activity and apoptosis induction in VCaP. Xentuzumab or xentuzumab + enzalutamide inhibited IGF type 1 receptor and AKT serine/threonine kinase (AKT) phosphorylation in VCaP, DuCaP, and MDA PCa 2b cells; xentuzumab had no effect on AKT phosphorylation and proliferation in PTEN-null LNCaP or PC-3 cells. Knockdown of PTEN led to loss of antiproliferative activity of xentuzumab and reduced activity of xentuzumab + enzalutamide in VCaP cells. Xentuzumab + enzalutamide inhibited the growth of castration-resistant LuCaP 96CR PDX with acquired resistance to enzalutamide, and improved survival in vivo. The data suggest that xentuzumab + enzalutamide combination therapy may overcome castration resistance and could be effective in patients who are resistant to enzalutamide alone. PTEN status as a biomarker of responsiveness to combination therapy needs further investigation.

T-cell engagers redirect T cells to a tumor specific target leading to lysis of tumor cells with demonstrated therapeutic benefit in hematological and solid tumors. Most T-cell engagers in development focus on surface exposed tumor antigens as targets. However, HLA/peptide complex directed (TCR mimic) T cell engagers enable targeting of tumour associated intracellular proteins and therefore broaden the cancer antigen space for T cell engagers. Potency and specificity are key attributes for the design of TCR mimic T cell engagers. Here, we employed a three pronged strategy to enhance pharmacological effectiveness of pHLA targeting TcEs: i) innovative bispecific formats employing avidity effect ii) TCRm affinity maturation by pHLA-Fv model based library design and phage display iii) pHLA-Fv crystal structure based affinity maturation in silico. The different strategies and combinations thereof enabled and improved lysis of tumor cells by T cell engager and informed on the structure-function relation of TCR mimic T cell engager. Citation Format: Nicolas Sabarth, Paul Adam, Sandeep Kumar, Yanyun Liu, Renate Konopitzky, Jark Boettcher, Tadas Panavas. Three pronged strategy to enhance pharmacological effectiveness of pHLA targeting TcEs [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A62.

Saltmarshes provide many valuable ecosystem services including storage of a large amount of ‘blue carbon’ within their soils. To date, up to 50% of the world’s saltmarshes have been lost or severely degraded primarily due to a variety of anthropogenic pressures. Previous efforts have aimed to restore saltmarshes and their ecosystem functions, but the success of these efforts is rarely evaluated. To fill this gap, we used a range of metrics, including organic carbon stocks, root production, soil respiration and microbial communities to compare natural and a 20-year restoration effort in saltmarsh habitats within the Sydney Olympic Park in New South Wales, Australia. We addressed four main questions: (1) Have above- and belowground plant biomass recovered to natural levels? (2) Have organic carbon stocks of soils recovered? (3) Are microbial communities similar between natural and regenerated saltmarshes? and (4) Are microbial communities at both habitats associated to ecosystem characteristics? For both soil organic carbon stocks and belowground biomass, we found no significant differences between natural and regenerated habitats (F(1,14) = 0.47, p = 0.5; F(1,42) = 0.08, p = 0.76). Aboveground biomass was higher in the natural habitat compared to the regenerated habitat (F(1,20) = 27.3, p

Although some green housing elements have become more commonplace in residential renovations in Canada, the undertaking of complete green retrofits is relatively uncommon. This paper explores the barriers to green retrofits, such as affordability and bureaucracy, in the urban context of the City of Toronto. The research was informed by one main case study, one supplementary case study, and six interviews with sustainable housing experts. The research has yielded nine recommendations that are directed towards three levels of government and related public and private housing organizations. These recommendations have been made in the hopes of making sustainable housing more ubiquitous in Toronto.

T-cell Engaging bispecific antibodies (TcEs) that can re-direct cytotoxic T-cells to kill cancer cells have been validated in clinical studies. To date, the clinical success with these agents has mainly been seen in hematologic tumor indications. However, an increasing number of TcEs are currently being developed to exploit the potent mode-of-action to treat solid tumor indications, which is more challenging in terms of tumor-cell accessibility and the complexity of the tumor microenvironment (TME). Of particular interest is the potential of TcEs as an immunotherapeutic approach for the treatment of non-immunogenic (often referred to as cold) tumors that do not respond to checkpoint inhibitors such as programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) antibodies. This has led to considerable discovery efforts for, firstly, the identification of tumor selective targeting approaches that can safely re-direct cytotoxic T-cells to cancer cells, and, secondly, bispecific antibodies and their derivatives with drug-like properties that promote a potent cytolytic synapse between T-cells and tumor cells, and in the most advanced TcEs, have IgG-like pharmacokinetics for dosing convenience. Based on encouraging pre-clinical data, a growing number of TcEs against a broad range of targets, and using an array of different molecular structures have entered clinical studies for solid tumor indications, and the first clinical data is beginning to emerge. This review outlines the different approaches that have been taken to date in addressing the challenges of exploiting the TcE mode-of-action for a broad range of solid indications, as well as opportunities for future discovery potential.