Implications of High Tumor Burden on Chimeric Antigen Receptor T-Cell Immunotherapy: A Review.

Importance: Chimeric antigen receptor (CAR) T-cell therapy has redefined the therapeutic landscape of several hematologic malignant tumors. Despite its clinical efficacy, many patients with cancer experience nonresponse to CAR T-cell treatment, disease relapse within months, or severe adverse events. Furthermore, CAR T-cell therapy has demonstrated minimal to no clinical efficacy in the treatment of solid tumors in clinical trials. Observations: A complex interplay between high tumor burden and the systemic and local tumor microenvironment on clinical outcomes of CAR T-cell therapy is emerging from preclinical and clinical data. The hallmarks of advanced cancers-namely, inflammation and immune dysregulation-sustain cancer progression. They negatively affect the production, expansion, antitumor activity, and persistence of CAR T-cell products. Understanding of CAR T-cell therapy, mechanisms underlying its failure, and adverse events under conditions of high tumor burden is critical for realizing the full potential of this novel treatment approach. Conclusions and Relevance: This review focuses on linking the efficacy and safety of CAR T-cell therapy with tumor burden. Its limitations relative to high tumor burden, systemic inflammation, and immune dysregulation are discussed. Emerging clinical approaches to overcome these obstacles and more effectively incorporate this therapeutic strategy into the treatment paradigm of patients with solid malignant tumors are also described.

B7-H3-targeted CAR T cell activity is enhanced by radiotherapy in solid cancers.

Adoptive cell therapy utilizing T cells genetically modified to express a chimeric antigen receptor (CAR) has demonstrated promising clinical results in hematological malignancies. However, solid cancers have not seen a similar success due to multiple obstacles. Investigating these escape mechanisms and designing strategies to counteract such limitations is crucial and timely. Growing evidence in the literature supports the hypothesis that radiotherapy has the potential to enhance the susceptibility of solid tumors to CAR T cell therapy, by overcoming mechanisms of resistance. Radiation treatment can increase the susceptibility of different types of solid cancers (TNBC, HNSCC, PDAC) to B7-H3 CAR T cell-mediated eradication. Multiple mechanisms, including reduced cancer cell proliferation, upregulation of the targeted antigen, modulation of apoptotic molecules may contribute to this signal. The information in the literature and the results we describesupport the ability of radiotherapy to improve the efficacy of CAR T cell therapy in solid tumors.

A horizon scan of global biological conservation issues for 2022.

We present the results of our 13th annual horizon scan of issues likely to impact on biodiversity conservation. Issues are either novel within the biological conservation sector or could cause a substantial step-change in impact, either globally or regionally. Our global panel of 26 scientists and practitioners identified 15 issues that we believe to represent the highest priorities for tracking and action. Many of the issues we identified, including the impact of satellite megaconstellations and the use of long-distance wireless energy transfer, have both elements of threats and emerging opportunities. A recent state-sponsored application to commence deep-sea mining represents a significant step-change in impact. We hope that this horizon scan will increase research and policy attention on the highlighted issues.

Raspberry Pi nest cameras: An affordable tool for remote behavioral and conservation monitoring of bird nests.

Bespoke (custom-built) Raspberry Pi cameras are increasingly popular research tools in the fields of behavioral ecology and conservation, because of their comparative flexibility in programmable settings, ability to be paired with other sensors, and because they are typically cheaper than commercially built models.Here, we describe a novel, Raspberry Pi-based camera system that is fully portable and yet weatherproof-especially to humidity and salt spray. The camera was paired with a passive infrared sensor, to create a movement-triggered camera capable of recording videos over a 24-hr period. We describe an example deployment involving "retro-fitting" these cameras into artificial nest boxes on Praia Islet, Azores archipelago, Portugal, to monitor the behaviors and interspecific interactions of two sympatric species of storm-petrel (Monteiro's storm-petrel Hydrobates monteiroi and Madeiran storm-petrel Hydrobates castro) during their respective breeding seasons.Of the 138 deployments, 70% of all deployments were deemed to be "Successful" (Successful was defined as continuous footage being recorded for more than one hour without an interruption), which equated to 87% of the individual 30-s videos. The bespoke cameras proved to be easily portable between 54 different nests and reasonably weatherproof (~14% of deployments classed as "Partial" or "Failure" deployments were specifically due to the weather/humidity), and we make further trouble-shooting suggestions to mitigate additional weather-related failures.Here, we have shown that this system is fully portable and capable of coping with salt spray and humidity, and consequently, the camera-build methods and scripts could be applied easily to many different species that also utilize cavities, burrows, and artificial nests, and can potentially be adapted for other wildlife monitoring situations to provide novel insights into species-specific daily cycles of behaviors and interspecies interactions.

HLA class I antigen processing machinery defects in antitumor immunity and immunotherapy.

Human leukocyte antigen (HLA) class I antigen-processing machinery (APM) plays a crucial role in the synthesis and expression of HLA class I tumor antigen-derived peptide complexes; the latter mediate the recognition and elimination of malignant cells by cognate T cells. Defects in HLA class I APM component expression and/or function are frequently found in cancer cells, providing them with an immune escape mechanism that has relevance in the clinical course of the disease and in the response to T-cell-based immunotherapy. The majority of HLA class I APM defects (>75%) are caused by epigenetic mechanisms or dysregulated signaling and therefore can be corrected by strategies that counteract the underlying mechanisms. Their application in oncology is likely to improve responses to T-cell-based immunotherapies, including checkpoint inhibition.

CAR T Cell-Based Immunotherapy for the Treatment of Glioblastoma.

Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor in adults. Current treatment options typically consist of surgery followed by chemotherapy or more frequently radiotherapy, however, median patient survival remains at just over 1 year. Therefore, the need for novel curative therapies for GBM is vital. Characterization of GBM cells has contributed to identify several molecules as targets for immunotherapy-based treatments such as EGFR/EGFRvIII, IL13Rα2, B7-H3, and CSPG4. Cytotoxic T lymphocytes collected from a patient can be genetically modified to express a chimeric antigen receptor (CAR) specific for an identified tumor antigen (TA). These CAR T cells can then be re-administered to the patient to identify and eliminate cancer cells. The impressive clinical responses to TA-specific CAR T cell-based therapies in patients with hematological malignancies have generated a lot of interest in the application of this strategy with solid tumors including GBM. Several clinical trials are evaluating TA-specific CAR T cells to treat GBM. Unfortunately, the efficacy of CAR T cells against solid tumors has been limited due to several factors. These include the immunosuppressive tumor microenvironment, inadequate trafficking and infiltration of CAR T cells and their lack of persistence and activity. In particular, GBM has specific limitations to overcome including acquired resistance to therapy, limited diffusion across the blood brain barrier and risks of central nervous system toxicity. Here we review current CAR T cell-based approaches for the treatment of GBM and summarize the mechanisms being explored in pre-clinical, as well as clinical studies to improve their anti-tumor activity.

A 2021 Horizon Scan of Emerging Global Biological Conservation Issues.

We present the results from our 12th annual horizon scan of issues likely to impact biological conservation in the future. From a list of 97 topics, our global panel of 25 scientists and practitioners identified the top 15 issues that we believe society may urgently need to address. These issues are either novel in the biological conservation sector or represent a substantial positive or negative step-change in impact at global or regional level. Six issues, such as coral reef deoxygenation and changes in polar coastal productivity, affect marine or coastal ecosystems and seven relate to human and ecosystem-level responses to climate change. Identification of potential forthcoming issues for biological conservation may enable increased preparedness by researchers, practitioners, and decision-makers.

B7-H3 targeted antibody-based immunotherapy of malignant diseases.

Introduction: Recent advances in immuno-oncology and bioengineering have rekindled the interest in monoclonal antibody (mAb)-based immunotherapies for malignancies. Crucial for their success is the identification of tumor antigens (TAs) that can serve as targets. B7-H3, a member of the B7 ligand family, represents such a TA. Although its exact functions and receptor(s) remain unclear, B7-H3 has predominantly a pro-tumorigenic effect mainly by suppressing the anti-tumor functions of T-cells.Areas covered: Initially we present a historical perspective on TA-specific antibodies for diagnosis and treatment of malignancies. Following a description of the TA requirements to be an attractive antibody-based immunotherapy target, we show that B7-H3 fulfills these criteria. We discuss its structure and functions. In a review and pooled analysis, we describe the limited B7-H3 expression in normal tissues and estimate B7-H3 expression frequency in tumors, tumor-associated vasculature and cancer initiating cells (CICs). Lastly, we discuss the association of B7-H3 expression in tumors with poor prognosis.Expert opinion: B7-H3 is an attractive target for mAb-based cancer immunotherapy. B7-H3-targeting strategies are expected to be highly effective and - importantly - safe. To fully exploit the diagnostic and therapeutic potential of B7-H3, its expression in pre-malignant lesions, serum, metastases, and CICs requires further investigation.

Improving the Clinical Significance of Preclinical Immunotherapy Studies through Incorporating Tumor Microenvironment-like Conditions.

Frequently, the results generated when testing novel antitumor immunotherapies in vitro do not correlate with data collected in in vivo models and/or in clinical settings. It is our hypothesis that this discrepancy is caused by the use of in vitro conditions, such as normoxia, a two-dimensional surface, optimal growth media, and lack of cell complexity and heterogeneity. These conditions do not accurately reflect the tumor microenvironment (TME) that the tested immunotherapeutic strategies experience in vivo While there are many variables which can have an impact upon the antitumor efficacy of an immunotherapy, the immunosuppressive TME is one in which several of the conditions commonly found in vivo can be mimicked in vitro These conditions, which include hypoxia, low pH, low glucose, presence of adenosine, cell complexity and heterogeneity, as well as the three-dimensional structure of TME, can all affect immune cell-tumor cell interactions. Here, we discuss the impact that these conditions, either individually or in combination, can have on these interactions. Furthermore, we propose that performing in vitro assays under TME-like conditions improves the clinical relevance of the yielded results. This, in turn, contributes to accelerate the speed, reduce the cost, and increase efficiency of screening novel immunotherapies and eventually the development of prospective clinical trials.

A Horizon Scan of Emerging Global Biological Conservation Issues for 2020.

In this horizon scan, we highlight 15 emerging issues of potential relevance to global conservation in 2020. Seven relate to potentially extensive changes in vegetation or ecological systems. These changes are either relatively new, for example, conversion of kelp forests to simpler macroalgal systems, or may occur in the future, for example, as a result of the derivation of nanocelluose from wood or the rapid expansion of small hydropower schemes. Other topics highlight potential changes in national legislation that may have global effect on international agreements. Our panel of 23 scientists and practitioners selected these issues using a modified version of the Delphi technique from a long-list of 89 potential topics.

Mixed chimerism established by hematopoietic stem cell transplantation is maintained by host and donor T regulatory cells.

Transplantation is an effective treatment of many clinical disorders, but the mechanisms that regulate immunological tolerance are uncertain and remain central to improving patient outcome. Hemopoietic stem cell transplantation (SCT) often establishes "mixed chimerism" in which immune cells from both the donor and patient coexist in vivo in a setting of immunological tolerance. We studied immune function in 69 patients within 2 months following SCT; 37 were fully donor and 32 displayed mixed chimerism. The proportion of T regulatory (Treg) cells was increased during mixed chimerism and comprised equal numbers of donor and host-derived regulatory cells. This was associated with a tolerogenic PD-L1+ profile on dendritic cells. Importantly, effector T cells from patients with mixed chimerism exhibited reduced cytotoxicity against host target cells in vitro, but this was restored following depletion of CD4+ Treg cells. These data show that Treg cells play a major role in sustaining immunological tolerance during mixed chimerism. These insights should help to guide novel interventions to improve clinical transplantation.

NK cells produce high levels of IL-10 early after allogeneic stem cell transplantation and suppress development of acute GVHD.

Natural killer (NK) cells rapidly reconstitute following allogeneic stem cell transplantation (allo-SCT), at the time when alloreactive T cell immunity is being established. We investigated very early NK cell reconstitution in 82 patients following T cell-depleted allo-SCT. NK cell number rapidly increased, exceeding T cell reconstitution such that the NK:T cell ratio was over 40 by day 14. NK cells at day 14 (NK-14) were donor-derived, intensely proliferating and expressed chemokine receptors targeted to lymphoid and peripheral tissue. Spontaneous production of the immunoregulatory cytokine IL-10 was observed in over 70% of cells and transcription of cytokines and growth factors was augmented. NK-14 cell number was inversely correlated with the incidence of grade II-IV acute graft versus host disease (GVHD). These findings reveal that robust reconstitution of immunoregulatory NK cells by day 14 after allo-SCT is an important determinant of the clinical outcome, suggesting that NK cells may suppress the development of the T cell-mediated alloreactive immune response through production of IL-10.

The number of CD56dim NK cells in the graft has a major impact on risk of disease relapse following allo-HSCT.

The graft-versus-leukemia (GVL) effect of allogeneic hemopoietic stem cell transplantation (allo-HSCT) is mediated by the donor immune system and acts to decrease the rate of disease relapse. Although studies of posttransplant immune reconstitution have identified correlates of clinical outcome, the number and profile of mature immune cells infused with the stem cell graft is also likely to be an important determinant and has been relatively poorly studied. We characterized immune cells within the stem cell graft of 107 patients who underwent T-cell-depleted allo-HSCT and related this to clinical outcome. The number of natural killer (NK) cells and T cells that were infused varied markedly between patients, but T-cell dose was not an important factor in subsequent outcome. In contrast, the number of NK cells was a powerful determinant of the risk of disease relapse. Patients who received an NK cell dose below the median level of 6.3 × 106 cells per kg had a relapse rate of 40% at 2 years posttransplant compared with only 6% for those whose stem cell graft contained a dose above this value. Analysis of NK subsets showed that this effect was mediated primarily by the CD56dim population of mature effector cells and that high-level expression of the activatory protein DNAM on donor NK cells was also strongly protective. These observations offer important insights into the mechanism of GVL and suggest that optimization studies of the number of NK cells within the stem cell graft should be considered as a means to reduce disease relapse.