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While impressive clinical responses have been observed using chimeric antigen receptor (CAR) T cells targeting CD19+ hematologic malignancies, limited clinical benefit has been observed using CAR T cells for a variety of solid tumors. Results of clinical studies have highlighted several obstacles which CAR T cells face in the context of solid tumors, including insufficient homing to tumor sites, lack of expansion and persistence, encountering a highly immunosuppressive tumor microenvironment, and heterogeneous antigen expression. In this review, we review clinical outcomes and discuss strategies to improve the antitumor activity of CAR T cells for solid tumors.

BackgroundSuccessful targeting of solid tumors with TCR-engineered T cells (TCR-T) will require eliciting of antigen-specific, multi-dimensional, sustained anti-tumor immune response by infused T cells while overcoming the suppressive tumor microenvironment. First-generation TCR-T approaches have demonstrated clinical efficacy in some solid cancers. However, effective treatment across several solid tumor indications may require engineered T cells with enhanced anti-tumor activity. Here, we show pre-clinical data from one of the engineering approaches currently being developed for next-generation ACTengine® TCR-T product candidates. We evaluated the impact of co-expression of different CD8 co-receptors on functionality of CD4+ and CD8+ T cells genetically modified with an HLA class I-restricted TCR and determined the depth and durability of anti-tumor response in vitro.MethodsHere, we used a PRAME-specific TCR currently being tested in the ACTengine® IMA203 clinical trial. T cells expressing either the TCR alone or co-expressing the TCR and CD8α homodimer (TCR.CD8α) or CD8αβ heterodimer (TCR.CD8αβ) were characterized for transgene expression, antigen-recognition, and functional efficacy in vitro. Comprehensive evaluation of CD4+ T cells expressing TCR.CD8α or TCR.CD8αβ was performed focusing on cytotoxic potential and the breadth of cytokine response against target-positive tumor cell lines.ResultsIntroduction of CD8α or CD8αβ enabled detection of transgenic TCR on the surface of CD4+ T cells via HLA multimer-guided flow cytometry otherwise lacking in the TCR only transduced T cells. Co-expression of either form of CD8 co-receptor endowed CD4+ T cells with the ability to recognize and kill target positive tumor cells; however, genetic modification with TCR.CD8αβ led to more pronounced CD4+ T cell activation as compared to TCR.CD8α. Most distinct differences were observed in the breadth and magnitude of cytokine responses, less in cytotoxic activity against tumor cells. T cells expressing TCR.CD8αβ showed superior induction of Th1 cytokines e.g. IFNγ, TNFα, IL-2, GM-CSF in vitro upon antigen stimulation as compared to TCR.CD8α-T cells. Additionally, TCR.CD8αβ T cells demonstrated more efficient engagement with antigen-presenting cells and consequently, modulation of cytokine response than TCR.CD8α-T cells.ConclusionsOur findings illustrate that engaging CD4+ T cells via CD8 co-expression potentiates anti-tumor activity of HLA class I restricted TCR-T cells in vitro. The pleiotropic effects mediated by activated CD4+ T cells including acquired cytotoxicity may potentially improve outcomes in solid tumor patients when applied clinically. In addition, the differential functional profile of TCR-T cells co-expressing either CD8α or CD8αβ suggests that optimizing the type of co-receptor is relevant to maximize anti-tumor response.

While impressive clinical responses have been observed using chimeric antigen receptor (CAR) T cells targeting CD19+ hematologic malignancies, limited clinical benefit has been observed using CAR T cells for a variety of solid tumors. Results of clinical studies have highlighted several obstacles which CAR T cells face in the context of solid tumors, including insufficient homing to tumor sites, lack of expansion and persistence, encountering a highly immunosuppressive tumor microenvironment, and heterogeneous antigen expression. In this review, we review clinical outcomes and discuss strategies to improve the antitumor activity of CAR T cells for solid tumors.

Cancer-associated fibroblasts (CAFs), the principle component of the tumor-associated stroma, form a highly protumorigenic and immunosuppressive microenvironment that mediates therapeutic resistance. Co-targeting CAFs in addition to cancer cells may therefore augment the antitumor response. Fibroblast activation protein-α (FAP), a type 2 dipeptidyl peptidase, is expressed on CAFs in a majority of solid tumors making it an attractive immunotherapeutic target. To target FAP-positive CAFs in the tumor-associated stroma, we genetically modified T cells to express a FAP-specific chimeric antigen receptor (CAR). The resulting FAP-specific T cells recognized and killed FAP-positive target cells as determined by proinflammatory cytokine release and target cell lysis. In an established A549 lung cancer model, adoptive transfer of FAP-specific T cells significantly reduced FAP-positive stromal cells, with a concomitant decrease in tumor growth. Combining these FAP-specific T cells with T cells that targeted the EphA2 antigen on the A549 cancer cells themselves significantly enhanced overall antitumor activity and conferred a survival advantage compared to either alone. Our study underscores the value of co-targeting both CAFs and cancer cells to increase the benefits of T-cell immunotherapy for solid tumors.

Current therapy for sarcomas, though effective in treating local disease, is often ineffective for patients with recurrent or metastatic disease. To improve outcomes, novel approaches are needed and cell therapy has the potential to meet this need since it does not rely on the cytotoxic mechanisms of conventional therapies. The recent successes of T-cell therapies for hematological malignancies have led to renewed interest in exploring cell therapies for solid tumors such as sarcomas. In this review, we will discuss current cell therapies for sarcoma with special emphasis on genetic approaches to improve the effector function of adoptively transferred cells.

BackgroundAdoptive immunotherapy with genetically modified T cells holds promise in improving outcomes for cancer patients. While a broad array of genetic modification strategies are being explored, few allow for the specific manipulation of adoptively transferred T cells in vivo. One successful example includes the introduction of an inducible ‘suicide gene’ to enable selective T-cell killing in the event of toxicities. Given the limited antitumor activity of adoptively transferred T cells for solid tumors in early clinical studies, we reasoned that introducing an inducible co-stimulatory molecule into T cells would allow for the selective activation of adoptively transferred T cells in vivo resulting in enhanced antitumor activity. Due to the role of MyD88 and CD40 signaling pathways to fine tune T-cell activation, and the recent success of using inducible (i) MyD88 and CD40 molecules to activate antigen-presenting cells, the goal of this project was to explore if T cells can be activated with iMyD88 and/or iCD40 molecules.Methods/resultsWe constructed a panel of retroviral vectors encoding mOrange as a marker gene and an inducible co-stimulatory molecule (iCO-STIM) consisting of a myristoylation tag, two FKBP dimerizer domains, and i) MyD88, ii) CD40, or iii) MyD88 + CD40. T cells expressing iMyD88, iCD40, or iMyD88.CD40 were generated by retroviral transduction, and transduction was confirmed by FACS analysis and Western blot. T cells expressing iCO-STIMs were activated with the CD3 monoclonal antibody OKT3 in the presence or absence of the chemical inducer of dimerization (CID), AP20187. iMyD88.CD40 T cells secreted the highest amount of IL2 in the presence of OKT3 + CID in comparison to iMyD88 or iCD40 T cells. To evaluate if activating iMyD88.CD40 in CAR T cells also enhances cytokine production, we generated T cells that expressed HER2-CARs and iMyD88.CD40 (HER2-CAR/iCO-STIM T cells). CID enhanced IL2 production of HER2-CAR/iCOSTIM T cells that were either stimulated with recombinant HER2 protein or HER2+ cell lines. Enhanced IL2 production was observed with 1st, 2nd, and 3rd generation HER2-CARs.ConclusionWe have generated CAR T cells with an inducible co-stimulatory molecule based on MyD88 and CD40. Preliminary functional analysis of CAR/iCO-STIM T cells is encouraging, warranting further active exploration of this approach to improve current T-cell therapy approaches for cancer.

The contribution of urban greenspaces to support biodiversity and provide benefits for people is increasingly recognized. However, ongoing management practices favor vegetation oversimplification, often limiting greenspaces to lawns and tree canopy rather than multi-layered vegetation that includes under- and midstorey, and the use of nonnative species. These practices hinder the potential of greenspaces to sustain indigenous biodiversity, particularly for taxa like insects that rely on plants for food and habitat. Yet, little is known about which plant species may maximize positive outcomes for taxonomically and functionally diverse insect communities in greenspaces. Additionally, while cities are expected to experience high rates of introductions, quantitative assessments of the relative occupancy of indigenous vs. introduced insect species in greenspace are rare, hindering understanding of how management may promote indigenous biodiversity while limiting the establishment of introduced insects. Using a hierarchically replicated study design across 15 public parks, we recorded occurrence data from 552 insect species on 133 plant species, differing in planting design element (lawn, midstorey, and tree canopy), midstorey growth form (forbs, lilioids, graminoids, and shrubs) and origin (nonnative, native, and indigenous), to assess (1) the relative contributions of indigenous and introduced insect species and (2) which plant species sustained the highest number of indigenous insects. We found that the insect community was overwhelmingly composed of indigenous rather than introduced species. Our findings further highlight the core role of multi-layered vegetation in sustaining high insect biodiversity in urban areas, with indigenous midstorey and canopy representing key elements to maintain rich and functionally diverse indigenous insect communities. Intriguingly, graminoids supported the highest indigenous insect richness across all studied growth forms by plant origin groups. Our work highlights the opportunity presented by indigenous understory and midstorey plants, particularly indigenous graminoids, in our study area to promote indigenous insect biodiversity in urban greenspaces. Our study provides a blueprint and stimulus for architects, engineers, developers, designers, and planners to incorporate into their practice plant species palettes that foster a larger presence of indigenous over regionally native or nonnative plant species, while incorporating a broader mixture of midstorey growth forms.

INTRODUCTION The rising prevalence of Alzheimer's disease and related dementias (ADRD) in California's aging population necessitates a well‐trained dementia care workforce. METHODS This study evaluated a multi‐week, competency‐based, online training for caregivers in California's Medicaid‐funded In‐Home Supportive Services (IHSS) program. Using a quasi‐experimental design, we assessed caregivers’ dementia knowledge, self‐efficacy, distress, depression, and care recipients’ healthcare use before and after the intervention. RESULTS The training significantly improved caregivers’ dementia knowledge and self‐efficacy but did not reduce caregivers’ distress and depression, nor decrease care recipients’ emergency room visits and hospitalizations. DISCUSSION The findings highlight the value of specialized dementia training in enhancing caregiver knowledge and skills, which could be implemented outside California. Clinical implications include bolstering caregiver well‐being to improve the quality of their support of care recipients with cognitive impairment. Policy implications include expanding access to training programs and bolstering workforce development initiatives that improve caregiver and care recipient outcomes. Highlights Multiweek online training improved home care workers’ dementia caregiving skills. Home care workers’ dementia knowledge improved significantly post‐training. Self‐efficacy to manage care recipients’ dementia symptoms improved significantly.

The contribution of urban greenspaces to support biodiversity and provide benefits for people is increasingly recognised. However, ongoing management practices still favour (1) vegetation oversimplification, often limiting greenspaces to lawns and tree canopy rather than multi-layered vegetation that includes under and midstorey; and (2) the use of nonnative plant species. These practices likely hinder the potential of greenspaces to sustain indigenous biodiversity, particularly for taxa like insects, that rely on plants for food and habitat. Yet, little is known about which plant species may maximise positive outcomes for taxonomically and functionally diverse insect communities in urban greenspaces. Additionally, while urban environments are expected to experience high rates of introductions, quantitative assessments of the relative occupancy of indigenous vs. introduced insect species in greenspace are rare, hindering understanding of how greenspace management may promote indigenous biodiversity while limiting the establishment of introduced insects. Using a hierarchically replicated study design across 15 public parks, we recorded occurrence data from 552 insect species on 133 plant species, differing in planting design element (lawn, midstorey and tree canopy), midstorey growth form (forbs, lilioids, graminoids and shrubs) and origin (nonnative, native and indigenous), to assess: (1) the relative contributions of indigenous and introduced insect species and (2) which plant species sustained the highest number of indigenous insects. Our data indicates that the insect community was predominately composed of indigenous rather than introduced species. Our findings further highlight the core role of multi-layered vegetation in sustaining high insect biodiversity in urban areas, with indigenous midstorey and canopy representing key elements to maintain rich and functionally diverse indigenous insect communities. Intriguingly, graminoids supported the highest indigenous insect richness across all studied growth forms by plant origin groups. Taken together, our study emphasise the opportunity posed by indigenous understory and midstorey plants, particularly indigenous graminoids in our study area, to promote indigenous insect biodiversity in urban greenspaces. Our work provides a blueprint and stimulus for built-environment professionals to incorporate into their practice plant species palettes that foster a larger presence of indigenous over regionally native or nonnative plant species, whilst incorporating a broader mixture of midstorey growth forms. Competing Interest Statement The authors have declared no competing interest.