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00006). Copy number losses and decreased expression of FLT3 in HCC were detected in about 64% of patients. Moreover, the PDXs derived from tumors with high FLT3 levels also displayed a better response to sorafenib. CONCLUSIONS Sorafenib may be able to delay tumor progression in FLT3-High HCC patients. This potential biomarker needs to be further validated in independent cohorts prior to helping stratify patients for precision therapy in advanced HCC. Copyright ©2020, American Association for Cancer Research.PURPOSE Drug induced interstitial lung disease (DILD) is a rare, but potentially fatal toxicity. Clinical and radiological features of DILD in the early experimental setting are poorly described. EXPERIMENTAL DESIGN 2499 consecutive advanced cancer patients on phase I clinical trials were included. DILD was identified by a dedicated radiologist and investigators, categorized per internationally recognized radiological patterns and graded per CTCAE and the Royal Marsden Hospital DILD score. Clinical and radiological features of DILD were analysed. RESULTS 60 patients overall (2.4%) developed DILD. Median time to onset of DILD was 63 days (range 14-336 days). 45% of patients who developed DILD were clinically asymptomatic. Incidence was highest in patients receiving drug conjugates (7.4%), followed by inhibitors of the PI3K/AKT/mTOR pathway (3.9%). Commonest pattern seen was hypersensitivity pneumonitis (33.3%), followed by non-specific interstitial pneumonia (30%) and cryptogenic organising pneumonia (26.7%). A higher DILD score (OR 1.47, 95% CI 1.19-1.81, p less then 0.001) and the pattern of DILD (OR 5.83 for acute interstitial pneumonia, 95% CI 0.38-90.26, p=0.002) were significantly associated with a higher CTCAE grading. The only predictive factor for an improvement in DILD was an interruption of treatment (OR 0.05, 95% CI 0.01-0.35, p=0.01). CONCLUSIONS DILD in early phase clinical trials is a toxicity of variable onset, with diverse clinical and radiological findings. Radiological findings precede clinical symptoms. The extent of the affected lung parenchyma, scored by the RMH DILD score, correlates with clinical presentation. Most events are low grade, and improve with treatment interruption which should be considered early. Copyright ©2020, American Association for Cancer Research.PURPOSE DNA damage response and repair (DDR) gene alterations are associated with increased tumor infiltrating lymphocytes, higher genomic instability, and higher tumor mutational burden (TMB) in cancer. Whether DDR alterations are associated with clinical outcomes to PD-(L)1 blockade in non-small cell lung cancer (NSCLC) is unknown. EXPERIMENTAL DESIGN Tumors from patients treated with PD-(L)1 inhibitors were analyzed using targeted next-generation sequencing (NGS). Cancers were categorized based on the presence or absence of deleterious mutations across a panel of 53 DDR genes. Clinical outcomes to PD-(L)1 inhibitors were evaluated according to DDR mutation status. RESULTS Of 266 patients with successful NGS who received PD-(L)1 inhibitors, 132 (49.6%) were identified as having deleterious DDR mutations (DDR-positive). DDR-positive and DDR-negative groups were similar in terms of baseline clinicopathological characteristics. The median TMB was significantly higher in the DDR-positive group compared to the DDR-negative group (12.1 vs 7.6 mutations/megabase, P less then 0.001). Compared to DDR-negative patients (N=134), DDR-positive patients had a significantly higher objective response rate (30.3 vs 17.2%, P=0.01), longer median progression-free survival (5.4 vs 2.2 months, HR 0.58 [95%CI0.45-0.76], P less then 0.001), and longer median overall survival (18.8 vs 9.9 months, HR 0.57 [95%CI0.42-0.77], P less then 0.001) with PD-(L)1 therapy. After adjusting for PD-L1, TMB, PS, tobacco use, and line of therapy, DDR-positive status was associated with a significantly longer PFS (HR 0.68 [95%CI0.51-0.92], P=0.01) and OS (HR 0.60 [95%CI0.43-0.85], P=0.004) in multivariate analysis. CONCLUSIONS Deleterious DDR mutations are frequent in NSCLC and are associated with improved clinical outcomes in patients with NSCLC treated with PD-(L)1 blockade. Copyright ©2020, American Association for Cancer Research.PURPOSE Clinical trials with immune checkpoint (IC) inhibition in sarcomas have demonstrated minimal response. Here, we interrogated the tumor microenvironment (TME) of two contrasting soft tissue sarcomas (STS) - Rhabdomyosarcomas (RMS) and Undifferentiated Pleomorphic Sarcomas (UPS) - with differing genetic underpinnings and responses to IC inhibition in order to understand the mechanisms that lead to response. EXPERIMENTAL DESIGN Utilizing fresh and Formalin Fixed Paraffin Embedded (FFPE) tissue from patients diagnosed with UPS and RMS, we dissected the TME by using immunohistochemistry (IHC), flow cytometry, and comparative transcriptomic studies. RESULTS Our results demonstrated both STS subtypes to be dominated by tumor associated macrophages (TAMs) and infiltrated with immune cells that localized near the tumor vasculature. Both subtypes had similar T-cell densities, however their in-situ distribution diverged. see more UPS specimens demonstrated diffuse intratumoral infiltration of T-cells, while RMS samples revealed intratumoral T-cells that clustered with B-cells near perivascular beds, forming tertiary lymphoid structures (TLS). T-cells in UPS specimens were comprised of abundant CD8+ T-cells exhibiting high PD-1 expression, which might represent the tumor reactive-repertoire. In RMS, T-cells were limited to TLS, but expressed ICs and immunomodulatory molecules which, if appropriately targeted, could help unleash T-cells into the rest of the tumor tissue. CONCLUSIONS Our work in STS revealed an immunosuppressive TME dominated by myeloid cells, which may be overcome with activation of T-cells that traffic into the tumor. In RMS, targeting T-cells found within TLS may be key to achieve anti-tumor response. Copyright ©2020, American Association for Cancer Research.PURPOSE Diffuse intrinsic pontine glioma (DIPG) bears a dismal prognosis. A genetically engineered brainstem glioma model harboring the recurrent DIPG mutation, ACVR1-G328V (mACVR1), was developed for testing an immune-stimulatory gene therapy. EXPERIMENTAL DESIGN We utilized the Sleeping Beauty transposase system to generate an endogenous mouse model of mACVR1 brainstem glioma. Histology was used to characterize and validate the model. We performed RNAseq analysis on neurospheres (NS) harboring mACVR1. mACVR1 NS were implanted into the pons of immune competent mice to test the therapeutic efficacy and toxicity of immune stimulatory gene therapy using adenoviruses expressing thymidine kinase (TK) and fms-like tyrosine kinase 3 ligand (Flt3L). mACVR1 NS expressing the surrogate tumor antigen ovalbumin were generated to investigate if TK/Flt3L treatment induces the recruitment of tumor-antigen specific T cells. RESULTS Histological analysis of mACVR1 tumors indicates that they are localized in the brainstem and have increased downstream signaling of bone morphogenetic pathway as demonstrated by increased phospho-smad1/5 and Id1 levels. Transcriptome analysis of mACVR1 NS identified an increase in the transforming growth factor beta (TGF-β) signaling pathway and the regulation of cell differentiation. Adenoviral delivery of TK/Flt3L in mice bearing brainstem gliomas resulted in anti-tumor immunity, recruitment of anti-tumor specific T cells and increased median survival. CONCLUSIONS This study provides insights into the phenotype and function of the tumor immune microenvironment in a mouse model of brainstem glioma harboring mACVR1. Immune stimulatory gene therapy targeting the hosts' anti-tumor immune response inhibits tumor progression and increases median survival of mice bearing mACVR1 tumors. Copyright ©2020, American Association for Cancer Research.The development of the most successful cancer immunotherapies in solid tumors, immune-checkpoint blockade, has focused on factors regulating T cell activation. Until recently, the field has maintained a predominately T-cell centric view of immunotherapy, leaving aside the impact of innate immunity and especially myeloid cells. Dendritic cells (DC) are dominant partners of T cells, necessary for initiation of adaptive immune responses. Emerging evidence supports a broader role for DCs in tumors including the maintenance and support of effector functions during T cell responses. This relationship is evidenced by the association of activated DCs with immune-checkpoint blockade responses and transcriptional analysis of responding tumors demonstrating the presence of type I interferon transcripts and DC relevant chemokines. T cell-inflamed tumors preferentially respond to immunotherapies compared to non-T cell inflamed tumors and this model suggests a potentially modifiable spectrum of tumor microenvironmental immunity. While host and commensal factors may limit the T cell-inflamed phenotype, tumor cell intrinsic factors are gaining prominence as therapeutic targets. For example, tumor WNT/ᵷ1;-catenin signaling inhibits production of chemokine gradients and blocking DC recruitment to tumors. Conversely, mechanisms of innate immune nucleic acid sensing, normally operative during pathogen response, may enhance DC accumulation and make tumors more susceptible to cancer immunotherapy. Elucidating mechanisms whereby DCs infiltrate and become activated within tumors may provide new opportunities for therapeutic intervention. Conceptually, this would facilitate conversion of non-T cell-inflamed to T cell-inflamed states or overcome secondary resistance mechanisms in T cell-inflamed tumors, expanding the proportion of patients who benefit from cancer immunotherapy. Copyright ©2020, American Association for Cancer Research.PURPOSE Endoglin is a coreceptor for Transforming Growth factor (TGF)-β ligands that is highly expressed on proliferating endothelial cells and other cells in the tumor microenvironment (TME). Clinical studies have noted increased programmed cell death (PD)1 expression on cytotoxic T-cells in the peripheral blood of cancer patients treated with TRC105, an endoglin targeting antibody. In the current study, we investigated the combination of endoglin antibodies (TRC105 and M1043) with an anti-PD1 antibody. EXPERIMENTAL DESIGN The combination anti-endoglin/anti-PD1 antibodies was tested in four preclinical mouse models representing different stages of cancer development. To investigate the underlying mechanism, Fc-receptor knockout mice were used complemented with depletion of multiple immune subsets in mice. Tumor growth and the composition of immune infiltrate was analyzed by flow cytometry. Finally, human colorectal cancer specimens were analyzed for presence of endoglin-expressing Tregs. RESULTS In all models, the combination of endoglin antibody and PD1 inhibition produced durable tumor responses, leading to complete regressions in 30-40% of the mice. These effects were dependent on the presence of Fc-y receptors, indicating the involvement of antibody-dependent cytotoxic responses and the presence of CD8+ cytotoxic T cells and CD4+ T-helper cells. Interestingly, treatment with the endoglin antibody TRC105 significantly decreased the number of intratumoral regulatory T cells (Tregs). Endoglin expressing Tregs were also detected in human colorectal cancer specimens. CONCLUSION Taken together these data provide a rationale for combining TRC105 and anti-PD1 therapy and provide additional evidence of endoglin's immunomodulatory role. Copyright ©2020, American Association for Cancer Research.
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