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Supplementary Tables 1-3 and Supplementary Tables 1-6

Interferon-γ (IFNγ) has been studied as a cancer treatment with limited evidence of clinical benefit. However, it could play a role in cancer immunotherapy combination treatments. Despite high expression of immunogenic cancer–testis antigens, synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) have a cold tumor microenvironment (TME), with few infiltrating T cells and low expression of major histocompatibility complex class I (MHC-I). We hypothesized that IFNγ treatment could drive inflammation in a cold TME, facilitating further immunotherapy. We conducted a phase 0 clinical trial treating 8 SS or MRCL patients with weekly systemic IFNγ. We performed pre- and posttreatment biopsies. IFNγ changed the SS and MRCL TME, inducing tumor-surface MHC-I expression and significant T-cell infiltration (P < 0.05). Gene-expression analysis suggested increased tumor antigen presentation and less exhausted phenotypes of the tumor-infiltrating T cells. Newly emergent antigen-specific humoral and/or T-cell responses were found in 3 of 7 evaluable patients. However, increased expression of PD-L1 was observed on tumor-infiltrating myeloid cells and in some cases tumor cells. These findings suggest that systemic IFNγ used to convert SS and MRCL into “hot” tumors will work in concert with anti–PD-1 therapy to provide patient benefit.

One obstacle for human solid tumor immunotherapy research is the lack of clinically relevant animal models. In this study, we sought to establish a chimeric antigen receptor (CAR) T-cell treatment model for naturally occurring canine sarcomas as a model for human CAR T-cell therapy.Canine CARs specific for B7-H3 were constructed using a single-chain variable fragment derived from the human B7-H3–specific antibody MGA271, which we confirmed to be cross-reactive with canine B7-H3. After refining activation, transduction, and expansion methods, we confirmed target killing in a tumor spheroid three-dimensional assay. We designed a B7-H3 canine CAR T-cell and achieved consistently high levels of transduction efficacy, expansion, and in vitro tumor killing. Safety of the CAR T cells were confirmed in two purposely bred healthy canine subjects following lymphodepletion by cyclophosphamide and fludarabine. Immune response, clinical parameters, and manifestation were closely monitored after treatments and were shown to resemble that of humans. No severe adverse events were observed.In summary, we demonstrated that similar to human cancers, B7-H3 can serve as a target for canine solid tumors. We successfully generated highly functional canine B7-H3–specific CAR T-cell products using a production protocol that closely models human CAR T-cell production procedure. The treatment regimen that we designed was confirmed to be safe in vivo. Our research provides a promising direction to establish in vitro and in vivo models for immunotherapy for canine and human solid tumor treatment.

Supplementary Figure from B7-H3 Specific CAR T Cells for the Naturally Occurring, Spontaneous Canine Sarcoma Model

One obstacle for human solid tumor immunotherapy research is the lack of clinically relevant animal models. In this study, we sought to establish a chimeric antigen receptor (CAR) T-cell treatment model for naturally occurring canine sarcomas as a model for human CAR T-cell therapy. Canine CARs specific for B7-H3 were constructed using a single-chain variable fragment derived from the human B7-H3–specific antibody MGA271, which we confirmed to be cross-reactive with canine B7-H3. After refining activation, transduction, and expansion methods, we confirmed target killing in a tumor spheroid three-dimensional assay. We designed a B7-H3 canine CAR T-cell and achieved consistently high levels of transduction efficacy, expansion, and in vitro tumor killing. Safety of the CAR T cells were confirmed in two purposely bred healthy canine subjects following lymphodepletion by cyclophosphamide and fludarabine. Immune response, clinical parameters, and manifestation were closely monitored after treatments and were shown to resemble that of humans. No severe adverse events were observed. In summary, we demonstrated that similar to human cancers, B7-H3 can serve as a target for canine solid tumors. We successfully generated highly functional canine B7-H3–specific CAR T-cell products using a production protocol that closely models human CAR T-cell production procedure. The treatment regimen that we designed was confirmed to be safe in vivo. Our research provides a promising direction to establish in vitro and in vivo models for immunotherapy for canine and human solid tumor treatment.

The effectiveness of antitumour immunity is dependent on intricate cytokine networks. Interleukins (ILs) are important mediators of complex interactions within the tumour microenvironment, including regulation of tumour-infiltrating lymphocyte proliferation, differentiation, migration and activation. Our evolving and increasingly nuanced understanding of the cell type-specific and heterogeneous effects of IL signalling has presented unique opportunities to fine-tune elaborate IL networks and engineer new targeted immunotherapeutics. In this review, we provide a primer for clinicians on the challenges and potential of IL-based treatment. We specifically detail the roles of IL-2, IL-10, IL-12 and IL-15 in shaping the tumour-immune landscape of gastrointestinal malignancies, paying particular attention to promising preclinical findings, early-stage clinical research and innovative therapeutic approaches that may properly place ILs to the forefront of immunotherapy regimens.

Immune cell infiltration into solid tumors, their movement within the tumor microenvironment (TME), and interaction with other immune cells are controlled by their directed migration towards gradients of chemokines. Dysregulated chemokine signaling in TME favors the growth of tumors, exclusion of effector immune cells, and abundance of immunosuppressive cells. Key chemokines directing the migration of immune cells into tumor tissue have been identified. In this review, we discuss well-studied chemokine receptors that regulate migration of effector and immunosuppressive immune cells in the context of cancer immunology. We discuss preclinical models that have described the role of respective chemokine receptors in immune cell migration into TME and review preclinical and clinical studies that target chemokine signaling as standalone or combination therapies.

ObjectiveProgrammed cell death protein 1 (PD-1) checkpoint inhibition and adoptive cellular therapy have had limited success in patients with microsatellite stable colorectal cancer liver metastases (CRLM). We sought to evaluate the effect of interleukin 10 (IL-10) blockade on endogenous T cell and chimeric antigen receptor T (CAR-T) cell antitumour function in CRLM slice cultures.DesignWe created organotypic slice cultures from human CRLM (n=38 patients’ tumours) and tested the antitumour effects of a neutralising antibody against IL-10 (αIL-10) both alone as treatment and in combination with exogenously administered carcinoembryonic antigen (CEA)-specific CAR-T cells. We evaluated slice cultures with single and multiplex immunohistochemistry, in situ hybridisation, single-cell RNA sequencing, reverse-phase protein arrays and time-lapse fluorescent microscopy.ResultsαIL-10 generated a 1.8-fold increase in T cell-mediated carcinoma cell death in human CRLM slice cultures. αIL-10 significantly increased proportions of CD8+T cells without exhaustion transcription changes, and increased human leukocyte antigen - DR isotype (HLA-DR) expression of macrophages. The antitumour effects of αIL-10 were reversed by major histocompatibility complex class I or II (MHC-I or MHC-II) blockade, confirming the essential role of antigen presenting cells. Interrupting IL-10 signalling also rescued murine CAR-T cell proliferation and cytotoxicity from myeloid cell-mediated immunosuppression. In human CRLM slices, αIL-10 increased CEA-specific CAR-T cell activation and CAR-T cell-mediated cytotoxicity, with nearly 70% carcinoma cell apoptosis across multiple human tumours. Pretreatment with an IL-10 receptor blocking antibody also potentiated CAR-T function.ConclusionNeutralising the effects of IL-10 in human CRLM has therapeutic potential as a stand-alone treatment and to augment the function of adoptively transferred CAR-T cells.

Interferon-γ (IFNγ) has been studied as a cancer treatment with limited evidence of clinical benefit. However, it could play a role in cancer immunotherapy combination treatments. Despite high expression of immunogenic cancer–testis antigens, synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) have a cold tumor microenvironment (TME), with few infiltrating T cells and low expression of major histocompatibility complex class I (MHC-I). We hypothesized that IFNγ treatment could drive inflammation in a cold TME, facilitating further immunotherapy. We conducted a phase 0 clinical trial treating 8 SS or MRCL patients with weekly systemic IFNγ. We performed pre- and posttreatment biopsies. IFNγ changed the SS and MRCL TME, inducing tumor-surface MHC-I expression and significant T-cell infiltration (P < 0.05). Gene-expression analysis suggested increased tumor antigen presentation and less exhausted phenotypes of the tumor-infiltrating T cells. Newly emergent antigen-specific humoral and/or T-cell responses were found in 3 of 7 evaluable patients. However, increased expression of PD-L1 was observed on tumor-infiltrating myeloid cells and in some cases tumor cells. These findings suggest that systemic IFNγ used to convert SS and MRCL into “hot” tumors will work in concert with anti–PD-1 therapy to provide patient benefit.

Objective Atypical (World Health Organization grade II) meningiomas (AMs) have been associated with a substantial risk of recurrence even after complete, gross total resection (GTR). The present study evaluated the clinical and AM tumor histopathological features that might predict for the risk of recurrence and survival within this patient population. Methods The data from 72 consecutive patients who had undergone primary GTR for AM from 2007 to 2016 and corresponding tumor specimens at a single institution were reviewed. The preoperative patient and tumor characteristics were correlated with the postresection outcomes, including recurrence and 1-year survival. Cox regression models on recurrence-free survival (RFS) and Kaplan-Meier survival estimates were performed. Results The overall 1-, 3-, and 5-year RFS estimates for the AM cohort were 100.0%, 82.4%, and 78.1% after resection, respectively. A high mitotic index was an independent predictor of RFS on Cox regression analysis (hazard ratio, 1.26; P = 0.008), and the tumor volume showed a trend toward a significant association (hazard ratio, 0.93; P = 0.079). Patient age and the mitotic index were significantly associated with 1-year mortality (odds ratio, 1.11 and 1.36, respectively; P = 0.028 and P = 0.045, respectively). Conclusions AM tumors with a high proliferative index showed an increased likelihood of recurrence and short-term survival even after complete GTR. A smaller tumor volume might also have contributed to an increased risk of recurrence for patients with AM. Although other histopathological features were not linked to recurrence or mortality for patients with AM, the biopsy findings can indicate key predictive information, and further molecular analysis might reveal additional prognostic markers.

Background With the advent of extensive endoscopic approaches for pituitary tumors, there has also been an increase in surgery for larger and more complex tumors. Intraoperative manipulation during endoscopic resection of sellar tumors poses potential risk in postoperative visual function in this tumor population. This study proposes a method of accurate intraoperative monitoring of visual evoked potentials (VEPs) and its role in predicting visual function outcomes. Methods Intraoperative VEPs were monitored for 42 resections from a single surgical team, with average tumor size of 2.84 cm. Changes in VEP amplitude and latency in excess of 50% were considered significant. Preoperative and postoperative visual information was obtained from ophthalmology and hospital records, along with patient demographics, comorbidities, and tumor characteristics. Results Patients were stratified as experiencing deteriorations in VEPs that did not restore to baseline (n = 4), deteriorations in VEPs that did restore to baseline (n = 6), no change in VEPs (n = 31), and improvement in VEPs (n = 1). Correlation between VEP changes and postoperative visual fields was measured through univariate ordered logistic regression. Improved intraoperative VEP measurements were associated with odds ratio (OR) of visual field improvement of 3.15 (95% confidence interval, 1.15–8.59). Specifically, changes in VEP amplitude were positively associated with visual field improvement with OR of 4.35 (OR, 1.29–14.7). No association was observed between VEPs and other patient or tumor characteristics. Conclusion Changes in VEP amplitude during endoscopic sellar tumor resection correlate with postoperative visual function. Intraoperative VEP monitoring can serve an important role in preventing postoperative visual field loss.

Microanatomical organization of innate immune cells within lymph nodes (LNs) is critical for the generation of adaptive responses. In particular, steady-state LN-resident dendritic cells (Res cDCs) are strategically localized to intercept lymph-draining antigens. Whether myeloid cell organization changes during inflammation and how that might affect the generation of immune responses are unknown. Here, we report that during type I, but not type II, inflammation after adjuvant immunization or viral infection, antigen-presenting Res cDCs undergo CCR7-dependent intranodal repositioning from the LN periphery into the T cell zone (TZ) to elicit T cell priming. Concurrently, inflammatory monocytes infiltrate the LNs via local blood vessels, enter the TZ, and cooperate with Res cDCs by providing polarizing cytokines to optimize T cell effector differentiation. Monocyte infiltration is nonuniform across LNs, generating distinct microenvironments with varied local innate cell composition. These spatial microdomains are associated with divergent early T cell effector programming, indicating that innate microenvironments within LNs play a critical role in regulating the quality and heterogeneity of T cell responses. Together, our findings reveal that dynamic modulation of innate cell microenvironments during type I inflammation leads to optimized generation of adaptive immune responses to vaccines and infections.

Background Chimeric antigen receptor (CAR) T cell therapy has transformed therapy for hematological malignancies but has not yet been established as standard of care for any solid tumors. One obstacle for human solid tumor immunotherapy research is the lack of clinically relevant, immunocompetent animal models. In this study, we sought to establish CAR T cells for naturally occurring canine sarcomas in client owned animals as a model for human CAR T cell therapy. Methods Archived FFPE, freshly isolated canine solid tumor samples as well as tumor lines were tested for B7H3 expression by immunohistochemistry (IHC) and flow cytometry analysis. We designed CARs using the scFv from the human B7H3-specific antibody MGA271 and confirmed the cross-reactivity to canine B7H3 (construct information see figure 1A). A truncated EGFR (tEGFR) was included in the construct to allow for IHC and flow cytometry testing for the presence of CAR T cells. Killing efficiency was evaluated using 3D tumor spheroid killing assays to monitor dynamics. Safety of the CAR products following lymphodepletion was confirmed in two healthy dogs (figure 1B). Results Canine solid tumors were confirmed to be B7H3 positive in almost all cases. Using the GALV-pseudotyped retrovirus system, transduction was efficient with up to 70% CAR+ cells. Post-transduction expansion was over 100 folds. B7H3 CAR transduced canine T cells were able to eliminate B7H3+ canine tumor spheroids effectively (figure 2). Safety of the CAR T cells (dose: 1 × 109/m2) were confirmed in both healthy animals following cyclophosphamide lymphodepletion. After week 6, cetuximab was given to the subjects to deplete EGFR+ cells. Subject 2 experienced fever after CAR T cell administration. Both dogs showed elevated serum ALP and ALT levels and returned to normal (figure 3). No other treatment-related adverse events were observed. Information of the CAR T cell products can be found in table 1. Conclusions We demonstrated that, similar to human cancers, B7H3 is a target in canine solid tumors. We successfully generated canine B7H3 specific CAR T cell products that are highly efficient at killing canine 3D tumor spheroids using a production protocol that closely models human CAR T cell production procedure and confirmed the safety in vivo. We plan to test and optimize various approaches to enhance CAR T cell efficacy for solid tumor treatment both in vitro and in canine sarcoma patients. Ethics Approval The study was approved by Fred Hutchinson Cancer Research Center‘s Institutional Animal Care and Use Committee (IACUC), approval number PROTO201900860

Dendritic cells (DCs) are professional antigen-presenting cells (APCs) of the immune system. They capture foreign antigens and can present them to lymphocytes, that is, T cells and B cells, to activate them. DCs are the most potent of all immune cells at inducing the adaptive immune system. Thus, the presence of DCs at the anatomical site of the immune challenge is imperative for the immune system to mount an effective immune response. From the anatomical site of the immune challenge, DCs cargo antigens to the draining lymph nodes, specialized immune organs where adaptive immunity is generated. DCs are heterogeneous as a type of immune cell, and various subsets of DCs have been reported and their functions described. In this chapter, we discuss various aspects of DC development and function. We further discuss how various tumor microenvironments can affect DC development, function, and migration, thus evading a strong adaptive immune response.

Background: Colorectal cancer liver metastasis (CRLM) causes major morbidity and mortality. Improved systemic therapies are crucial. We previously reported that macrophages infiltrated CRLM and expressed the immunosuppressive cytokine interleukin-10 (IL-10). In patient-derived CRLM tumor slice cultures, we found that a neutralizing antibody against IL-10 (anti-IL-10) caused tumor apoptosis. Here, we investigated the efficacy and immune-dependent mechanisms of IL-10 blockade in a larger cohort of CRLM patients. Methods: Tumor specimens were obtained from consenting patients at the time of surgery and cut into 250mm-thick tumor slice cultures as previously described. Tumor slices were treated with control or neutralizing antibodies against programmed cell death protein 1 (PD-1, EH12.1), IL-10 (JES3-9D7), IL-10 receptor alpha (IL-10RA, 3F9), major histocompatibility complex (MHC) class I (G46-2.6) or class II (Tu39). After 4-6 days of treatment, tumor apoptosis was evaluated by cleaved caspase-3 (CC3) immunohistochemistry (IHC) or terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Tumors were evaluated by IHC and in situ hybridization (ISH) for immune markers. Student's t-test, paired t-test, or 1-way ANOVA was used as indicated. p < 0.05 was defined as significant. Results: We generated tumor slice cultures from 34 unique CRLM patients, 76% (26/34) of whom received preoperative chemotherapy, and all of whom had either microsatellite stable tumors (76%, 26/34) or unknown microsatellite status. Anti-PD-1 did not generate tumor apoptosis (n = 4 patients' tumors). In contrast, anti-IL-10 caused nearly 2-fold increased tumor apoptosis compared with control, in the majority of 34 CRLM patients' tumors evaluated (median 50.1% versus 27.4% apoptotic cells, p < 0.0001). IL-10 receptor blockade generated a similar but non-significant increase in apoptosis. Tumors treated with anti-IL-10 demonstrated increased frequency of CD8+ T cells (median 17.8% versus 7.0% of total cells, n = 5 patients' tumors, p = 0.02) and a non-significant increase in activated PD-1+CD3+ T cells. IL-10 blockade also increased tumor IFNG expression (median 2.9 versus 2.3 counts per total cell number, n = 6 patients' tumors, p < 0.05). Macrophage frequency did not increase, but MHC class II expression nearly doubled (median 19.5% versus 11.5% of total cells, n = 5 patients' tumors, p = 0.02). To test which immune cells were required for anti-IL-10 effect, we treated human CRLM slices with anti-IL-10 +/- blocking antibodies against MHC class I or II. In the 3 of 4 patients' tumors that responded to anti-IL-10, the effect was nearly completely reversed by aMHC-I or aMHC-II (p = 0.0005). Conclusion: IL-10 is a dominant and reversible mechanism of immune evasion in human CRLM. IL-10 blockade nearly doubled tumor apoptosis in a heterogeneous cohort of CRLM patients' tumors, through a mechanism that required intact CD8+ T cell and antigen-presenting cell function. IL-10 is a compelling immunotherapeutic target for CRLM. Citation Format: Teresa S. Kim, Kevin Sullivan, Xiuyun Jiang, Cynthia Hsu, Kevin Labadie, Karan Kohli, Heidi Kenerson, Sara Daniel, Arezou Abbasi, Raymond Yeung, Venu Pillarisetty. Interleukin-10 is a dominant and reversible mechanism of immune evasion in human colorectal cancer liver metastasis [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P037.

BackgroundAdoptive cellular therapy (ACT) is a promising treatment for synovial sarcoma (SS) with reported response rates of over 50%. However, more work is needed to obtain deeper and more durable responses. SS has a ‘cold’ tumor immune microenvironment with low levels of major histocompatibility complex (MHC) expression and few T-cell infiltrates, which could represent a barrier toward successful treatment with ACT. We previously demonstrated that both MHC expression and T-cell infiltration can be increased using systemic interferon gamma (IFN-γ), which could improve the efficacy of ACT for SS.Case presentationWe launched a phase I trial incorporating four weekly doses of IFN-γ in an ACT regimen of high-dose cyclophosphamide (HD Cy), NY-ESO-1-specific T cells, and postinfusion low-dose interleukin (IL)-2. Two patients were treated. While one patient had significant tumor regression and resultant clinical benefit, the other patient suffered a fatal histiocytic myocarditis. Therefore, this cohort was terminated for safety concerns.ConclusionWe describe a new and serious toxicity of immunotherapy from IFN-γ combined with HD Cy-based lymphodepletion and low-dose IL-2. While IFN-γ should not be used concurrently with HD Cy or with low dose IL-2, IFN-γ may still be important in sensitizing SS for ACT. Future studies should avoid using IFN-γ during the immediate period before/after cell infusion.Trial registration numbersNCT04177021,NCT01957709, andNCT03063632.

Objective Neurosurgeons have taken on the role of innovators, continuing to move the field forward over the centuries. More recently, innovation has taken the form of new technological devices and therapeutics, which require patenting. The aim of this study is to identify major areas of innovation in the field of neurosurgery by evaluating patent records. Methods This study quantifies the number of patents the American Association of Neurological Surgeons (AANS) neurosurgeons hold across different subspecialties. The United States Patent and Trademark Office (USPTO) patent database was queried using the names of 7,293 AANS members who filed patents between 1976 and 2019. Results A total of 346 (4.7%) AANS neurosurgeons hold a total of 1,025 patents. The number of patents held by each neurosurgeon ranged from one to 109. The areas that patents were filed under include cellular and genetic science (40), drug delivery (45), image guidance (82), neuromodulation (52), pain (7), peripheral nerve stimulation (24), spine (398), surgical devices (148), trauma (16), tumor (78), vascular (67), and other (68). No patents were filed under pediatrics (0). The fields with the greatest number of filed patents are spine, instruments/devices, and image guidance. Conclusion Given the technical nature of the field of neurosurgery, instruments and devices that improve localization, visualization, targeting, and spinal reconstruction are often in demand. Furthermore, since the rates of spinal procedures and implants continue to increase, higher patenting may be motivated by the opportunity to develop new products that can result in royalty payments to neurosurgeons. The advent of new technologies undoubtedly continues to push the field of neurosurgery forward.

Gastrointestinal stromal tumor (GIST) is a devastating disease, especially in the setting of metastasis. The natural progression of GIST has been significantly altered by the development of small molecule tyrosine kinase inhibitors (TKIs), including imatinib, sunitinib, and regorafenib, all of which are FDA approved. However, TKIs are not always well-tolerated, and the refractory disease continues to be a problem. For these reasons, alternative treatments are needed. In this report, we discuss a patient with metastatic wild-type (WT) GIST refractory to multiple TKIs, but with a durable clinical response to the anti-programmed cell death protein 1 (PD-1) antibody, nivolumab. This report suggests that continued research evaluating checkpoint inhibitors in GIST is warranted.

Background Benign meningiomas constitute 80%–90% of all meningiomas and represent the most common type of central nervous system tumor in adults. The vast majority of meningiomas are minimally symptomatic or asymptomatic early in their onset and thereby can often result in delayed diagnosis. Early diagnosis of meningioma is critical, as it can maximize treatment options and improve outcomes and survival. Although seizures and focal neurologic deficits are considered to be the most prevalent symptoms, depression also may be an important and significant sign. A subtle neurologic depression may be an even early presenting sign of meningioma and may precede more traditional presenting symptoms. Methods We performed a comprehensive literature review that analyzes the results of prospective studies and case reports on this topic. Results Our findings show evidence to suggest that depression may be correlated with meningioma presentation. Its prevalence is possibly increased with an anterior location of the tumor. Conclusions For patients who exhibit nuances of depression without a history of psychiatric illness, an index of suspicion for meningioma may be warranted.

Background: Multiple factors, including dense stroma and high infiltration of suppressive immune cells make pancreatic ductal adenocarcinoma (PDA) challenging to treat with immunotherapy. The presence of intra-tumoral T cells positively correlates with improved survival for PDA patients. Gamma chain cytokines (GCCs) can augment T cell mediated anti-tumor immunity and various GCC agonist drugs have been applied in clinical trials for cancer. Besides evaluating the effect of GCC derived agonists using recovered blood or biopsies of treated patients, it is challenging to mechanistically study the effect of GCCs on tumor-resident immune cells in human samples. Methods: Here we apply organotypic slice culture of surgically resected tumor tissues to study the effect of GCCs on intra-tumoral immune cells. We treated slices of PDAs with GCCs (IL-2, IL-7, IL-15 and IL-21) for 6 days. Immune cells, especially T cells emigrated from the tumor slices into the culture supernatant. On day 6 we fixed intact tumor slices for multiplex immunohistochemistry (mIHC) and analyzed emigrated cells using flow cytometry. Results: IL-15 and IL-7 potently induced T cell proliferation. The effect of IL-7 and IL-15 on T cell proliferation was higher for T cells that expressed markers of antigen experience such as CD39 and PD1 (Table 1). While IL-15 had the strongest effect on tumor-derived T cells, IL-15 and IL-7 were similar in their effect on T cells in the blood of the same patient, suggesting that IL-15 is especially effective in inducing the proliferation of tumor-infiltrating T cells. The effect of IL-15 on enhanced T cell proliferation was also seen within tumor slices, as revealed by mIHC. Conclusion: Our data suggest that IL-15 is the most potent GCC at inducing in situ expansion of tumor-resident T cells, including T cells that show signs of antigen experience. Table 1.IL-15 induces in situ T cell proliferation in PDA.AssayGroupsUntreatedIL-2IL-7IL-15IL-21ParameterFlow Cytometry%Ki67+CD8+cells of live cells0.090.040.360.595.001.3514.331.200.310.14%CD39+CD103+of CD8+0.130.150.110.040.290.140.620.180.130.08%PD1+of CD8+25.107.2223.233.1030.484.7446.483.5037.402.32mIHC%CD8+Ki67+ of all cells0.16 0.04(n=2)0.83 (n=1)0.550.38(n=2)2.200.04(n=2)0.490.41(n=2)n=4 slices for each group for flow cytometry. Data are from one experiment*. MeanSD is shown. Two doses (10-fold difference) for each cytokine were tested and results only for the low dose are shown.*Another experiment with groups IL-2 and IL-2+IL-15 was performed and had similar results for the effect of IL-15 Citation Format: Karan Kohli, Shihong Zhang, Xiuyun Jiang, Cynthia Hsu, Arezou Abbasi, Teresa S. Kim, Venu G. Pillarisetty. IL-15 is the most potent of tested gamma chain cytokines at inducing in situ proliferation of T cells in human pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 607.

Author(s): Kohli, Karan; Yao, Lu; Nowicki, Theodore Scott; Zhang, Shihong; Black, Ralph Graeme; Schroeder, Brett A; Farrar, Erik A; Cao, Jianhong; Sloan, Heather; Stief, Dawn; Cranmer, Lee D; Wagner, Michael J; Hawkins, Douglas S; Pillarisetty, Venu G; Ribas, Antoni; Campbell, Jean; Pierce, Robert H; Kim, Edward Y; Jones, Robin L; Riddell, Stanley R; Yee, Cassian; Pollack, Seth M | Abstract: BackgroundSynovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are ideal solid tumors for the development of adoptive cellular therapy (ACT) targeting NY-ESO-1, as a high frequency of tumors homogeneously express this cancer-testes antigen. Data from early phase clinical trials have shown antitumor activity after the adoptive transfer of NY-ESO-1-specific T cells. In these studies, persistence of NY-ESO-1 specific T cells is highly correlated with response to ACT, but patients often continue to have detectable transferred cells in their peripheral blood following progression.MethodWe performed a phase I clinical trial evaluating the safety of NY-ESO-1-specific endogenous T cells (ETC) following cyclophosphamide conditioning. Peripheral blood mononuclear cells (PBMCs) from treated patients were evaluated by flow cytometry and gene expression analysis as well as through ex vivo culture assays with and without IL-15.ResultsFour patients were treated in a cohort using ETC targeting NY-ESO-1 following cyclophosphamide conditioning. Treatment was well tolerated without significant toxicity, but all patients ultimately had disease progression. In two of four patients, we obtained post-treatment tumor tissue and in both, NY-ESO-1 antigen was retained despite clear detectable persisting NY-ESO-1-specific T cells in the peripheral blood. Despite a memory phenotype, these persisting cells lacked markers of proliferation or activation. However, in ex vivo culture assays, they could be induced to proliferate and kill tumor using IL-15. These results were also seen in PBMCs from two patients who received gene-engineered T-cell receptor-based products at other centers.ConclusionsETC targeting NY-ESO-1 with single-agent cyclophosphamide alone conditioning was well tolerated in patients with SS and those with MRCL. IL-15 can induce proliferation and activity in persisting NY-ESO-1-specific T cells even in patients with disease progression following ACT. These results support future work evaluating whether IL-15 could be incorporated into ACT trials post-infusion or at the time of progression.

Plasmacytoid dendritic cells (pDCs) have been shown to induce tolerance to innocuous antigens. Their migratory properties allow them to take up antigens from the periphery and transport them to the draining lymph nodes or to the thymus. However, pDC-T-cell interaction in the primary and secondary lymphoid organs still remains poorly defined. In this study, we show that resting pDCs loaded with exogenous antigen could induce tolerance when transferred intralymphatically into a single lymph node of wild-type C57BL/6 mice. However, this was a result of antigen transfer from pDCs to endogenous antigen presenting cells and subsequent abortive proliferation of cognate CD4+ T cells. pDCs could not directly induce the proliferation of CD4+ T cells, as observed in mice lacking MHC class II gene. Moreover, pDCs failed to make physical contacts with OT-II cells as revealed by two-photon imaging. Thus, the role of resting pDCs in tolerance induction seems to be independent of its direct interaction with cognate CD4+ T cells.

Introduction Socioeconomic topics such as federal mandates/regulations, conflict of interest, and practice management have become increasingly important for all neurosurgeons. Graduating residents immediately need a host of skills to successfully navigate neurosurgical practice. Surgical and medical skills are closely evaluated through the American Board of Neurological Surgery, and a formal socioeconomic curriculum has been developed with defined milestones. Nevertheless, little has been done to evaluate neurosurgery resident competence in socioeconomic and medicolegal principles. The purpose of this study was to assess the competence of Accreditation Council for Graduate Medical Education neurosurgical residents in socioeconomic knowledge. Methods Neurosurgery resident members of the American Association of Neurological Surgeons (N = 1385) were sent a Survey Monkey of 10 questions. The survey covered the most basic of socioeconomic principles. Initial survey responses were collected across a 1-month period from April to May 2018. Results The response rate was 14% (194/1385). Overall, neurosurgery residents would have received a grade of D, with an average score of 67% on the survey. For 7 of the 10 questions, the majority (>50%) of neurosurgery residents answered correctly. Furthermore, for 3 questions, more than 90% of residents selected the correct answer. However, for one-half of all questions, residents averaged a score of less than 65%. Residents tended to answer questions correctly for physician compensation and compensation models, but incorrectly for topics of informed consent, Controlled Substances Act, and conflicts of interest. Conclusion With the increasing complexity of neurosurgery practice, solid knowledge of socioeconomic topics is essential. The study confirms suspected deficiencies in socioeconomic proficiency among neurosurgery residents, despite the availability of a validated curriculum. This knowledge gap will likely affect career success and satisfaction. Nevertheless, this survey had a significantly low response rate, and it may be an incomplete representation of the neurosurgical resident mind. Focused educational initiatives through the neurosurgical Residency Review Committee and individual training programs must facilitate an action plan that ensures the effective implementation of socioeconomic curricula.

Background Medical malpractice litigation is an issue of major concern in neurosurgery, with 19.1% of neurosurgeons facing a claim annually. Neurosurgery possesses the greatest risk of malpractice of any specialty, likely owing to the complex clinical environment and disease severity. In the present study, we have characterized such litigation to determine the common factors that compel plaintiffs to file these claims. Methods WestLawNext, a prominent legal database, was used to identify all cases from 1985 to 2016 related to brain tumors. A total of 225 cases were identified, and each was analyzed for the cause of litigation (multiple causes were permitted). Because many had >1 ground for litigation, the reported percentages were based on the total counts of litigation rather than the number of cases. Additional information was collected from each case, including location, tumor type, and physician specialty. Results The cases were distributed across 36 states and U.S. territories: California (n = 42; 20%) and New York (n = 28; 13%) had the greatest number of cases. The top reasons for litigation were failure to diagnose (n = 109; 28%), failure to treat (n = 72; 18%), procedural error (n = 63; 16%), and failure to refer for diagnostic tests (n = 55; 14%). The most common diagnoses included pituitary adenoma (n = 26; 12%), acoustic neuroma (n = 27; 12%), and meningioma (n = 23; 10%). Conclusions Malpractice litigation contributes to high overhead and physician burnout and escalates the cost of patient care. We found that benign brain tumors were the most common in litigation and that surgical issues accounted for only a small percentage.

OBJECTIVEWith increasing general use of antidepressants (ADs), multiple studies have noted a small protective effect of ADs for patients with glioma, but their impact on meningioma has not been established. This study aims to evaluate the role of ADs in the context of additional clinical factors in relation to long-term risk of meningioma recurrence.METHODSOne hundred five patients with an intracranial meningioma presenting from 2011–2014 with at least 3 years of follow-up (median 4.2 years) after resection were reviewed. AD use along with demographics, tumor characteristics, and outcomes were recorded. Multivariate logistic regression was used to analyze the association of AD use with tumor recurrence, including other clinical measures significantly associated with recurrence as covariates.RESULTSTwenty-nine patients (27.4%) were taking ADs (27 selective serotonin reuptake inhibitors, 2 norepinephrine-dopamine reuptake inhibitors) prior to tumor recurrence. Their tumors largely affected the frontal (31.0%) or parietal lobe (17.2%) and were located in convexity, parasagittal, or falcine (CPF) areas more frequently than skull base areas relative to the tumors of non-AD users (p = 0.035). AD use was found to be an independent predictor of recurrence, in addition to subtotal resection and WHO grade II/III classification (p values < 0.05). The median time from AD prescription to tumor recurrence was 36.6 months (interquartile range [IQR] = 20.9–62.9 months) and median length of AD use was 41.4 months (IQR = 24.7–62.8 months).CONCLUSIONSAD use was an independent predictor of meningioma recurrence. This association may be due to mood or affective changes caused by tumor location in CPF regions that may be a sign of early recurrence. The finding calls attention to AD use in the management of patients with meningioma, and warrants further exploration of an underlying relationship.

To characterize the dynamics of a structure accurately and to minimize uncertainties, it is important to perform modal testing in various configurations. However, performing such rigorous testing of structures can be a resource intensive process. In addition, simulating certain conditions may not be possible in the lab. Developing a calibrated and a validated model that can predict the dynamic response of a structure accurately can be a key to address this issue. In this paper, a model calibration and validation case study performed on a rectangular steel plate structure is presented. The geometric and material properties used in the model were updated to calibrate the model. The accuracy of the calibrated model was confirmed by performing a validation process involving perturbed mass and constrained boundary condition FE modal analysis and modal testing. The validation criteria were achieved using the calibrated model and thus proved that the model could reliably predict the dynamic response of the structure.

From a system modeling perspective, it is important to develop an accurate mathematical model of a structure. Such a model can be built with measured frequency response functions obtained from a modal test. The test structure can be subjected to free, constrained or operating boundary conditions. Setting up a structure with either constrained or operating boundary conditions is impractical/prohibitive. It is easier to approach free boundary condition in the lab using soft supports, such as foam, shock cords, air suspension, etc. A good support system should have the least intrusion. It should not introduce nonlinearity or damping. The effectiveness of a good support system is quantified by the extent of separation of the rigid body modes from the elastic modes and a high degree of uncoupling of the dynamics of support system and the structural modes. The influence of various boundary conditions and soft support systems chosen for modeling a lightweight structures, such as Formula SAE racecar space frame, a rectangular steel plate structure and a circular aluminum plate are discussed.