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The recent clinical successes of immunotherapy, as a result of a broader and more profound understanding of cancer immunobiology, and the leverage of this knowledge to effectively eradicate malignant cells, has revolutionised the field of cancer therapeutics. Immunotherapy is now considered the fifth pillar of cancer care, alongside surgery, chemotherapy, radiotherapy, and targeted therapy. Recently, the success of genetically modified T cells that express chimeric antigen receptors (CAR T cells) has generated considerable excitement. CAR T-cell therapy research and development has built on experience generated by laboratory research and clinical investigation of lymphokine-activated killer cells, tumour-infiltrating lymphocytes, and allogeneic haemopoietic stem-cell transplantation for cancer treatment. This Review aims to provide a background on the field of adoptive T-cell therapy and the development of genetically modified T cells, most notably CAR T-cell therapy. Many challenges exist to optimise efficacy, minimise toxicity, and broaden the application of immunotherapies based on T cells.

The abscopal effect following ionizing radiation therapy (RT) is considered to be a rare event. This effect does occur more frequently when combined with other therapies, including immunotherapy. Here we demonstrate that the frequency of abscopal events following RT alone is highly dependent upon the degree of adrenergic stress in the tumor-bearing host. Using a combination of physiologic, pharmacologic and genetic strategies, we observe improvements in the control of both irradiated and non-irradiated distant tumors, including metastatic tumors, when adrenergic stress or signaling through β-adrenergic receptor is reduced. Further, we observe cellular and molecular evidence of improved, antigen-specific, anti-tumor immune responses which also depend upon T cell egress from draining lymph nodes. These data suggest that blockade of β2 adrenergic stress signaling could be a useful, safe, and feasible strategy to improve efficacy in cancer patients undergoing radiation therapy. Abscopal responses in patients and preclinical models following radiation therapy are rare. Here the authors show that, in murine tumor models, reducing adrenergic stress or β2-adrenergic receptor signalling not only improves control of the irradiated tumor but significantly increases abscopal events.

We conducted a systematic review and meta-analysis to evaluate outcomes following chimeric antigen receptor T cell (CAR-T) therapy in relapsed/refractory acute myeloid leukemia (RR-AML). We performed a literature search on PubMed, Cochrane Library, and Clinicaltrials.gov. After screening 677 manuscripts, 13 studies were included. Data was extracted following PRISMA guidelines. Pooled analysis was done using the meta-package by Schwarzer et al. Proportions with 95% confidence intervals (CI) were computed. We analyzed 57 patients from 10 clinical trials and 3 case reports. The pooled complete and overall response rates were 49.5% (95% CI 0.18-0.81, I =65%) and 65.2% (95% CI 0.36-0.91, I =57%). The pooled incidence of cytokine release syndrome, immune-effector cell associated neurotoxicity syndrome, and graft-versus-host disease was estimated as 54.4% (95% CI 0.17-0.90, I =77%), 3.9% (95% CI 0.00-0.19, I =22%), and 1.6% (95%CI 0.00-0.21, I =33%), respectively. CAR-T therapy has demonstrated modest efficacy in RR-AML. Major challenges include heterogeneous disease biology, lack of a unique targetable antigen, and immune exhaustion.

Background The role of neutrophil–lymphocyte ratio (NLR) as a predictor for survival in single fraction SBRT-treated non-small cell lung cancer (NSCLC) patients remains unclear. We performed an observational cohort study to determine the role of pretreatment NLR in predicting survival of early-stage NSCLC patients after single fraction SBRT. Methods A single-institution database of peripheral early-stage NSCLC patients treated with SBRT from February 2007 to May 2022 was queried. Optimal threshold of neutrophil–lymphocyte ratio (NLR) was defined based on maximally selected rank statistics. Cox multivariable analysis (MVA), Kaplan–Meier, and propensity score matching were performed to evaluate outcomes. Results A total of 286 patients were included for analysis with median follow up of 19.7 months. On Cox multivariate analysis, as a continuous variable, NLR was shown to be an independent predictor of OS (adjusted hazards ratio [aHR] 1.06, 95% CI 1.02–1.10, p  = 0.005) and PFS (aHR 1.05, 95% CI 1.01–1.09, p  = 0.013). In addition, NLR was associated with DF (aHR 1.11, 95% CI 1.05–1.18, p  < 0.001). Maximally selected rank statistics determined 3.28 as the cutoff point of high NLR versus low NLR. These findings were confirmed upon propensity matching. Conclusions Pretreatment NLR is an independent predictor for survival outcomes of peripheral early-stage NSCLC patients after single fraction SBRT.

In their GTP-bound (active) form, Rab proteins interact with effector proteins that control downstream signaling. One such Rab15 effector is Rep15, which is known to have a role in receptor recycling from the endocytic recycling compartment but otherwise remains poorly characterized. Here, we report the characterization of the Rep15:Rab15 interaction and identification of Rab3 paralogs and Rab34 as Rep15 interacting partners from a yeast two-hybrid assay. Biochemical validation of the interactions is presented and crystal structures of the Rep15:Rab3B and Rep15:Rab3C complexes provide additional mechanistic insight. We find that Rep15 adopts a globular structure that is distinct from other reported Rab15, Rab3 and Rab34 effectors. Structure-based mutagenesis experiments explain the Rep15:Rab interaction specificity. Rep15 depletion in U138MG glioblastoma cells impairs cell proliferation, cell migration and receptor recycling, underscoring the need for further clarification of the role of Rep15 in cancer. Rep15 is an effector that interacts with the GTPase Rab15. Here, the authors show that Rep15 also interacts with Rab3 paralogs and Rab34, present crystal structures of Rep15:Rab complexes and find that Rep15 depletion in glioblastoma cells decreases proliferation and mobility.

Background Esophageal cancer (ESC) is an aggressive disease which often presents at an advanced stage. Despite trimodal therapy, 40–50% patients can develop metastatic disease by 18 months. Identification of patients at risk for metastatic spread is challenging with need for improved prognostication. We investigated whether the immune landscape of pretreatment tissue was associated with relapse in ESC patients. Methods Between April 2010 and October 2018, we identified 25 patients who had undergone trimodal therapy for ESC and had pretreatment biopsies suitable for analyses. We performed high-throughput multispectral immunofluorescence (mIF) analysis on formalin-fixed paraffin embedded biopsy samples. Analysis of 27 unique populations via immune and exhaustion mIF panels was performed and expression was normalized to total cell counts. Results Of the 25 patients analyzed, the median follow-up time was 23.9 months, during which 12 (48%) patients suffered a relapse with a median time to progression of 13.1 months. mIF revealed higher expression of HLA-DR ( p  = 0.019), CD8/LAG3 ( p  = 0.046), and CD8/CTLA4 ( p  = 0.027) among patients without relapse. Time to progression (TTP) and disease-specific survival (DSS) were stratified by median expression of each significant subpopulation and formally tested by the log-rank test. Higher than median expression of HLA-DR ( p  = 0.027), CD8/LAG3 ( p  = 0.039), and CD8/CTLA4 ( p  = 0.039) were significantly associated with TTP. Similarly, HLA-DR ( p  = 0.0069) and CD8/CTLA4 ( p  = 0.036) were significantly associated with improved DSS, whereas no significant observations were found with CD8/LAG3 ( p  = 0.11) expression. Stromal, but not tumoral expression of CD163 and CD163/PDL1 were significantly associated with improved TTP and DSS. Conclusions High expression of HLA-DR, CD8/CTLA4, and stromal expression of CD163 and CD163/PDL1 within pretreatment biopsy ESC samples was associated with significantly reduced rates of relapse. Increased presence of these markers suggests that an improved immune landscape is associated with less aggressive disease and may provide an opportunity for risk-based treatment strategies.

Background Despite numerous studies on racial/ethnic disparities among patients with breast cancer, there is a paucity of literature evaluating racial/ethnic differences in 21-gene recurrence score (RS) and survival differences stratified by RS risk categories. We thus performed an observational cohort study to examine racial/ethnic disparities in the context of RS. Methods The National Cancer Database (NCDB) was queried for female patients diagnosed between 2006 and 2018 with estrogen receptor (ER)-positive, pT1-3N0-1aM0 breast cancer who received surgery followed by adjuvant endocrine therapy and had RS data available. Logistic multivariable analysis (MVA) was built to evaluate variables associated with RS ≥ 26. Cox MVA was used to evaluate OS. Subgroup analyses were performed to compare the magnitude of racial/ethnic differences stratified by RS. P values less than 0.017 were considered statistically significant based on Bonferroni correction. Results A total of 140,133 women were included for analysis. Of these, 115,651 (82.5%), 8,213 (5.9%), 10,814 (7.7%), and 5,455 (3.9%) were NHW, Hispanic, Black, and API women, respectively. Median (IQR) follow up was 66.2 months (48.0–89.8). Logistic MVA showed that, compared with NHW women, Black women were associated with higher RS (≥ 26 vs < 26: adjusted odds ratio [aOR] 1.19, 95% confidence interval [CI] 1.12–1.26, p  < 0.001), while HW (aOR 0.93, 95% CI 0.86–1.00, p  = 0.04) and API women (aOR 1.03, 95% CI 0.95–1.13, p  = 0.45) were not. Cox MVA showed that, compared with NHW women, Black women had worse OS (adjusted hazards ratio [aHR] 1.10, 95% CI 1.02–1.19, p  = 0.012), while HW (aHR 0.85, 95% CI 0.77–0.94, p  = 0.001) and API (aHR 0.66, 95% CI 0.56–0.77, p  < 0.001) women had better OS. In subgroup analysis, similar findings were noted among those with RS < 26, while only API women were associated with improved OS among others with RS ≥ 26. Conclusion To our knowledge, this is the largest study using nationwide oncology database to suggest that Black women were associated with higher RS, while HW and API women were not. It also suggested that Black women were associated with worse OS among those with RS < 26, while API women were associated with improved OS regardless of RS when compared to NHW women.

Background Given the role of systematic inflammation in cancer progression, lymphocyte-monocyte ratio (LMR) from peripheral blood has been suggested as a biomarker to assess the extent of inflammation in several solid malignancies. However, the role of LMR as a prognostic factor in head and neck cancer was unclear in several meta-analyses, and there is a paucity of literature including patients in North America. We performed an observational cohort study to evaluate the association of LMR with survival outcomes in North American patients with head and neck cancer. Methods A single-institution, retrospective database was queried for patients with non-metastatic head and neck cancer who underwent definitive chemoradiation from June 2007 to April 2021 at the Roswell Park Comprehensive Cancer Center. Primary endpoints were overall survival (OS) and cancer-specific survival (CSS). The association of LMR with OS and CSS was examined using nonlinear Cox proportional hazard model using restricted cubic splines (RCS). Cox multivariable analysis (MVA) and Kaplan–Meier method were used to analyze OS and CSS. Pre-radiation LMR was then stratified into high and low based on its median value. Propensity scored matching was used to reduce the selection bias. Results A total of 476 patients met our criteria. Median follow up was 45.3 months (interquartile range 22.8–74.0). The nonlinear Cox regression model showed that low LMR was associated with worse OS and CSS in a continuous fashion without plateau for both OS and CSS. On Cox MVA, higher LMR as a continuous variable was associated with improved OS (adjusted hazard ratio [aHR] 0,90, 95% confidence interval [CI] 0.82–0.99, p  = 0.03) and CSS (aHR 0.83, 95% CI 0.72–0.95, p  = 0.009). The median value of LMR was 3.8. After propensity score matching, a total of 186 pairs were matched. Lower LMR than 3.8 remained to be associated with worse OS (HR 1.59, 95% CI 1.12–2.26, p  = 0.009) and CSS (HR 1.68, 95% CI 1.08–2.63, p  = 0.02). Conclusion Low LMR, both as a continuous variable and dichotomized variable, was associated with worse OS and CSS. Further studies would be warranted to evaluate the role of such prognostic marker to tailor interventions.

Background Progesterone receptor (PR)-negative tumors have been shown to have worse prognosis and were underrepresented in recent trials on patients with estrogen receptor (ER)-positive breast cancer. The role of PR-negative status in the context of 21-gene recurrence score (RS) and nodal staging remains unclear. Methods The National Cancer Database (NCDB) was queried for women diagnosed between 2010 and 2017 with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative, pT1-3N0-1a breast cancer. Logistic and Cox multivariable analyses (MVA) were performed to identify association of PR status with high RS (> 25) and overall survival (OS), respectively. Results Among 143,828 women, 130,349 (90.6%) and 13,479 (9.4%) patients had PR-positive and PR-negative tumors, respectively. Logistic MVA showed that PR-negative status was associated with higher RS (> 25: aOR 16.15, 95% CI 15.23–17.13). Cox MVA showed that PR-negative status was associated with worse OS (adjusted hazards ratio [aHR] 1.20, 95% CI 1.10–1.31). There was an interaction with nodal staging and chemotherapy ( p  = 0.049). Subgroup analyses using Cox MVA showed the magnitude of the chemotherapy benefit was greater among those with pN1a, PR-negative tumors than pN1a, PR-positive tumors (PR-positive: aHR 0.57, 95% CI 0.47–0.67; PR-negative: aHR 0.31, 95% CI 0.20–0.47). It was comparable among those with pN0 tumors regardless of PR status (PR-positive: aHR 0.74, 95% CI 0.66–0.82; PR-negative: aHR 0.63, 95% CI 0.51–0.77). Conclusion PR-negative tumors were independently correlated with higher RS and were associated with greater OS benefits from chemotherapy for pN1a tumors, but not pN0 tumors.

For a local complete intersection subvariety 𝑋 = 𝑉 (𝓘) in ℙ𝑛 over a field of characteristic zero, we show that, in cohomological degrees smaller than the codimension of the singular locus of X, the cohomology of vector bundles on the formal completion of ℙ𝑛 along 𝑋 can be effectively computed as the cohomology on any sufficiently high thickening 𝑋𝑡 = 𝑉 (𝓘𝑡); the main ingredient here is a positivity result for the normal bundle of 𝑋. Furthermore, we show that the Kodaira vanishing theorem holds for all thickenings 𝑋𝑡 in the same range of cohomological degrees; this extends the known version of Kodaira vanishing on 𝑋, and the main new ingredient is a version of the Kodaira-Akizuki-Nakano vanishing theorem for 𝑋, formulated in terms of the cotangent complex.