tbuckley/cabot-search huggingface dataset:
Hypoxia-responsive synthetic gene circuits to improve safety and potency of CAR T cell therapy for solid tumors.
Authors: Yannick Schreiber, Joshua Leonard
Journal: Journal of Clinical Oncology (2024)

37 Background: Engineered cell therapies expressing a chimeric antigen receptor (CAR) in human T cells have demonstrated great promise for the treatment of hematological malignancies. However, unique challenges remain in translating the success of CAR T cell therapies to solid tumors, namely: (1) specificity: there are few truly unique antigens present on solid tumors, leading to off-target effects that damage normal tissue and pose safety risks; and (2) suppression: solid tumors develop microenvironments that are immunosuppressive and decrease T cell survival and tumor-directed cytotoxicity. To address these challenges and improve the safety and potency of solid tumor cell therapy, we engineered cells with synthetic genetic circuits containing a previously validated hypoxia biosensor (HBS) that responds to upregulation of the native HIF1α and HIF2α transcription factors by hypoxia, enabling the cells to sense and respond to the hypoxic tumor microenvironment ubiquitous among solid tumors. Methods: We evaluated CAR expression from circuit architectures containing the HBS promoter driving expression of both CAR and native HIF1α, HIF2α, as well as from circuit architectures containing the HBS promoter and our toolkit of synthetic transcription factors and promoters. Circuits were integrated into HEK293 cells via PiggyBac transposon vector to generate stable cell lines. Cells were subsequently cultured in normoxia (21% O 2 ) and hypoxia (1% O 2 ), and harvested for flow cytometric analysis to evaluate CAR surface expression across a three day time frame. Results: We identified novel circuits providing fast reporter output with minimal background signal under hypoxic conditions, and elucidated design rules that enable or restrict amplification of transgene in native HIF1α and HIF2α-containing circuits. We observed differences in CAR transgene expression in hypoxia between circuits containing HIF1α and HIF2α-mediated feedback, suggesting mechanistic differences in regulation of HIF1α and HIF2α when overexpressed. Additionally, we observed greatly amplified transgene expression in circuit topologies containing feedback mediated by our synthetic transcription factor and promoter toolkit compared to native HIF1α and HIF2α-containing circuits and cells constitutively expressing CAR. Conclusions: We present a new therapeutic technology that senses hypoxic environments and enables high-output sense and respond behaviors with therapeutic outputs. We envision that this technology will enable development of safer, more effective cell therapies for solid tumors, as well as provide new biological and mechanistic insights that can inform the future development of hypoxia-responsive cell therapies.
<sup>68</sup>Ga-FAPI-04 positron emission tomography/computed tomography (PET/CT) for detecting occult peritoneal metastasis in locally advanced gastric cancer: A single-center prospective cohort study.
Authors: Qiancheng Hu, Shunyu Zhang, Ming Gang Su, Kun Yang, Hongfeng Gou, Jiankun Hu
Journal: Journal of Clinical Oncology (2024)

61 Background: Occult peritoneal metastasis (OPM) is a common finding in patients diagnosed with advanced gastric cancer. Preoperative diagnosis of OPM is crucial for developing treatment strategies and for evaluating the prognosis of patients with locally advanced gastric cancer. To evaluate the accuracy of 68 Ga-FAPI-04 PET/CT in diagnosing OPM in locally advanced gastric cancer. Methods: This was a prospective, observational, single-center, single-blind, cohort study. Patients with histologically proven locally advanced gastric or gastroesophageal junction adenocarcinoma on initial staging evaluation were recruited. Laparoscopic staging and cytological analysis of peritoneal washing served as reference standards for the final diagnosis. The primary outcome was the proportion of participants changing treatment strategy from curative to palliative treatment. Results: A total of 49 patients were recruited between November 2022 and July 2023 . Nine of the 49 patients were diagnosed with OPM following 68 Ga-FAPI-04 PET/CT examinations. A total of 18.4% (n=9) of patients with locally advanced disease on initial staging evaluation by contrast-enhanced CT were upstaged to stage IV for peritoneal metastasis on 68 Ga-FAPI-04 PET/CT. The sensitivity of 68 Ga-FAPI-04 PET/CT in detecting OPM was 85.7%, and the specificity was 92.3%. The overall diagnostic accuracy of 68 Ga-FAPI-04 PET/CT was 91.8%. Based on ROC curve analysis, the area under the curve (AUC) was 0.893 (95% CI: 0.734–1). Conclusions: The findings of this study suggest a significantly additional value of 68 Ga-FAPI-04 PET/CT in detecting OPM. Thus, it would be useful to include 68 Ga-FAPI-04 PET/CT in the guidelines for staging locally advanced gastric cancer, instead of laparoscopic staging. Clinical trial information: ChiCTR2300067591 .
Circulating tumor DNA analysis in patients with esophageal cancer treated with neoadjuvant chemoradiotherapy followed by surgery.
Authors: Mian Xie
Journal: Journal of Clinical Oncology (2024)

69 Background: The aim of this prospectively study is to investigate circulating tumor DNA (ctDNA) as a prognostic marker for survival in locally advanced esophageal squamous cell cancer (ESCC) patients treated with neoadjuvant chemoradiotherapy (nCRT) and surgery. Methods: Serial plasma samples were collected from 68 ESCC patients treated with neoadjuvant chemoradiotherapy before surgery. ctDNA was detected before treatment, after neoadjuvant chemoradiotherapy and after surgery by personalized, next-generation sequencing assay. Cox regression analyses were used to evaluate the prognostic significance of ctDNA for recurrence-free survival (RFS) and overall survival (OS). Results: ctDNA was detectable in 89.7%, 17.2%, and 6.9% of pretreatment, post-neoadjuvant chemoradiotherapy and post-surgery plasma samples, respectively. The conversion of ctDNA status from positive at baseline to negative at 4-6 weeks after neoadjuvant chemoradiotherapy was significantly associated with pathological complete response (pCR) ( P = 0.02). Significant worse RFS was related to detectable ctDNA after neoadjuvant chemoradiotherapy ( P = 0.008) or after surgery ( P = 0.001). Detectable ctDNA at baseline ( P = 0.01) and after surgery ( P = 0.008) were associated with worse OS. In multivariate analysis, detectable postoperative ctDNA was significantly associated with RFS ( P = 0.012) and OS ( P = 0.025) after adjusting for other clinicopathological risk factors. Conclusions: ctDNA status is a strong prognostic factor of recurrence in locally advanced ESCC patients. Consequently, ctDNA could potentially improve pre- and post-treatment risk assessment and facilitate individual therapy for ESCC patients.
The prognostic value of deep learning-based percentage of tumour-infiltrating lymphocytes in nasopharyngeal carcinoma.
Authors: Tianzhu Lu, Fei Xie, Shenghua Zhan, Yujun Hu, Fangyan Zhong, Junjun Chen, Jian-ji Pan, Xiaopeng Xiong, Shaojun Lin, Xiaochang Gong, Shaojun Lin, Qiaojuan Guo, Melvin L.K. Chua, Jingao Li
Journal: Journal of Clinical Oncology (2024)

133 Background: To calculate the percentage of tumor-infiltrating lymphocytes (TILs) in nasopharyngeal carcinoma (NPC) using deep-learning (DL) algorithms based on digital pathology images and differentiate the outcome. Methods: We recruited 435 patients with primary non-metastatic NPC and 63 patients with de novo metastatic NPC received immunotherapy. TIL DL percentage was calculated using the convolutional neural network model, and its ability to differentiate metastasis risk and independent prognostic value were analyzed using Kaplan–Meier survival and multivariate analyses (MVA). Results: The median follow-up time of the training and validation cohorts was 69, and 76 months, respectively. Kaplan–Meier survival analysis showed that the 5-year distant metastasis-free survival (DMFS) and overall survival (OS) of patients with high TIL DL were significantly better than those of patients with low infiltration. MVA showed that TIL DL degree is an independent prognostic factor for DMFS (training cohort: HR=0.197, 95% CI: 0.077-0.503, p=0.001; validation cohort: HR=0.119, 95% CI: 0.028-0.503, p=0.004) and OS (training cohort: HR=0.418, 95% CI: 0.200-0.873, p=0.020; validation cohort: HR=0.158, 95% CI: 0.048-0.520, p=0.002). The concordance index (C-index) of TIL DL was higher than that of the immunohistochemical CD3+, CD8+ T-cell, and CD20+ B-cell densities in terms of the DMFS and OS prediction accuracy. In an immunotherapy cohort of de novo metastatic NPC (n=63), MAV revealed that high TIL DL percentage were an independent prognostic factor for PFS (HR=0.368, p= 0.008). Conclusions: TIL DL percentage exhibited discriminative capabilities regarding the risk of metastasis and mortality in non-metastatic NPC, and has potential to be a biomarker for dmNPC received immunotherapy. This model will help select patients with a high risk of metastasis and provides a reference for improved individualized treatment.
Addressing ovarian cancer research gaps in under-resourced settings using individual initiatives: The OVANORDEST pilot project in Morocco.
Authors: Khalid El Bairi
Journal: Journal of Clinical Oncology (2024)

183 Background: In Morocco, ovarian cancer (OC) is a neglected women’s cancer. To bridge this gap, early-career cancer researchers might develop and engage in individual initiatives to enhance research outcomes. In this perspective, I recently launched the OVANORDEST project as an individual initiative. This plan outlines a three-step strategy designed to promote OC research, highlighting specific milestones. This abstract presents the findings from the initial feasibility study, which focuses on real-world evidence, implementing inexpensive precision medicine approaches, supporting women in oncology, and enhancing meta-research. Methods: Initially, a bibliometric study was conducted to find research gaps in the field of OC in Morocco. A 16-year real-world retrospective study was conducted at the Hassan II Oncology Center (October 2005-June 2020). To implement precision medicine approaches, quality evidence on several potentially inexpensive blood-based biomarkers such as Pan-Immune Inflammation-Value (PIIV) were explored using a PROSPERO-registered umbrella systematic review and then investigated in an original cohort. Cox regression analyses were applied to identify the effects of different biomarkers on survival outcomes. Meta-research was developed by publishing two special thematic issues and one edited book on OC biomarkers. The project also included a mentorship program designed to empower women oncologists. Results: A total of 258 patients with OC were included. Most patients had advanced FIGO stages at diagnosis. The median overall survival (OS) for the entire cohort was 32 months, with a median progression-free survival (PFS) of 14.6 months. CA-125 positivity, advanced disease stage, and presence of residual disease after surgery were prognostic factors that adversely affected survival. In the multivariable analysis after adjustment for the FIGO stage, high PIIV was an independent predictive factor of OS (HR= 1.83; 95% CI: 1.18-2.84, p=0.007). Two specialized thematic issues were published alongside a book dedicated to ovarian cancer biomarkers. Additionally, careers of a group of women oncologists were boosted and a local patient advocacy group was supported in adopting supportive strategies for patients. Conclusions: Engaging early-career cancer researchers through individual initiatives in under-resourced settings may considerably improve research outcomes. In this context, I propose that sharing this experience, which has been successfully applied in Morocco, could empower health systems and facilitate the generation of research outputs in low- and middle-income countries.
Evaluating interaction between tumor educated platelets and cancer stem cells on breast cancer subtypes.
Authors: Aishwarya Guha, Jasmine Sultana, Avishek Bhuniya, Mohona Chakravarti, Saurav Bera, Anirban Sarkar, Sukanya Dhar, Juhina Das, Nilanjan Ganguly, Tapasi Das, Neyaz Alam, Indranil Ghosh, Srabanti Hajra, Anamika Bose, Rathindranath Baral, Saptak Banerjee
Journal: Journal of Clinical Oncology (2024)

5 Background: Thrombocytosis has been reported to be responsible for poor prognosis of numerous malignancies. This swarm of platelets acts as foe for the body but as mate for the cancer cells by providing a protective shield around them, helping them to escape immunosurveillance process. A bidirectional interaction between platelets and tumor cells promote their conversion to an activated tumor educated platelet (TEP) state. The present report reveals the critical role played by TEPs to promote metastasis in BC subtypes by interacting with cancer stem cells (CSCs). Methods: Status of intra-tumoral and humoral TEPs (CD41 + /CD62P + ) was screened in luminal A (LumA) and triple negative (TNBC) BC subgroups. The impact of TEPs on lin - /CD44 + /CD24 - CSCs of both the categories in-vitro, was deciphered by performing mammosphere assay, clonogeneic and migration assays, with final validation in murine system. Effect on various genes and proteins related to stemness, metastasis and angiogenesis as a result of this interaction was elucidated by RT-PCR, flow cytometry and western blotting. Results: High percentage of TEPs in the peripheral blood is a potential biomarker and responsible for poor prognosis in BC subtypes. Both Lum A and TNBC patients had elevated TEP frequency, compared to healthy blood. Further, patients in the pre-carcinogenic stage had platelet count of &gt;3.5 lakhs. Additionally, screening of breast tumor sections revealed intra-tumoral enrichment of TEPs, comparatively to a greater extent in TNBC than LumA, supporting their role in disease aggression. Also, a positive correlation was noted between TEP and CSC frequencies proving their synergistic interactions. Moreover, in-vitro, TEP influenced CSCs exhibited enormous clonogenic and tumorigenic potentialities. Their metastatic nature was confirmed by their enhanced migratory, invasive, angiogenic capacities with higher VIMENTIN and TWIST along with HIF1α, CD31 and MMP9 expression compared to E-CADHERIN. In line with in-vitro observations, in-vivo too, TEP~CSC produced metastatic colonies in murine lungs. Upon investigation, it was disclosed that it is through WNT-βcatenin-VEGFR2 axis that this mutual interdependency was functioning. Conclusions: This study advocates for the importance of TEPs as potential biomarker in BC diagnosis. Their alliance with vicious CSCs to promote disease advancement acquiesce them as a novel restorative agent.
Effect of ZCRB1 on the glycolysis via PKM2-HIF1α axis and promotion of immune tolerance in nasopharyngeal carcinoma.
Authors: Gengde Hong, Meng-Yao Wang, Dong-ping Chen
Journal: Journal of Clinical Oncology (2024)

130 Background: Nasopharyngeal carcinoma (NPC) is characterized by abundant lymphocyte infiltration. The failure of immune checkpoint inhibitors in NPC may be related to immune tolerance. Methods: Bioinformatics analysis was performed to identify the correlation between the ZCRB1 mRNA level and immune cell infiltration in NPC tissues. Quantitative real time PCR and immunoblotting were used to determine the mRNA and protein expression, respectively. Functional experiments (CCK8, colony formation assay, cell migration assay and tumor xenograft) were used to explore the effect of ZCRB1 on the malignant phenotype in NPC cells. Glucose and lactate measurement assays as well as Seahorse XF glycolysis stress assay, were conducted to investigate the effects of ZCRB1 on glycolysis in NPC cells. RNA sequencing, QPCR and minigene analysis were used to confirm the splicing switch between PKM1 and PKM2. Luciferase assay was performed to detect the transcription activity of HIF1-α. Finally, correlation analysis between the ZCRB1 expression and glycolysis level was performed to in NPC samples. Results: The expression of ZCRB1 was negatively correlated with checkpoint-related genes and immune regulation-related gene sets in head and neck cancer. Likewise, in NPC, the expression of ZCRB1 was negatively correlated with lymphocyte infiltration, tumor immune microenvironment score and tumor-infiltrating CD4+ T cells, CD8+ T cells, and dendritic cells. Low expression of ZCRB1 was associated with better prognosis. Functional assays demonstrated that ZCRB1 significantly promoted NPC cells growth, clonogenicity, migratory capacity and glycolysis. Mechanistically, ZCRB1 was mainly involved in the hypoxic signaling pathway. Cells with ZCRB1 downregulation downregulated glycolysis-related genes and significantly reduced the transcriptional activity of HIF-1α. Moreover, minigene assays showed that the intron 9 region spliced by PKM in cells with ZCRB1 downregulation. Finally, bioinformatics analysis showed that the mRNA expression of ZCRB1 was positively correlated with the immune infiltration score significantly during glycolysis. Conclusions: ZCRB1 promotes the growth and migration of nasopharyngeal carcinoma cells and is associated with immune tolerance. Further, ZCRB1 accelerates the glycolysis via enhancing the transcriptional activity of HIF-1α through increasing PKM2 isoform splicing, providing a scientific basis for tumor metabolic reprogramming to reshape the immune microenvironment.
Mortality and economic cost in common primary cancer admitted with COVID-19: Analysis of NIS 2020.
Authors: Thanathip Suenghataiphorn, Phuuwadith Wattanachayakul, Thitiphan Srikulmontri, Narathorn Kulthamrongsri, Nutchapon Xanthavanij, Narisara Tribuddharat, Kochakorn Buasri, Pojsakorn Danpanichkul, Sakditad Saowapa, Tuntanut Lohawatcharagul, Soravis Alm Osataphan
Journal: Journal of Clinical Oncology (2024)

182 Background: Recent data showed the detrimental effects of COVID-19 infection on various conditions, resulting in a wide range of health disparities and worsening outcomes, as well as an increased burden of cost. However, limited information exists on the impacts of COVID-19 infection on the most commonly admitted with primary cancer, regarding clinical and economic impact. Methods: We analyzed the 2020 U.S. National Inpatient Sample (NIS) to investigate the effects of COVID-19 infection on cases primarily admitted with the most common admitted with primary cancer, using relevant ICD-10 CM codes. Adjusted odds ratios (aORs) for specified outcomes were calculated through multivariable logistic and linear regression analyses. The primary outcome was inpatient mortality, with secondary outcomes including the cost of hospitalization and length of stay. Statistical significance was established at a p-value of 0.05. Results: We estimated 919,104 hospitalizations with a primary discharge diagnosis of cancer conditions. Of these, 0.54% (4,985/919,104) had a concurrent diagnosis of COVID-19 infection and 46.1% were female. The mean age was 63.6 years old and Caucasians dominated the majority of the records (69.7%), followed by Hispanics (13.1%). In a multivariable logistic and linear regression model adjusting for patient and hospital factors, COVID-19 infection was associated with higher in-hospital mortality for all cancer conditions and other outcome. The txable denotes all-type and subpopulation analysis. Conclusions: In conclusion, our study encompasses all most common admitted primary cancer conditions and shed light how COVID-19 infection is associated with higher in-hospital mortality, prolonged hospital stays, and increased economic burden in various condition. Future longitudinal studies are warranted to comprehensively assess the long-term health sequelae in this population. [Table: see text]
Therapeutic response and outcomes with uncommon breast cancer subtypes in the I-SPY trial 2010-2022.
Authors: Alexandra Thomas, Denise M. Wolf, Ronald Balassanian, Yunn-Yi Chen, Julia Ye, Poonam Vohra, Evin H. Gulbahce, Alexander D. Borowsky, Lamorna Brown Swigart, Gillian L. Hirst, Sara Venters, Rita Nanda, Rebecca Arielle Shatsky, Ralph D'Agostino, Rita A. Mukhtar, Sarah Hatcher, Christina Yau, Angela DeMichele, Laura van 't Veer, Laura Esserman
Journal: Journal of Clinical Oncology (2024)

1 Background: Uncommon histologies are over-represented among high-risk breast cancer (BC) and denote an area with limited trial data and of significant unmet medical need. To better understand trial outcomes in this group and identify signals of tumor responsiveness, we report pathologic complete response (pCR) and early event-free survival (EFS) by disease subtype in the I-SPY2 trial. Additionally, the I-SPY2 trial currently utilizes a combination of tumor molecular signature and receptor status to determine response predictive subtype (RPS) first developed from 987 I-SPY2 patients [Wolf et al, Cancer Cell 2022]. We report disease response rates for those who received what is now known to be optimal RPS guided therapy. Methods: The I-SPY2 platform trial tests novel agents given neo-adjuvantly with a chemotherapy backbone in high-risk BC (HER2 positive, triple negative and high molecular risk estrogen receptor positive BC). Histologic images of research biopsies, local biopsy and surgical pathology reports were reviewed centrally by I-SPY pathologists. Receptor subtype distribution and pCR rates were summarized; and EFS was estimated using the Kaplan Meier method. Association between pCR and EFS was evaluated using the Cox proportional hazard model with significance assessed by the log rank test. Results: 144/2118 (7%) of I-SPY2 participants were identified with metaplastic (60), lobular (55), mucinous (9), micropapillary (8), neuroendocrine (4) and other (8) BCS. Tumor receptor status, pCR rate and EFS by tumor type are shown in the Table. For the full cohort, pCR was associated with better EFS (hazard ratio (95% CI): 0.12 (0.02 - 0.88), p = 0.01). Within metaplastic (metapBC) 11/32 (34%) and 5/28 (18%) patients had a pCR with or without checkpoint blockade, respectively. By RPS group, 9 of 18 (50%) (13 metapBC, 3 other, 2 lobular) in the HER2-Immune+ group who received RPS optimized therapy had a pCR. In this group 6/13 (46%) with metapBC had a pCR. In the HER2+ driven RPS groups, pCR rate in the HER+HER2orBasal was 88% (7/8) and 0% (0/3) in the HER2+Luminal. Conclusions: High pCR rates observed in metapBC and other among subsets of often difficult to treat BC subtypes support novel approaches and provide a roadmap for future study of uncommon BCs. Outcomes were improved when therapy matched RPS vulnerabilities. Participants presenting with uncommon BC subtypes will be prospectively identified in the I-SPY2.2 trial to further develop effective approaches for this group. Clinical trial information: NCT01042379 .[Table: see text]