bluuebunny/crossref_metadata_2025_split huggingface dataset:
Erythrocyte-αPD-1 conjugates overcome resistance to checkpoint blockade immunotherapy: A first-in-human study.
Authors: Nie Xiaoqian , Yang Liu , Liu Yuehua , Chen Zheling , Gao Xiaofei 
Published: June 2024

2557 Background: While the immune checkpoint blockade (ICB) therapy has revolutionized the field of tumor therapy. the resistance remains a major challenge. We have previously developed WTX-212, an erythrocyte-antibody conjugate covalently linking anti-PD-1 antibody to erythrocyte membranes. Unlike conventional antibodies, WTX-212 exhibits natural accumulation in the spleen and remodels the splenic immune landscape in tumor-bearing mice. WTX-212 treatment efficiently activates CD8+ T cells in the spleen, which subsequently infiltrate into tumors and exhibit anti-tumor cytotoxicity. Additionally, activated T cells reduce the splenic reservoir of Myeloid-derived suppressor cells (MDSC) and those within tumors, further enhancing overall anti-tumor responses. Pre-clinical studies have demonstrated that WTX-212 can significantly suppress tumor growth in xenograft tumor models resistant to anti-PD-1 immunotherapies. A first-in-human (FIH) clinical trial is now investigating its potential in human cancer patients. Methods: The FIH trial (NCT05707325) is aimed to investigate the safety, pharmacokinetics and preliminary efficacy of WTX-212 in cancer patients with advanced malignancies. All of patients had previously received anti-PDs therapies and developed resistance to these treatments. By Feb 5th, 2024, the tumor lesions were assessed using RECIST v1.1 criteria. Blood and tumor samples were collected for correlative analysis. Results: 7 metastasized patients with various solid tumors, having undergone a median of 3.1 prior lines of therapy (ranging from 1-6), received WTX-212 monotherapy. None of patients treated with WTX-212 experienced treatment-related adverse events greater than Grade 3, indicating a high safety profile. WTX-212 was detectable in peripheral blood at the end of cycle in a dose dependent manner. Disease control was achieved in 5/7 patients (DCR=71%). Specifically, a patient with esophageal cancer, achieved a confirmed complete remission after 6-cycle treatment. Additionally, two patients, one with esophageal cancer (3L) and another with HPV-negative cervical cancer (4L), maintained stable disease for over 40 and 30 weeks, respectively. Consistent with our pre-clinical findings, a substantial reduction in MDSCs were observed in 6/7 patients (ranging from 24%-82%). Furthermore, a median 1.5-fold increase in T cells was noted in all patients in the peripheral blood after the 1st cycle of the treatment. Conclusions: WTX-212 treatment is safe and tolerable and shows promising clinical signs in cancer patients resistant to anti-PD-1 immunotherapy, supporting further investigation and exploration of WTX-212 monotherapy and combination therapy. Clinical trial information: NCT05707325 .
Transforming tumor immune microenvironments with a novel systemic enveloped oncolytic virotherapy targeting all tumor sites.
Authors: Nguyen Duong , Kang Yunyi , Streule Karolin , Songco Stephanie , Schulte Lina , Schneider Laura Edith , Alemu Selamawit Worku , Smith Trevor , Alamillo Ashley , Sy-Quia Ana , Neuharth Forrest , Minev Ivelina , Stewart Jacob , Seikkula Matthew , Minev Boris , Herrmann Thomas , Santidrian Antonio F. 
Published: June 2024

2559 Background: Systemic oncolytic virotherapy offers a promising solution for treating both local and metastatic diseases. However, the rapid inactivation of virotherapeutics by the immune system has resulted in disappointing clinical efficacy. To address this challenge, we have built a new program (ImmunoNova) to develop a cellular-based technology that protects oncolytic virotherapy, allowing for successful targeting of the therapy to tumor sites and effectively overcoming clinical challenges. This approach involves utilizing a newly selected and engineered, tumor-selective strain of vaccinia virus (RT-01). This strain produces high levels of extracellular enveloped virions (EEVs) that contain a second human cell-derived membrane, providing augmented protection against elimination by the immune system when administered systemically. The process requires specific manufacturing methods to preserve this crucial second human cellular membrane. Methods: The resistance of the manufactured enveloped RT-01 (envRT-01) virus against human humoral immunity and its rapid spread were assessed ex-vivo using a plaque assay. EnvRT-01 was administered in various xenograft and syngeneic models to evaluate its specificity in targeting tumors and its therapeutic efficacy, either alone or in combination with cell therapies. The amplification of virus-encoded RFP was monitored using an imaging system. Additionally, flow cytometry and immunohistochemistry (IHC) were employed to analyze immune infiltration in both treated and untreated tumors. Results: EnvRT-01 particles exhibited an approximately 80% survival rate in the presence of active complement. In animal studies, a single systemic dose of envRT-01 selectively targeted three distinct human cancer indications (lung, melanoma, head & neck), leading to the suppression of tumor growth in all three cases. Similarly, in an immunocompetent syngeneic lung tumor model, envRT-01 effectively targeted and reduced multiple murine lung tumors with just a low single dose of treatment. EnvRT-01 was capable of targeting and expressing viral-encoded proteins in all tumor sites and drastically modifying the tumor immune microenvironment, favoring an anti-tumor immune phenotype and facilitating other cell therapies such as innate-based cell therapies. Conclusions: The development of this innovative enveloped oncolytic virotherapeutic, coupled with advancements in its manufacturing methods, opens up new possibilities in the realm of cancer therapy. It addresses the limitations posed by untargetable and untreatable metastatic diseases, presenting a transformative solution with broad implications for the field.
Nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) as first-line (1L) treatment for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Expanded efficacy analysis from CheckMate 8HW.
Authors: Lenz Heinz-Josef , Lonardi Sara , Elez Elena , Van Cutsem Eric , Jensen Lars Henrik , Bennouna Jaafar , Mendez Guillermo , Schenker Michael , De La Fouchardiere Christelle , Limon Maria Luisa , Yoshino Takayuki , Li Jin , Manzano Jose Luis , Tortora Giampaolo , Garcia-Carbonero Rocio , Joshi Rohit , Cela Elvis , Chen Tian , Jin Lixian , Andre Thierry 
Published: June 2024

3503 Background: NIVO + IPI demonstrated superior progression-free survival (PFS) vs chemo in patients (pts) with previously untreated MSI-H/dMMR mCRC in the randomized phase 3 CheckMate 8HW study (NCT04008030). We report expanded efficacy analysis from the prespecified interim analysis of NIVO + IPI vs chemo in the 1L setting. Methods: Pts with unresectable or mCRC and MSI-H/dMMR status by local testing were enrolled across different lines of therapy and randomized 2:2:1 to NIVO (240 mg) + IPI (1 mg/kg) Q3W (4 doses, then NIVO 480 mg Q4W), NIVO (240 mg) Q2W (6 doses, then NIVO 480 mg Q4W), or chemo ± targeted therapies; treatments continued until disease progression or unacceptable toxicity (all arms) or for up to 2 years (NIVO ± IPI arms). In pts with blinded independent central review (BICR)–documented progression with chemo, crossover to NIVO + IPI was permitted. Dual primary endpoints were PFS by BICR per RECIST v1.1 for NIVO + IPI vs chemo (1L) and NIVO + IPI vs NIVO (all lines) in pts with centrally confirmed MSI-H/dMMR mCRC. PFS2 (time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death) was a key exploratory endpoint. Results: Among 303 pts randomized to NIVO + IPI (n = 202) or chemo (n = 101), 171 pts in the NIVO + IPI arm and 84 pts in the chemo arm had centrally confirmed MSI-H/dMMR. At 31.5-months (mo) median follow-up (range 6.1–48.4), NIVO + IPI demonstrated superior PFS vs chemo (HR 0.21; 97.91% CI 0.13–0.35; P < 0.0001). Subsequent systemic therapy was received by 20 (12%) and 57 (68%) pts in the NIVO + IPI and chemo arms, respectively. In the chemo arm, 56 (67%) pts received subsequent immunotherapy (39 [46%] crossed over to NIVO + IPI on study; 17 [20%] received non-study immunotherapy). Median PFS2 was not reached (NR) with NIVO + IPI and 29.9 mo with chemo (HR 0.27; 95% CI 0.17–0.44; Table). Any grade and grade 3/4 treatment-related adverse events (TRAEs) are presented (Table). Treatment-related deaths were reported for 2 pts in the NIVO + IPI arm. Conclusions: Clinical benefit with 1L NIVO + IPI vs chemo was maintained after subsequent therapy, as shown by improved PFS2 in pts with centrally confirmed MSI-H/dMMR mCRC. No new safety concerns were identified with NIVO + IPI. These results further support NIVO + IPI as a standard-of-care 1L treatment option for pts with MSI-H/dMMR mCRC. Clinical trial information: NCT04008030 . [Table: see text]
Clinical validation of Histotype Px Colorectal in patients in a U.S. colon cancer cohort.
Authors: Arole Vidya , De Raedt Sepp , Maupin Jessica , Boutros Sandra , Noonan Anne M. , Lujan Giovanni , Miller Eric David 
Published: June 2024

3622 Background: According to current guidelines, most patients with high-risk stage II and stage III colon cancer should receive adjuvant chemotherapy (ACT). However, risk determination is controversial and most patients do not benefit from ACT. Histotype Px Colorectal is a novel artificial intelligence-based biomarker validated for R0 stage II-III colorectal adenocarcinoma that analyzes digitized routine H&E-stained FFPE tumor resections. Combined with clinical parameters, patients are stratified into distinct low, intermediate, and high-risk groups. This pilot study seeks to validate the applicability of Histotype Px Colorectal in an independent cohort from the United States. Methods: This was a retrospective analysis of patients diagnosed with pathological stage II-III colon adenocarcinoma at Ohio State University from 2016-2020. Anonymized slides were collected and digitized using the Aperio AT2 scanner. Clinical parameters and outcome data were extracted from patient records. Histotype Px Colorectal biomarker was blindly applied to each scan and subsequently linked to clinical outcomes. Statistical analysis was performed using Cox proportional hazards regression analysis. The pre-specified primary outcome was cancer-specific survival with a secondary outcome of time-to-recurrence. Results: Baseline characteristics of the 159 eligible patients included median age of 63 years (range 22-91), 52% female, 52% stage III, 64% right-sided tumors, and 31% MSI. 18% of stage II and 70% of stage III patients received ACT, respectively, with FOLFOX in 61%. Median follow-up for all patients was 54.2 months. For stage II patients, 21% were classified as intermediate-risk and 79% as low-risk. Only 6 (8%) of the 76 stage II patients had a cancer-related death with 3 of those patients classified as intermediate-risk. For stage III patients, 26% were classified as high-risk, 22% as intermediate-risk, and 52% as low-risk. 18 (22%) of the 83 stage III patients had a cancer-related death with 14 of those patients classified as high or intermediate-risk. Overall, Histotype Px Colorectal was a significant predictor of cancer-specific survival with HR=7.80 (95% CI 2.96-20.56, p<0.001) for high vs. low-risk patients and 2.81 (95% CI 0.98-8.04, p=0.05) for intermediate vs. low-risk patients. In addition, it was found to be a significant predictor for time-to-recurrence with HR=7.59 (3.56-16.20, p<0.001) for high vs. low-risk patients and 2.67 (1.20-5.96, p=0.02) for intermediate vs. low-risk patients. Conclusions: The findings from this study highlight the potential utility of this innovative biomarker in guiding clinical decisions regarding ACT. Further research involving a larger and more diverse patient cohort and subsequent clinical studies are planned to solidify these initial findings and to enable personalized treatment strategies based on individual risk assessments.
Contrasting comprehensive genomic profiles of adenocarcinomas of the appendix in younger versus older patients.
Authors: Shahnawaz Myera , Mitchell Jasmine , Ross Jeffrey S. , Basnet Alina 
Published: June 2024

3626 Background: Adenocarcinoma of the appendix (AAC) is a rare form of intestinal malignancy that can pursue an aggressive clinical course. Little is known about the clinical and biologic features of this disease when it presents in young patients under 40. Methods: 1,840 cases of clinically advanced AAC were selected and analyzed by hybrid capture based comprehensive genomic profiles (CGP) to evaluate all classes of genomic alterations (GA). MSI high status and tumor mutation burden (TMB) were determined from sequencing results and PD-L1 was measured by immunohistochemistry (Dako 22C3). Results: 135 (7.3%) of the AAC were identified in patients of 39 years of age or younger (“younger”). The mean age of the younger patients was 32.9 years and for the 40 and over (“older”) patients it was 60.4 years. The slight female gender preponderance was higher in the older patients than the younger patients (Table). The GA per sample were similar. The younger patients had a significantly higher frequency of KRAS GA (71.1% vs 60.4%; p=.017) and TP53 GA (56.3% vs 41.3%; p=.0008). The KRAS G12C mutation frequency was similarly low in both cohorts. Targetable GA in BRAF and ERBB2 were infrequent in both groups as were GA in PIK3CA, PTEN and FBXW7. GA in the APC gene was significantly more frequent in the older patients (10.8% vs 3.7%; p=.007). Biomarkers of immune-oncology (IO) drug efficacy were infrequently identified in both groups including MSI-High status, TMB levels and PD-L1 expression. Conclusions: At a 7.3% incidence, AAC is a relatively infrequent form of gastrointestinal malignancy in young patients. The data analysis shows significant differences in the genomics found in younger and older patients suffering from this disease. These results can have a crucial impact on current and future clinical trials used to design novel treatments. Further exploration into this subject can change the overall approach and even treatment guidelines for this type of cancer. [Table: see text]
Personalized neoadjuvant strategy in ER positive and HER2 negative breast cancer to increase BCS rate (PLATO): A prospective, multicenter, phase II clinical trial.
Authors: Han Wonshik , Kang Eunhye , Kim Hong-Kyu , Lee Han-Byoel , KIM Jisun , Shin Hee-Chul , Kim Hyun-Ah , Kim Eun-Kyu , Son Byung Ho 
Published: June 2024

595 Background: Neoadjuvant therapy significantly enhances the likelihood of breast-conserving surgery (BCS) in breast cancer patients. However, in ER-positive and HER-2 negative breast cancer, the response to neoadjuvant chemotherapy (NCT) is not as good as HER-2 positive or triple-negative breast cancer. In addition, with the evolution of multi-gene assays, many patients of this subtype may not require adjuvant chemotherapy. This study explores the potential of tailored neoadjuvant treatments (NCT or endocrine therapy (NET)) guided by 70-gene assay (Mammaprint, Agendia) to improve BCS rates in ER-positive/HER-2 negative breast cancer. Methods: A prospective, multicenter cohort study was conducted across four Korean centers from 2019 to 2023. Participants were clinical stage II-IIIA, ER-positive/HER2-negative breast cancer patients deemed unsuitable for BCS. Suitability was further verified by an independent three-surgeon panel using mammography or MRI. Out of 130 screened patients, 100 were enrolled. We analyzed 90 patients, excluding 10 cases; 2 with a basal type or HER2 type result in the blueprint, 7 who refused neoadjuvant therapy, and 1 who underwent surgery at another hospital. Before initiation of therapy, each surgeon recorded a target tumor size at which the surgeon would be able to do BCS considering location of the tumor and patient’s breast size. Based on the 70-gene assay results from core needle biopsies, high-genomic-risk patients received NCT (anthracycline + cyclophosphamide for 4 cycles, followed by 4 cycles of docetaxel), while low-risk patients underwent 16 weeks of NET with letrozole (±leuprolide for premenopausal women). Results: Out of the patients, 66 (73%) were high-genomic-risk and underwent NCT, while 24 (27%) received NET. Median tumor size was 3.7cm (85.6% clinical T2 and 14.4% T3/4). The primary endpoint, achieving the pre-established target tumor size for BCS, was reached by 70.0% (95% CI: 59.4-79.2%) of patients, significantly surpassing the set goal of 50.8% (a 15% increase from historical control). The rates were 74.2% for NCT and 58.3% for NET. The actual BCS rate was 58.9% overall (63.6% for NCT and 45.8% for NET). Clinically, 5.6% exhibited complete response (CR), 74.4% partial response (PR), 18.8% stable disease (SD), and 1.1% progressive disease (PD). Pathologic complete response (pCR) was achieved in 2.2% (all in the NCT group). No severe adverse events beyond expectations were observed. No pre-treatment clinical or pathological factor was significantly predictive for the BCS conversion. Conclusions: For ER positive, HER2 negative breast cancer patients initially ineligible for BCS, the use of pre-treatment multi-gene assays to guide selective NCT or NET could substantially increase BCS rates and reduce unnecessary chemotherapy. Clinical trial information: NCT03900637 .
Ten-year outcomes of targeted axillary surgery after neoadjuvant chemotherapy in breast cancer.
Authors: Lee Jeeyeon , Park Junhyun , Kang Byeongju , Jung Jin Hyang , Keum Heejung , Kim Hye Jung , Kim Won Hwa , Chae Yee Soo , Lee Soo Jung , Lee In Hee , Park Ji-young , Park Jee-Young Nora , Park Ho Yong 
Published: June 2024

600 Background: When pathological complete response (pCR) is achieved in node-positive breast cancer after neoadjuvant chemotherapy (NAC), identifying traces of the previous lesion becomes challenging which makes accurate surgery difficult. We conducted targeted axillary surgery (TAS) in node-positive breast cancer after NAC, which involves accurately targeting the lymph nodes where metastasis occurred and performing surgery using a less extensive method. The 10-year outcomes were compared with those of patients who underwent conventional axillary lymph node dissection (ALND). Methods: We conducted a retrospective analysis of 235 patients with cT1-3N1-2 breast cancer who received NAC from 2012 to 2017. In this cohort, 78 patients underwent TAS only, and 157 underwent conventional ALND, including 31 patients who initially received TAS followed by additional ALND. Oncologic results, including locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and overall survival (OS), were assessed over a 10-year follow-up period. Survival outcomes for all patients and each subtype were analyzed using Kaplan-Meier survival methods. Results: The TAS group had significantly more postmenopausal patients (p=0.022), and the most common type of breast cancer was invasive ductal carcinoma [TAS: 75 (96.2%); ALND: 157 (100.0%)]. There was no statistical difference in the T stage and the number of lymph nodes suspected of metastasis at diagnosis (p=0.062, 0.985). Mastectomy was performed in 60.3% of patients in the TAS group and 93.0% in the ALND group (p<0.001), and 68 (87.2%) of the TAS group and 41 (26.1%) of the ALND group received additional axillary radiotherapy (p=0.019). There was no significant difference in oncologic outcomes between the TAS and ALND groups in all patients (LRFS, p=0.673; DMFS, p=0.729; OS, p=0.396) and based on subtypes, including hormone receptor (HR)-positive, HER2-positive, and triple-negative breast cancer (TNBC). In the HR-positive breast cancer group, the TAS and ALND groups showed very similar trends (LRFS, p=0.954; DMFS, p=0.993; OS, p=0.617). In HER2-positive breast cancer, although not statistically significant, the survival outcomes were better in the TAS group than in the ALND group (LRFS, p=0.967; DMFS, p=0.999; OS, p=0.423). However, the OS in the TAS group for TNBC was lower than that in the ALND group, though not significantly (LRFS, p=0.411; DMFS, p=0.697; OS, p=0.210). Conclusions: This study demonstrates that TAS is comparable to ALND in terms of 10-year oncological outcomes across different types of node-positive breast cancer, suggesting its potential as a viable alternative. However, further research focusing on patient quality of life and postoperative complications is essential to establish TAS as a superior surgical option to ALND.
Pretreatment neutrophil to lymphocyte ratio as a predictor of pathological complete response to neoadjuvant immunotherapy in early breast cancer.
Authors: Du Tian , Wang Yan , Zhao Zixuan , Chen Yuhong , Deng Rong , Tang Jun 
Published: June 2024

e12545 Background: Neoadjuvant immunotherapy has been increasingly used in early breast cancer, while lack of accessible predictive biomarkers of response remains an open question. High pretreatment neutrophil to lymphocyte ratio (NLR) was associated with worse prognosis and treatment responses to neoadjuvant chemotherapy in multiple cancers including breast cancer. However, it remains unclear whether NLR was associated with response to neoadjuvant immunotherapy in early breast cancer. Methods: We retrospectively analyzed 89 early breast cancer patients who received neoadjuvant chemotherapy in combination with at least 4 cycles of immunotherapy and subsequent breast surgery in Sun Yat-sen University Cancer Center. Pretreatment NLR was calculated, and Miller-Payne grade 5 in primary tumor site was considered pathological complete response (pCR) to neoadjuvant therapy. Univariate and multivariate analyses were used to evaluate the associations between clinicopathological markers and pCR. Results: 49.4% (44/89) of the patients achieved pCR. Compared to non-pCR patients, pCR patients had significantly lower pretreatment NLR (1.93 vs 2.87, p<0.001) and lower percentage of pretreatment cT3/T4 stage (11.4% vs 37.7%, p=0.006), and received more cycles of neoadjuvant immunotherapy (6.5 vs 6.0, p<0.05). More pCR patients received TCb based neoadjuvant therapy (86.4% vs 51.1%, p<0.001). In multivariate analysis, the pretreatment NLR (p=0.002) and cT3/T4 (p=0.010, as compared to cT1/T2) were independent predictive factors for pCR. Conclusions: Lower pretreatment NLR was associated with higher possibility of achieving pCR in early breast cancer treated with neoadjuvant immunotherapy. [Table: see text]