bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of a CCR8 monoclonal antibody to block CCR8 signaling and to abolish the immunosuppressive function of Treg for the treatment of cancers.
Authors: Fan Guohuang , Wang JianFei , Wang Zhilong , Zhang Yong , Zhang Yuanyuan , Tian Binle 
Published: June 2023

e14506 Background: The tumor microenvironment (TME) contains regulatory T (Treg) cells, which play a critical role in immunosuppression and are thus an attractive target for cancer therapy. The ideal approach would be to inhibit Tregs within tumors while sparing those in peripheral and normal tissues. Tumor-associated Tregs express the chemokine receptor CCR8, which is involved in the induction, expansion, migration, and immunosuppression of Tregs, making targeted inhibition of CCR8 signaling a potential therapeutic strategy against cancer. Methods: We have developed IPG0521, a monoclonal antibody antagonist of CCR8, and characterized its properties, including signaling blocking, chemotaxis, species cross-reactivity, anti-tumor efficacy, and synergistic antitumor effect with PD1 antibody. Single-cell RNA sequencing with CD45+ cells isolated from tumors treated with or without IPG0521 was also employed for profiling the mechanism of the antitumor effect of IPG0521 in the murine H22 cancer model. Results: IPG0521 inhibits receptor-mediated signaling and chemotaxis in Treg cells with a single-digit nanomolar IC50. It is cross-reactive in five species: mouse, rat, dog, monkey, and human. IPG0521 has shown excellent anti-tumor efficacy in several murine syngeneic cancer models, and its anti-tumor effect is enhanced when combined with a PD-1 antibody. Its sustained anti-tumor efficacy has been demonstrated in the murine H22 cancer model via even withdrawing the antibody during the study. The results of deep single-cell RNA sequencing on tumor-infiltrating lymphocytes (TILs) showed that the transcriptional profiles of these Treg cells could be distinguished into three distinct subsets based on molecular, functional, and immunosuppressive properties. These subsets were defined as the Treg_Foxp3 high subset, which exhibited low immunosuppression, the Treg_Foxp3 mild subset, which demonstrated mild immunosuppression, and the Treg_Foxp3 low subset, which had high proliferation. IPG0521 treatment resulted in a significant increase in the Treg_ Foxp3 high subset and a significant decrease in the Treg _ Foxp3 mild subset while no change in the Treg_ Foxp3 low subset, indicating a reduction in Treg immunosuppression. This change in Treg cells also altered the composition of other immune cells, including a significant increase in neutrophils and natural killer (NK) cells, which ultimately inhibited tumor growth. Conclusions: IPG0521 has potent anti-tumor effects in multiple tumor types, including lung, liver, and breast cancers, in both syngeneic and immune-humanized mouse models. It inhibits Tregs immunosuppression and activates CD8+ T cells to achieve its anti-tumor effects. These results support the development of IPG0521, which is currently under IND filing, as a novel therapeutic agent for the treatment of cancers.
In vivo anti-tumor effects of XON7 in association with ICIs.
Authors: Ciron Carine , Duvaux Odile , Shneiker Françoise 
Published: June 2023

e14520 Background: The advent of immune checkpoint inhibitors (ICIs) has rapidly transformed the treatment paradigm for multiple cancer types. This remarkable shift has been driven in large part by unprecedented durability that is characteristic of ICIs responsiveness. However, ICIs promote tumor cell immune escape; indeed, the response rate to single agent PD-1 blockade in unselected patients ranges from 40 to 70% in some diseases, while the response rates in most other approved diseases is limited to 10–25%. These observations support the need to strengthen immunotherapy and bring additional benefits for patients. XON7, is a glyco-humanized polyclonal antibody (GH-pAb) targeting multiple tumor antigens and active in vitro and in vivo in several solid tumors and hematological malignancies. Methods: A human lung carcinoma chorio-allantoic membrane (CAM) model was used to evaluate the efficacy of XON7 + anti PD-1 treatment. Fertilized white Leghorn eggs were incubated until Day 9, then inoculated in the upper CAM with 1.106 H460 cells. Treatments were administrated at E10, E12, E14, E15 and E17. Two groups were included: control group (n=20) received a non-immune GH-pAb + anti-PD-1 (10 mg/kg + 2,5 mg/kg respectively); treated group (n=20) received XON7 and anti-PD-1 at the same doses. Upper CAM, lower CAM and brain were collected from the embryos at E18. Tumor growth was evaluated by tumor weight using one-way ANOVA. Metastasis were quantified by qPCR for Alu sequences. Immune cell infiltration was analyzed by RT-qPCR with specific primers for chicken CD3, CD4 and CD8 sequences, with GAPDH as reference gene expression. Results: Significant reduction in tumor growth (~30%, p=0.02) and metastasis (>90%, p=0.001) was observed in both the brain and the lower CAM in the XON7+ICI group compared to control group. No differences in lymphocyte infiltrates (CD3, CD4, and CD8) were observed between groups. However, a significant increase in the M1/M2 ratio was observed in the XON7 + anti-PD-1 group over control. No toxicity from the treatment appeared in this model. Conclusions: In vivo data showed a significant increase of response rate and decrease of metastasis when XON7 is associated with anti PD-1. Combination of GH-pAb with ICI could constitute an immunotherapy combination likely to overcome resistance to anti-PD1.
The SPEARHEAD-1 trial of afamitresgene autoleucel (afami-cel [formerly ADP-A2M4]): Pooled analysis of cytokine release syndrome across cohorts in patients with advanced synovial sarcoma.
Authors: D'Angelo Sandra P. , Ganjoo Kristen N. , Blay Jean-Yves , Valverde Claudia , Araujo Dejka M. , Abdul Razak Albiruni Ryan , Le Cesne Axel , Schuetze Scott , Wagner Michael J , Attia Steven , Forcade Edouard , Druta Mihaela , Pollack Seth , Bai Jane , Lunt Colin , Sun Amy , Yule Murray , McAlpine Cheryl , Williams Dennis , Van Tine Brian Andrew 
Published: June 2023

e14531 Background: Afami-cel is an autologous, T-cell receptor T-cell therapy engineered to target melanoma-associated antigen A4 (MAGE-A4) in human leukocyte antigen (HLA) A*02–eligible patients (pts) with advanced solid tumors. SPEARHEAD-1 (NCT04044768) is a Phase 2, two cohort, open-label trial to evaluate the efficacy and safety of afami-cel in pretreated pts with advanced/metastatic synovial sarcoma or myxoid/round cell liposarcoma. Here we report data on cytokine release syndrome (CRS) in the pts with advanced synovial sarcoma treated with afami-cel across Cohort 1 and Cohort 2. Methods: Eligible pts had advanced synovial sarcoma and were HLA-A*02 positive with MAGE-A4–positive tumors. Pts received afami-cel after lymphodepleting chemotherapy containing fludarabine and cyclophosphamide. Tocilizumab administration was permitted for Grade 1 CRS if symptoms persisted for ≥ 24 hours or if the pt had co-morbidities, and for Grade ≥2 CRS. Results: As of August 29, 2022, 72 pts with synovial sarcoma received afami-cel (n = 44 Cohort 1; n = 28 Cohort 2). Afami-cel dose range was 1.92–10.00×109 transduced T-cells. The median age was 39.5 years (range: 16–73 years), 47.2% of pts were female, 88.3% of pts were white, and tumor MAGE-A4 expression H-score was 244.5 (range: 66–300). CRS occurred in 72.2% of the pts with synovial sarcoma receiving afami-cel, including Grade 1 in 50% (36/72), Grade 2 in 20.8% (15/72), and Grade 3 in 1.4% (1/72) of pts as per American Society for Transplantation and Cellular Therapy grading. The median time to onset was 2.5 days (range: 1–5 days), and the median time to resolution was 3 days (range: 1 to 14 days). Twenty-seven of 72 (37.5%) pts received at least one dose of tocilizumab. Consistent with expectations, higher serum IL-6 levels were associated with CRS events and the indicated use of tocilizumab for management. RECIST v1.1 responses were observed in pts with and without CRS. Correlation of clinical factors and CRS with response will be presented. Conclusions: CRS was common after afami-cel administration but was mostly low grade. Administration of tocilizumab in SPEARHEAD-1 was effective in the management of CRS. Clinical trial information: NCT04044768 .
Association between bispecific T cell engager (BiTE) therapy and inflammatory adverse effects (AEs) in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Xu Michael , Wummer Brandon , Kelly William Kevin , Bashir Babar 
Published: June 2023

e14534 Background: Cancer immunotherapies have offered limited efficacy in treating mCRPC. A novel class of immunotherapy are BiTEs, which target both a specific cancer antigen and CD3 to enhance T cell anti-tumor activity. Although BiTEs are a promising avenue for cancer research, their safety profiles are not well-understood. Thus far, it is known that first-in-class blinatumomab is associated with AEs such as cytokine release syndrome, neurotoxicity, and febrile neutropenia. Given their mechanism of action and possible propensity to produce a general inflammatory environment, we aimed to explore the systemic and inflammatory AEs of BiTEs in mCRPC patients. Methods: A retrospective chart review was performed on an IRB-approved database. Inclusion criteria included a history of mCRPC and BiTE therapy. There were no exclusion criteria. Study objectives were to evaluate whether BiTE therapy led to de novo inflammatory AEs or exacerbation of pre-existing inflammatory disorders. AEs were defined/graded as immune system disorders per Common Terminology Criteria for Adverse Effects v5.0. Results: 24 mCRPC patients in our clinic received at least 1 dose of BiTE therapy. Mean (range) age was 67.3 (54-79) years. 5 (20.8%) had pre-existing inflammatory disorders. Mean (range) treatment course was 14 (0-44) weeks. 6 (25.0%) discontinued due to inflammatory AEs, 15 (62.5%) discontinued due to disease progression, 1 (4.2%) discontinued due to noncompliance, and 2 (8.4%) are currently on BiTE therapy. Notable de novo AEs included arthralgia (8.4%), thrombophlebitis (8.4%), myocarditis (4.2%), giant cell arteritis (4.2%), and pneumonitis (4.2%). Patients with pre-existing inflammatory conditions (5/5) were statistically more likely to develop inflammatory AEs after BiTE therapy initiation compared to those without (4/19) (p < 0.01). Of the 9 patients who developed inflammatory AEs, 6 (66.7%) developed inflammatory AEs after the first dose of BiTE therapy. After the first dose, mean C-reactive protein was significantly elevated in patients with pre-existing inflammatory conditions (10.0) compared to those without (1.6) (p = 0.041). Conclusions: Our analysis suggests that BiTE therapies are associated with inflammatory AEs other than cytokine release syndrome, neurotoxicity, and febrile neutropenia. In particular, some of our patients developed vasculitis, myocarditis, or pneumonitis. Furthermore, patients with pre-existing inflammatory conditions are at significantly greater risk of developing inflammatory AEs compared to patients without pre-existing inflammatory conditions. Thus, patients with pre-existing inflammatory conditions who are receiving BiTE therapy should be cautiously observed. Additional data from larger BiTE therapy clinical trials is needed to further support these findings.
The practice of thyroid monitoring in patients treated with lenalidomide for hematological malignancies: A single-center retrospective analysis.
Authors: lakra rachaita , Hassan Zara , Ramadas Poornima 
Published: June 2023

e14535 Background: Thyroid dysfunction in the form of both hypothyroidism and hyperthyroidism is a known fact and is seen in 5-10 % of patients treated with Lenalidomide. Since the potential impact of thyroid disease on a patient being treated for malignancies can be devastating, surveillance evaluation of thyroid function has been recommended on a bi-monthly basis. This single center retrospective analysis is an effort to understand if this recommendation is practiced by hematologists. Methods: Data for this retrospective chart review was extracted from electronic medical records. 225 patients who received Lenalidomide from the year January 2019 to October 2022 were included. Thyroid monitoring was estimated through thyroid stimulating hormone (TSH) if done and was further classified as baseline (TSH before lenalidomide initiation) versus three months. Abnormal thyroid testing was perceived as TSH outside of our institute’s normal range (0.40-4.0 uIU/mL). Any other risk factors of developing thyroid disease (neck radiation exposure, autoimmune disorders or other drugs contributing to thyroid disfunction) were also recorded. Descriptive statistics with interquartile ranges and frequencies were analyzed. Results: Doses of Lenalidomide used ranged between 5 and 25 mg, over a time period ranging between 1 and 48 months. Reasons for discontinuation of Lenalidomide included bone marrow suppression (N=32, 14%), neuropathy (N=14, 0.06%), intolerable fatigue (N=7, 0.03%) and one patient had concerns for drug induced hypothyroidism. Seven patients were found to have pre-existing thyroid disease, which was well controlled with replacement before initiation of Lenalidomide. 52% had a baseline TSH documented prior to initiation of treatment, while only 18 patients (0.08%), had three monthly thyroid monitoring. Conclusions: Lenalidomide caused hypothyroidism was seen in one of our patients, however 48% never had a TSH documented, while 99.2% were not monitored as per recommendations. This study reflects on the principle of “primum non nocere” and adequate treatment of missed thyroid anomalies in patients treated with lenalidomide can improve quality of life. We recommend hard reminders of bi-monthly TSH monitoring through electronic medical record, for patients receiving Lenalidomide which has been initiated in our institute post this study.
Pressurized intra-peritoneal aerosol as a delivery system for macrophage reprogramming cellular therapy in conjunction with chemotherapy for the treatment of advanced peritoneal malignancies.
Authors: Ben-Yaacov Almog , Adileh Mohammad , Hershkovitz Oren , Galamidi Einat , Amor Veronique , Binder Lior , Mevorach Dror , Nissan Aviram 
Published: June 2023

e14537 Background: Novel intraperitoneal delivery systems like Pressurized Intra Peritoneal Aerosol Chemotherapy (PIPAC) increase the therapeutic access with encouraging responses in patients with peritoneal carcinomatosis unresponsive to systemic therapy. However, survival rates remain at 11-16 months, and treatment options are limited, especially in patients with high tumor burden. Allocetra, an innovative immunomodulatory cellular therapy, has demonstrated antitumor activity in preclinical peritoneal tumor models, reprogramming macrophage function in the tumor microenvironment. The clinical study assesses the applicability and safety of Allocetra given by pressurized intra-peritoneal aerosol, in conjunction with PIPAC. Methods: Allocetra is manufactured from mononuclear cells collected from healthy non-matched donors, and induced to undergo early apoptosis. Safety of administration via pressurized aerosol was assessed by cell recovery and function. The clinical study is a dose-finding safety study with inter- and intra-patient dose escalation of Allocetra to determine safety of intraperitoneal Allocetra administration via pressurized aerosol system (Capnopen, Capnomed, Germany), with PIPAC. Patients have advanced peritoneal cancer, non-eligible for Cytoreductive Surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC). Two cohorts (n=3) are treated with escalating doses of Allocetra at 6-week intervals. Two subsequent cohorts (n=3) include patients treated at the maximal tolerated dose, to evaluate the sequencing of Allocetra and PIPAC. Results: Allocetra pressurized aerosol delivery demonstrated stable and acceptable cellular profiles, recovery and potency. In the first clinical cohort (n=3), patients received escalating doses of 1 x 109, 2.5 x 109 and 5 x 109 Allocetra cells, followed by PIPAC. Patients’ primary diseases were advanced colon and appendicular carcinomas with multiple prior treatment cycles (chemotherapy, biologics and immunotherapy). Patients were followed for a median 15 weeks (range 7-32) for adverse events. Adverse event profile following combined treatment with Allocetra included mostly mild common post surgical events: abdominal pain, pain around surgical wound, shoulder pain, abdominal wall hematoma, rash around surgical wound, urinary tract infection, inferior epigastric artery bleeding, and infected hematoma. None were considered related to Allocetra. All the patients are alive and continue to be followed. Conclusions: Initial results from the study indicate a favorable safety profile following pressurized intra-peritoneal aerosol administration of Allocetra cellular therapy. Additional patients will be treated with escalating doses of Allocetra to assess safety and initial response to treatment. Clinical trial information: NCT05431907 .
Safety and efficacy of loading-dose thymosin α1 in patients with advanced and refractory solid tumors with lower absolute T lymphocyte.
Authors: Xu Meiling , Zhao Xiangrong , Kong Yuehong , Xing Pengfei , Zhang Junjun , Zhang Liyuan 
Published: June 2023

e14543 Background: Nowadays immune checkpoint inhibitors (ICIs) has been reshaping the paradigm of cancer therapy, including various refractory advanced solid tumors. Many studies have shown that low baseline peripheral blood-based immune cells, such as lymphocytes, was one of the most relevant parameters associated with immunotherapy efficacy and prognosis. Thymosin a1, a synthetic polypeptide, has been demonstrated to increase the number of peripheral lymphocytes, especially T cells in patients with solid malignancies. In this current study, we aimed to evaluate the efficacy of loading-dose thymosin a1 (Ta-1) on peripheral lymphocytes and subpopulations in advanced solid tumors and identify how it affects the clinical outcome. Methods: Participants with confirmed the number of peripheral blood-based CD3+ T cells less than 0.5 ´ 109/L, advanced solid tumors that had progressed after standard treatment, or intolerance were enrolled. In this study, those received 3.2mg thymosin α1 subcutaneously in a daily loading dose for 7 days, and the peripheral blood immune indexes were detected on the ninth day. Afterwards, these patients were decided whether to receive radiotherapy and PD-(L)1 inhibitor based on the clinician’s judgement. The primary endpoint was overall survival (OS) and the secondary endpoint were treatment-related adverse events and a panel of circulating lymphocytic subpopulations. Results: As of the cutoff date of February 6th, 2023, a total of 27 patients were enrolled.The median age of them was 61 years old (range: 39-78). Twenty-two patients (81.5%) had poor ECOG performance status of 2 and 3. Eight (29.6%) patients had received at least 3 prior lines of systematic treatments. Most patients (19, 70.3%) had 2 or more metastatic sites. After treated daily with 3.2mg Ta-1 for 7 days, twenty-four patients (88.9%) were subsequently received radiotherapy and PD-(L)1 inhibitors. By data cut-off, median duration of follow-up was 19.2 months (95%CI: 6.2 to NA;), and median OS was 19.6 months (95%CI: 6.6 to 27.2). We found that peripheral CD3+T cells, CD3+CD4+ T cells, CD3+CD8+ T cells, and natural killer (NK) cells were significantly increased after Ta-1 treatment. In an attempt to identify whether the increasing number of lymphocytes after Ta-1 treatment affects the clinical outcome, we compared the subgroup with increasing rate≥30 with that < 30%, which showed a trend of longer median OS in ≥30 subgroup than < 30% (19.6 months vs 3.9 months). No Grade ≥3 treatment-related adverse events occurred in all enrolled patients when treated with loading-dose Ta-1. Conclusions: In this study, we demonstrated that a daily loading-dose Tα-1 treatment increased the number of peripheral lymphocytic subpopulations, and this effect appears to benefit survival outcomes, shedding new light for patients with advanced or refractory solid tumors when initiated ICI treatment.
Dysregulation of immune checkpoint proteins in patients with newly diagnosed early breast cancer undergoing neoadjuvant chemotherapy: A comparison between patients with triple negative breast cancer (TNBC) and non-TNBC.
Authors: Smit Teresa , Rapoport Bernardo Leon , Steel Helen C. , Benn Carol , Nayler Simon , Heyman Liezl , Theron Annette J. , Hlatswayo Nomsa , Kwofie Luyanda LI , Meyer Pieter , Anderson Ronald 
Published: June 2023

e14546 Background: Checkpoint proteins regulate the immune system. Breast cancer is associated with up-regulation or down-regulation of these proteins to evade anti-tumor immune responses. Soluble forms of immune checkpoint molecules (sICMs) can be measured in human plasma. The study aimed to measure the systemic levels of a series of co-stimulatory and co-inhibitory ICMs at diagnosis, post-neo-adjuvant chemotherapy (NAC) and post-surgery in newly- diagnosed BC patients (pts) and compare the biological behaviour of these sICMs between TNBC and non-TNBC patients. Methods: Soluble ICMs were measured using multiplex bead array technology in plasma from 72 BC pts and 45 healthy controls. Data were prospectively obtained and levels were compared between pre-treatment, post-NAC, and post-surgery using non-parametric tests (Mann-Whitney & Kruskal-Wallis). Results: Following NAC, the plasma levels of six soluble co-stimulatory checkpoints (CD28, CD40, ICOS, CD27, CD80, GITR), all involved in the activation of CD8+ cytotoxic T cells, were significantly increased (p < 0.04-p < 0.00001). Four of the soluble co-inhibitory checkpoints (LAG-3, PDL1, TIM-3 and HVEM) increased significantly post-NAC, reaching levels significantly greater than those of the control group. PD-1 remained unchanged, while BTLA and CTLA-4 decreased significantly (p < 0.03 and p < 0.00001, respectively). Normalization of soluble co-stimulatory immune checkpoints seemingly indicates a reversal of systemic immune dysregulation following the administration of NAC in early BC. In contrast, recovery of immune homeostasis may explain the increased levels of several negative checkpoint proteins, albeit with the exceptions of CTLA-4 and PD-1. No significant differences were detected between the changes of 16 sICMs levels at pre-NAC, post-NAC and post-surgery when comparing the TNBC and non-TNBC patients. Conclusions: This study demonstrates low levels of co-stimulatory and co-inhibitory sICMs in newly-diagnosed, non-metastatic BC pts. Following treatment with NAC, the sICMs levels increase substantially, except CTLA-4. In the case of co-stimulatory sICMs, these novel findings are indicative of an immune-restorative mechanism. The pattern of co-inhibitory sICMs (elevated levels of PD-L1, LAG-3, TIM-3 and HVEM), might be indicative of immune-therapeutic resistance, underscoring the augmentative immune-therapeutic promise of targeting these molecules, either individually or in combination, to improve the outcome of pts with early BC. These differences were not significant between TNBC and non-TNBC patients.