Clinical Investigation Research Articles

Staged Surgical Treatment of the Giant Pituitary Neuroendocrine Tumors

To investigate the long-term clinical outcomes of staged surgical resection in giant Pituitary Neuroendocrine Tumors(pitNET).Method We performed a retrospective analysis of the clinical data of 16 patients who underwent surgery. The patients were diagnosed and underwent surgery at the Department of Neurosurgery of Shiyan Taihe Hospital from January 2013 to March 2021. Among the cases, 12 patients underwent primarily transsphenoidal surgery followed by secondary transcranial surgery, while 4 patients underwent primarily transsphenoidal surgery followed by secondary transsphenoidal surgery. Before the surgery, all patients underwent a pituitary MRI scan, pituitary hormone level examination, visual acuity, and visual field examination. A pituitary MRI was rechecked within 1 week after the operation. A tumor resection rate of 100% on MRI was considered as a total resection, between 90% to 100% as a subtotal resection, and lower than 90% as a partial resection. After the surgery, regular clinical visits and telephone or internet platform follow-ups were conducted. Outcome In our clinical investigation, after staged surgery 10 patients had a total resection, 5 had a subtotal resection, and 1 had a partial resection depending on the tumor size and invasion. The clinical outcomes showed that 1 case suffered from postoperative intracranial infection, 1 case had decreased visual acuity, and 6 cases experienced decreased pituitary function after surgery.Postoperative complications were cured after symptomatic treatment, except for 1 patient who experienced decreased vision and 1 patient sufferred hypopituitarism required long-term oral levothyroxine tablet treatment. No cases of intracranial hemorrhage or death were caused by intentionally staged resection surgery. Conclusion Staged surgery for giant pitNET is a safe and effective clinical surgery strategy.

Intracellular retention of TCRαβ/CD3 and CD7 to generate novel allogeneic CAR-T cells targeting CD7 for treating T-cell malignancies.

e14531 Background: The treatment for patients with T-ALL/LBL who relapse after hematopoietic stem cell transplantation (HSCT) are currently restricted. CD7 is highly expressed on the surface of T-ALL/LBL T cells and CAR-T cell therapy provides a promising avenue towards remission. However, CD7-targeting immunotherapies may be compromised by T-cell fratricide. Furthermore, in addition to the long production time, high cost, and high risk of production failure, the biggest challenges of autologous CAR-T cell therapy are how to isolate a sufficient number of healthy T cells from malignant T cells. Thus, allogeneic CAR-T cells can overcome these hurdles. Methods: A novel non-gene-editing allogeneic CAR-T platform was developed on the base of intracellular retention of membrane proteins, and named ThisCART (TCR and/or HLA-I intracellular sequestered). CD7-directed ThisCART cells are readily produced with a single lentiviral vector, encoding both a CD7-targeting CAR, an anti-CD7and anti-CD3 single chain antibody with the KDEL peptide fused to its C-termini. The surface expression of CAR, TCRαβ/CD3 and CD7 was measured by flow cytometer. Specific tumor cytotoxicity was evaluated both in vitro and in vivo. Furthermore, the safety of donor derived ThisCART cells were tested in a xenogeneic GvHD model. Results: The manufacturing platform of CD7 ThisCART was able to achieve over 130-folds of ex vivo CAR-T expansion in all batches, with the purity of products (CAR-positive/CD7-negative/TCRαβ-negative) above 99%. In preclinical models, CD7 ThisCART did not induce GvHD, and exhibited superior antitumor function compared to Control T. CD7 ThisCART cells were readily produced to a quantity and quality supporting clinical investigation. Conclusions: CD7 ThisCART cells based on intracellular retention of TCRαβ/CD3 complex and CD7 demonstrated superior CD7-dependent cytotoxicity and no xenogeneic GvHD in murine models. With streamlined single-vector-based production and potent cytotoxicity and favored preclinical safety profile, CD7 ThisCART warrant clinical investigation.

First-in-class PD-1/IL-2 bispecific antibody fusion protein IBI363 in patients with other solid tumors: Safety and efficacy results from a phase I study.

e14593 Background: IBI363 is a first-in-class PD-1/IL-2α-bias bispecific antibody fusion protein which could block PD-1 checkpoint and rejuvenate exhausted tumor-specific T cells by cis-activating α-bias IL-2. It was well tolerated and showed encouraging efficacy in patients (pts) with advanced melanoma, non-small cell lung cancer and colorectal cancer. Herein, we report a phase I study of IBI363 in patients (pts) with other solid tumors. Methods: Eligible pts with advanced biliary tract cancer (BTC), head and neck squamous cell carcinoma (HNSCC), cervical cancer (CC) and ovarian cancer (OC) who failed or intolerant to standard therapy were enrolled. IBI363 was intravenously administered at different dose levels ranging from 600 to 1500 μg/kg QW/Q2W/Q3W. Primary objective of the study was safety. Secondary objective was efficacy assessed by investigator per RECIST v1.1 including objective response rate (ORR) and disease control rate (DCR). Results: As of January 26, 2024, 24 pts were enrolled including 13 pts with BTC, 3 pts with HNSCC, 4 pts with CC and 4 pts with OC. In BTC, 6 (46.2%) pts received IBI363 treatment for more than 3 months and the maximum treatment duration was 7 months. In HNSCC, CC and OC, the maximum treatment duration was 4.6, 6.2 and 6.5 months respectively. Pts with at least 1 tumor assessment were included in efficacy evaluable set (n = 18). The overall ORR was 22.2% and DCR was 77.8%. In 11 evaluable pts with BTC, best overall response (BOR) was confirmed partial response (cPR) in 1 pt (600 μg/kg Q2W, immunotherapy (IO)-failed), stable disease (SD) in 9 pts (including 6 pts with tumor regression) and progressive disease (PD) in 1 pt. ORR was 9.1% and DCR was 90.9%. In 2 evaluable pts with HNSCC, 1 pt had cPR (600 μg/kg Q2W, IO-naïve, PD-L1 expression negative) and 1 pt had PD. In 3 evaluable pts with CC, 1 pt had cPR (1000 μg/kg Q2W, IO-failed), 1 pt had SD and 1 pt had PD. In 2 evaluable pts with OC, 1 pt had cPR (1000 μg/kg Q2W, platinum-resistant) and 1 pt had PD. All cPR pts had previous 1-2 lines of treatments and had tumor regression ranging from 45% to 87%. Durable tumor responses were observed with cPR remained at week 30 in BTC and remained at week 24 in HNSCC, CC and OC. In 4 pts with cPR, 3 pts still on treatment and 1 pt with HNSCC received curative resection. No new safety signals of IBI363 were observed. More updated data on safety and efficacy will be presented at the meeting. Conclusions: IBI363 showed promising and durable efficacy in pts with various solid tumors including refractory tumors such as BTC and IO or platinum-resistant tumors such as CC and OC. Further clinical investigations on these tumors using IBI363 alone or in combination with other treatments are ongoing. Clinical trial information: NCT05460767 .

Serabelisib, sapanisertib (PIKTOR) and paclitaxel: A combinatorial approach to improve PI3K/mTOR/AKT pathway inhibition and treatment response in solid tumors.

e15134 Background: Despite high mutation rates in genes of the PI3K/mTOR/AKT pathway in cancer, therapeutic strategies to inhibit this pathway featuring single targeted therapies have achieved limited clinical success. An alternate approach inhibiting multiple parts of the pathway simultaneously demonstrated improved activity (Starks et al, GynOnc 2022). The Phase 1 study combined the targeted PI3K-alpha and mTOR inhibitors serabelisib and sapanisertib (PIKTOR) with paclitaxel showing reasonable safety and promising clinical efficacy in patients with advanced endometrial, breast and ovarian tumors that had progressed on prior taxane. The ORR was 47% including 3 complete responses, with a PFS of 11 months in 15 evaluable subjects (NCT03154294). We sought to better understand the mechanistic basis for the efficacy of this triplet drug combination in models of endometrial and breast cancer to support successful clinical development of this regimen. Methods: Signaling activity in PI3K/mTOR/AKT pathway was probed by western blot for phospho-S6 and phospho-4EBP1 in human endometrial and breast cancer cell lines with PI3K/mTOR/AKT mutations. Single and combinatorial dose-response curves were established for serabelisib, sapanisertib and paclitaxel versus FDA-approved pathway inhibitors. Mechanisms of cytotoxicity and paclitaxel sensitization were probed with cell death assays. The impact of single and combined agents on tumor growth was assessed with in vivo xenograft studies. Results: In human endometrial and breast cancer cell lines, the combination of serabelisib and sapanisertib achieved markedly improved PI3K/mTOR/AKT pathway inhibition versus FDA-approved single agents. Serabelisib and sapanisertib increased the cytotoxicity of paclitaxel, supporting prior work that identifies PI3K/mTOR/AKT pathway activation as a key mediator of taxane resistance. Further, interrogation of a range of clinically relevant doses and scheduling led to an optimized regimen in which serabelisib and sapanisertib substantially improved the response to paclitaxel in vivo. Conclusions: Simultaneous inhibition of PI3K-alpha, mTORC1 and mTORC2 with PIKTOR offers potential for superior PI3K/mTOR/AKT pathway inhibition, suggesting that rational drug combination approaches may offer two important benefits: (1) more complete PI3K/mTOR/AKT pathway inhibition by targeting multiple signaling nodes, and (2) greater tumor cell cytotoxicity by sensitization to taxanes. These data, combined with the promising efficacy and safety signal from PIKTOR plus paclitaxel in a Phase 1 trial (NCT03154294), provide a compelling rationale for further clinical investigation. Future studies will focus on tumors known to have high rates of PI3K mutations including gynecologic tumors where there is a high unmet need.

Homozygosity of a Founder Variant c.1508dupC in DOK7 Causes Congenital Myasthenia With Variable Severity.

Description of 15 patients with the same variant in DOK7 causing congenital myasthenic syndrome (CMS). Nine adult and 6 pediatric patients were studied with molecular genetic and clinical investigations. All patients were identified with the c.1508dupC variant in DOK7, of whom 13 were homozygous and 2 patients compound heterozygous. Only 2 patients had limb girdle phenotype, while all adult patients also had ptosis, ophthalmoplegia, facial weakness, as well as inspiratory stridor. Pediatric patients had severe respiratory insufficiency and feeding difficulties at birth. The disease severity in our patients varied extensively from ventilator or wheelchair dependence to mild facial weakness, ptosis, and ophthalmoparesis. Most of the patients had normal transmission in conventional 3 Hz stimulation electrophysiologic studies, making the diagnosis of CMS challenging. Our cohort of adult and pediatric patients expands the phenotype of DOK7 CMS and shows the importance of correct and early diagnosis.

Hydrogenated oxide material-based hyperthermia and radiotherapy: A new treatment option for esophageal squamous carcinoma.

e16127 Background: Radiotherapy (RT) is the mainstay of esophageal squamous carcinoma (ESCC) treatment, and hyperthemia could exert synergistic effects to refractory diseases. Hydrogenated oxide material (HMO) is a newly developed photothermal agent, featured by selectively targeting tumors, high photothermal conversion efficiency under 1064 nm near-infared (NIR) illumination and safe degradation. This study aims at investigating the combination effects of HMO-based hyperthermia and RT in ESCC. Methods: mEC25 murine ESCC cells were cultured and treated with RT alone (prescribed cumulative dose of 10Gy), HMO-based hyperthermia (incubated with 100ug/ml HMO for 20min and irradiated with 1064nm NIR continuously for 15min) or combination therapy (RT followed by HMO-based hyperthermia). FLIR-One was applied to monitor temperature alterations in HMO-based hyperthermia. Flow cytometry was performed to detect apoptosis rates 24h after treatment. Results: The temperature was increased by 21.3[19.8-23.7]℃ after NIR irradiation. The apoptosis rates were 19.4%[19.4%, 19.5%], 43.8%[43.6%, 44.0%] and 61.4%[58.5%, 61.8%] in RT alone, HMO-based hyperthermia and combination therapy group respectively. Considerably low apoptosis rates were observed in HMO-incubation and NIR-irradiation only groups, which was 6.2% and 6.6% respectively, similar to that of treatment-naive cells. Conclusions: The combination of HMO-based hyperthermia and RT provided a promising treatment modality for ESCC, while its effects in rodent models and potentials in clinical practice merit further investigations.

Evaluating antitumor activity and response determinants to trastuzumab deruxtecan in pediatric solid tumors.

10049 Background: Trastuzumab deruxtecan (T-DXd) is an anti-HER2 antibody-drug conjugate (ADC) linked to a topoisomerase inhibitor FDA-approved for several indications, including the treatment of HER2+ breast and gastric cancer. Although HER2 amplification is uncommon in pediatric cancers, recent demonstration of T-DXd efficacy in HER2-low breast cancer patients prompted us to examine the potential clinical relevance of T-DXd in pediatrics by evaluating HER2 expression and activity of T-DXd in preclinical pediatric solid tumor models. Methods: Cell viability was assessed in a panel of histologically diverse pediatric solid tumor cell lines and 2 HER2-amplified adult cancer cell lines treated with T-DXd, payload (DXd), and a control IgG-ADC. HER2 protein expression in patient-derived xenograft (PDX) tumors was evaluated by immunohistochemistry (IHC) using 5 clinically validated anti-HER2 antibodies. RNAseq was performed on clinical (n=290) and PDX (n=184) tumors to determine relative expression of ERBB2. In vivo activity of T-DXd was evaluated in osteosarcoma (OS, n=10), Wilms tumor (WT, n=1) and malignant rhabdoid tumor (MRT, n=1) PDX models and a desmoplastic small round cell tumor (DSRCT) cell line xenograft model. Differences in tumor volume and time to disease progression was assessed and compared across treatments and models. Responses were correlated with HER2 expression by IHC. Results: In vitro, HER2-amplified control cell lines demonstrated a >30-fold reduction of IC50 when comparing T-DXd to ADC control. In contrast, the ADC control IC50 was nearly identical to T-DXd across all pediatric cancer cell lines, consistent with the absence of HER2 amplification in these models. We observed focal and membranous staining of HER2 by IHC in PDXs but was quite variable across antibodies tested: WT 0-17% HER2+ cases (n=6), MRT 0-40% (n=5), DSRCT 0-33% (n=24), OS 0-7% (n=30). ERBB2 gene expression was highest in DSRCT followed by WT, OS and MRT. In vivo efficacy studies demonstrated complete and partial responses in OS, WT, and DSRCT and improved disease control rates (OS: 67%, p=0.006, Mann-Whitney; WT: 100%; DSRCT: 100%). However, T-DXd and ADC control demonstrated similar activity in all tumor types with no consistent correlation between in vivo response and HER2 expression. Consistent with these preclinical studies, 4 patients with progressive DSRCT were treated with T-DXd via compassionate/off-label access with signs of clinical and radiographic responses. Conclusions: T-DXd shows significant preclinical antitumor activity across multiple pediatric solid tumors but little correlation with HER2 expression suggesting a mechanism of action similar to the clinical activity observed in HER2-low breast cancer. Xenograft efficacy studies and preliminary clinical experience with T-DXd in DSRCT patients warrant formal clinical trial investigation in this largely incurable disease.

Clinical course of respiratory tuberculosis relapses in the Kazakh population depending on HLA-DRB1 gene alleles.

The study aimed to ascertain the prevalence and frequency of relapses of respiratory tuberculosis (TB) and examine the characteristics of its clinical progression in members of the Kazakh population based on the alleles of the HLA-DRB1 gene. Methods of clinical and genetic research, statistical processing and analysis of the obtained data were used to achieve this goal. The research led to an analysis of the statistical processing of clinical and genetic investigations that found out how often TB in the respiratory tract is found and how different HLA-DRB1 gene alleles affect the disease's progression. To find out how exposure to certain HLA-DRB1 gene alleles affects the chance of relapse, the number of times they were found was compared between people who had relapsed and people who had just been diagnosed with TB. The impact of these alleles on the progression of the disease was assessed based on their frequency of detection of different clinical forms of TB (infiltrative, fibro-cavernous, generalised, disseminated), unilateral and bilateral lung damage, lung tissue deterioration, and the presence of bacterial secretions. The highest detection rate for all comparisons had gene alleles HLA-DRB1*01 (9.5%), *08 (4.2%), *15 (3.9%), *09 (1.6%), *12 (1.3%), *13 (0.9%), *11 (0.2%). The study found that Kazakhs with the HLA-DRB1*01, *08, and 15 gene alleles are more likely to develop recurrent respiratory TB. The study's practical value lies in its potential to utilise its findings for the prompt identification and eradication of genetic variables contributing to the recurrence of TB.

Survival outcomes of Zo-NAnTAx: a five-year analysis of zoledronic acid added to a neoadjuvant regimen for HER2-positive breast cancer.

Zoledronic acid (ZA) improved outcomes in breast cancer. In pre-clinical studies, ZA increased tumour regression in combination chemotherapy and anti-human epidermal growth factor receptor 2 (HER2) target therapy. The Zo-NAnTax study, a clinical trial combining ZA with neoadjuvant therapy for HER2-positive tumours met the primary endpoint, showing a higher pathological complete response (pCR) rate than predicted in patients receiving surgery. Here, we report the exploratory relapse-free survival (RFS) and overall survival (OS) analysis after five years of follow-up. Adult women with HER2-positive breast cancer amendable to curative surgery who consented to the study received four cycles of ZA at 4 mg + doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 followed by four cycles of ZA at 4 mg + docetaxel 100 mg/m2 + trastuzumab 6 mg/kg (8 mg/kg as a loading dose), all in a 21 days-cycle, totalizing 8 cycles before surgery. To achieve the primary endpoint of pCR rate between 22% and 35%, 56 patients were needed. The secondary endpoints included safety, gene expression according to treatment response, prediction of pCR rate by an interim breast magnetic resonance imaging (bMRI). Beyond the overall pCR rate of 42%, alongside a good safety profile, we showed similar pCR rates in both hormonal receptor (HR) positive (40%) and HR-negative (44%). RFS and OS at five years were evaluated in 58 subjects, and the overall rate was 79.3% and 86.2%, respectively. Numerically higher values of both RFS and OS were observed in patients achieving pCR vs. non-achieving, respectively 83.3% vs. non-pCR 76.5% (P=0.57) and 95.8% vs. non-pCR 79.4% (P=0.08). Although not statistically significant, OS was numerically equivalent according to HR status, respectively 85.7% vs. 87.5% for HR-positive and HR-negative (P=0.91), which contrasted with RFS, HR-positive 81% vs. HR-negative 75% (P=0.58). None of the assessed clinicopathological biomarkers significantly correlated with survival. ZA plus neoadjuvant therapy in HER2-positive breast cancer shows provoking survival outcomes. Clinical and pre-clinical investigation with dual anti-HER2 blockage is warranted.

Clinical Profile and Outcome of Severe Acute Respiratory Illness (SARI) in Children Amidst the COVID-19 Pandemic.

Beginning in December 2019, COVID-19 rapidly emerged as a global pandemic. Though its severity in children was reported to be less than that in adults, data on its epidemiology in relation to severe acute respiratory illness (SARI) caused by other microbes needed to be generated. This study compares theclinical profile and outcome of children hospitalized with COVID-19-positive and negative SARI. This is a prospective observational analytical study involving children 1 month to 18 years old, hospitalized with COVID-19-positive and negative SARI during the pandemic. All eligible patients were enrolled after obtaining informed parental consent. Their clinical manifestations, investigations, and outcomes were documented on a predesigned case record form. A nasopharyngeal swab sample for COVID-19 reverse transcription polymerase chain reaction was sent, and results were noted. From May 2020 to July 2021, 267 children were hospitalized with a diagnosis of SARI. Out of these, 146 (54.7%) were boys and 78.7% were under five years of age. Other presentations included fever and cough, breathlessness, nausea, vomiting, diarrhea, rash, seizures, and altered sensorium. Twenty-eight patients (10.5%) tested positive for COVID-19. COVID-19 patients were similar in terms of demographic characteristics and presenting symptoms to non-COVID-19 patients but had a lower absolute lymphocyte count (p = 0.019) and higher serum alanine transaminase levels (p = 0.013). Acute respiratory distress syndrome (OR, 4.3; 95% CI, 1.8-10.0),shock (OR, 3.9; 95% CI, 1.9-7.9), and need for intensive care unit admission (OR, 9.9; 95% CI, 6.9-14) were more common in COVID-19 SARI patients. Death occurred in 18% of COVID-19 and 9% of non-COVID-19 patients (p = 0.07). SARI nonsurvivors had significantly lower blood pH and platelet counts than survivors. Comparison of COVID-19-positive and negative SARI patients showed subtle differences between the two groups, with COVID-19-positive children having an increased severity of illness. Also, laboratory evidence of multiorgan dysfunction at admission was associated with higher mortality.

Phytochemical and Pharmacological Attributes of Nerium oleander: A Review

Background: Nerium Oleander is an Indian folk medicine popularly known as oleander, contains numerous phytoconstituents and nutritional agents for the treatment of multiple ailments. Objective: The prime objective for the current comprehensive review is to focus on the elaboration of phytochemistry along with the Pharmacological significance of N. oleander. Methods: As per literature investigations it was noticed that plant contains various phytochemical constituents, including Oleandric acid, Kaneroside, Cardenolide, Nerizoside, Neritaloside, Odoroside- H,3-Ocaffeoylquinic acid along with structural isomer, 5-Ocaffeoylquinic acid, α-tocopherol, Oleandrin, Digitoxgenin along with nutritional ingredients viz essential fatty acids like omega- 3 fatty acids, and other polyphenols reported in N. oleander. Results: In recent investigations, it was observed that oleander possesses a wide range of medicinal attributes viz. anti-inflammatory, larvicidal, anti-cancer, Antidiabetic, Cellular/humoral immune response, Hepatoprotective, Wound healing, Anti-microbial, Antioxidant, Antinociceptive, Locomotor, Diuretic, and Anti leukemic activities. Conclusion: N. oleander could be an excellent candidate for discovering new medications because of its wide range of pharmacological action and the large diversity of active phytochemicals. However, to disclose the favorable therapeutic, safety, and pharmacological virtues of N. oleander and its phytoconstituents, more clinical and experimental investigations are needed.

Turning the operating room into a mixed-reality environment: a prospective clinical investigation for cerebral aneurysm clipping.

The overall aim of this study was to demonstrate the potential benefit of a novel mixed-reality-head-mounted display (MR-HMD) on the spatial orientation of surgeons. In a prospective clinical investigation, the authors applied for the first time a new multicamera navigation technology in an operating room setting that allowed them to directly compare MR-HMD navigation to standard monitor navigation. In the study, which included 14 patients with nonruptured middle cerebral artery aneurysms, the authors investigated how intuitively and effectively surgical instruments could be guided in 5 different visual navigation conditions. The authors demonstrate that multicamera tracking can be reliably integrated in a clinical setting (usability score 1.12 ± 0.31). Moreover, the technology captures large volumes of the operating room, allowing the team to track and integrate different devices and instruments, including MR-HMDs. Directly comparing mixed-reality navigation to standard monitor navigation revealed a significantly improved intuition in mixed reality, leading to navigation times that were twice as fast (2.1×, p ≤ 0.01). Despite the enhanced speed, the same targeting accuracy (approximately 2.5 mm, freehand tool use) in comparison to monitor navigation could be observed. Intraoperative planning strategies with mixed reality clearly outperformed classic preoperative planning: surgeons scored the mixed-reality plan as the best trajectory in 63% of the cases (chance level 33%). The incorporation of mixed reality in neurosurgical operations marks a significant advancement in the field. The use of mixed reality in brain surgery enhances the spatial awareness of surgeons, enabling more instinctive and precise surgical interventions. This technological integration promises to refine the execution of complex procedures without compromising accuracy.

Clinical Investigation of Decreased SpO<sub>2</sub> Caused by Oral Administration of Diaphenylsulfone (DDS, Dapsone)

Clinical Investigation of Decreased SpO<sub>2</sub> Caused by Oral Administration of Diaphenylsulfone (DDS, Dapsone)

Glutamate and excitotoxicity in central nervous system disorders: ionotropic glutamate receptors as a target for neuroprotection

AbstractRecent advances in neuroscience have illuminated the central role of glutamate dysregulation in various neurological disorders. The glutamatergic system has emerged as a central player in the pathophysiology of various neurological disorders. The dysregulation of glutamate signaling, leading to excitotoxicity and neuronal cell death, has been a focal point in understanding the underlying mechanisms of these conditions. This has prompted a paradigm shift in neuroprotection research, with a growing emphasis on targeting ionotropic glutamate receptors (iGluRs) to restore glutamatergic homeostasis. This review provides a comprehensive overview of recent advancements in the field of iGluR‐targeted neuroprotection. We further investigate the implications of glutamate dysregulation in the central nervous system (CNS) disorders, highlighting the complex interplay between excitotoxicity and neuroprotection. We elucidate the multifaceted factors that render neurons vulnerable to excitotoxic damage, emphasizing the need for innovative therapeutic approaches. This review provides an extensive survey of the burgeoning field of iGluR‐targeted neuroprotection. It showcases the significant potential of a wide array of compounds, encompassing both natural and synthetic agents, to modulate iGluRs and ameliorate excitotoxicity and oxidative stress‐induced neuronal damage. These compounds have demonstrated impressive neuroprotective effects in diverse experimental models, from glutamate‐induced toxicity to traumatic brain injuries. We advocate for further research and clinical investigations to harness the full therapeutic potential of iGluR modulation, heralding a promising era in neuroprotection and CNS disorder management.

CS12192: A novel selective and potent JAK3 inhibitor mitigates acute graft-versus-host disease in bone marrow transplantation

BackgroundDespite the significant role of JAK3 in various autoimmune diseases, including graft-versus-host disease (GVHD), there has been a lack of potent and selective JAK3 inhibitors specifically studied for GVHD. In our preclinical investigations, we evaluated a novel JAK3 inhibitor called CS12192, which is already undergoing clinical investigation in autoimmune diseases. MethodsWe evaluated the efficacy of CS12192 in GVHD through mixed lymphocyte reaction (MLR) in both mouse and human cells, as well as allogeneic bone marrow transplantation (BMT) in a murine model. ResultsCS12192, starting at a concentration of 0.5 μM, dose-dependently reduced the intracellular positivity for cytokines TNF-α and IFN-γ in CD4+ T cells (p < 0.05 to p < 0.0001) and CD8+ T cells (p < 0.01 to p < 0.0001) during mouse allogeneic MLR assays. This effect was observed for both single and double positivity of the cytokines. Moreover, In MLR assays with three different human donors, CS12192 also demonstrated a dose-dependent reduction in the proportion of IFN-γ positive CD4+ T cells (p < 0.0001) and CD8+ T cells (p < 0.01 to p < 0.0001). Additionally, it suppressed T cell proliferation in the mouse MLR (p < 0.05 to p < 0.0001), but this effect was observed in only one human donor (p < 0.001 to p < 0.0001). Furthermore, the administration of CS12192 at 40 and 80 mg/kg BID significantly improved the survival rate in the BMT model, resulting in cumulative 62-day survival rates of 88.89% (p < 0.01) and 100% (p < 0.001), respectively, compared with prednisolone (p < 0.05). ConclusionsCS12192 is a novel, potent and selective JAK3 inhibitor demonstrating great potential to mitigate acute GVHD.

Moving Immunotherapy Into the Treatment of Resectable Non-Small Cell Lung Cancer.

Clinical investigation of immune checkpoint inhibitors (ICIs) has expanded from indications in metastatic non-small cell lung cancer (NSCLC) to add to the treatment of early-stage or resectable NSCLC. Although completed randomized trials supported the approvals of some ICIs as perioperative therapies (ie, adjuvant, neoadjuvant, or neoadjuvant followed by adjuvant), ongoing trials are evaluating other anti-PD-(L)1 antibodies for similar indications, or in combination with stereotactic body radiotherapy (SBRT). The incorporation of immunotherapy brings potential to improve outcomes of patients with resectable NSCLC, but these advances have also increased the complexity of the treatment landscape and created important knowledge gaps. This article reviews the current standards for local therapies in NSCLC, describes the clinical trials exploring the combination of ICIs to SBRT, and explains the recent approvals of ICIs as perioperative therapies. A discussion follows to highlight three important areas of uncertainty: (1) the contribution of ICIs given in each treatment phase (neoadjuvant and adjuvant) to the overall effect of neoadjuvant chemoimmunotherapy followed by adjuvant ICIs; (2) the selection of regimens to serve as comparators in future randomized trials of perioperative therapies; and (3) the role of pathologic complete response as an intermediate end point and aid for selection of patients for adjuvant therapy. Moving forward, stakeholders will need to engage in concerted research efforts to address the relevant clinical questions regarding the optimal management of resectable NSCLC.

ESG401, a trophoblast cell-surface antigen 2 (TROP2) antibody drug conjugate (ADC), for the treatment of first-line metastatic triple negative breast cancer (mTNBC).

e13132 Background: ESG401, a novel ADC comprising a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to the Topoisomerase I Inhibitor SN-38, with the Drug-Antibody Ratio at 8, by a stable cleavable linker, exhibited preliminary efficacy and tolerability in the Phase Ia trial (Ma, ASCO 2023). This report summarizes current results from the first-line mTNBC cohort of the Phase Ib trial. Methods: Patients (pts) aged ≥18 years with confirmed local advanced/unresectable or metastatic TNBC, without prior metastatic treatment, received ESG401 (16 mg/kg IV on Day 1,8, and 15, with a 28-day cycle) until unacceptable toxicity, progressive disease, or consent withdrawal. Results: As of the cutoff date (Jan 30th, 2024), 23 pts in the cohort received ≥1 dose of ESG401. Median age was 52 years (range: 33-73), 34.8% were ECOG 0, 26.1% were de novo stage IV, 73.9% had visceral disease (8.7% brain, 34.8% liver, 52.2% lung), 43.5% received radiotherapy, and 73.9% received chemotherapy (73.9% Taxanes, 69.6% Anthracycline, 4.3% Platinum)as prior treatments for early-stage disease. Among 14 Efficacy Evaluable (EE) pts, the ORR was 78.6%, including one (7.1%) patient who achieved a complete response. DCR was 100%, and CBR was 85.7%. Eight pts (57.1%) achieved confirmed Partial Response (PR). As of the cutoff date, 14 pts (63.6%) remained on treatment, with the longest on-treatment duration being 8.0 mons. Two (2) pts in this cohort had brain metastases. One pt achieved a complete intracranial response, and the overall response evaluation was PR. The evaluation time for the other pt has not yet been reached. Across the entire Phase Ia/1b trials, including 15 EE pts with brain metastases, the best overall intracranial response rate was 33%, with an intracranial disease control rate of 73%. The response of the intracranial tumor lesion is correlated with the response of the non-CNS lesion. The safety profile of ESG401 remained consistent with previous reports, showing no new or unexpected safety signals. The most common TRAEs were leukopenia (65.2%), neutropenia (69.6%), anemia (43.5%), fatigue (21.7%), nausea (43.5%), and vomiting (34.8%). The most common TRAEs≥ Grade 3 were neutropenia (43.5%). There was no ≥ Grade 3 diarrhea. No interstitial lung disease (ILD) has been reported so far for the entire PhIa/b trials containing 139 pts. Conclusions: ESG401 demonstrates promising antitumor activity in the first-line mTNBC pts, with efficacy comparable to the combination therapy reported by the BEGONIA Study. Additionally, the efficacy of ESG401 in brain metas in the first-line mTNBC pts is in alignment with our previous observations made in the late-line mTNBC and HR+/HER2- BC pts. These results warrant further clinical investigation of ESG401. Clinical trial information: NCT04892342 .

Phase I safety and preliminary efficacy of PM1009, a bispecific antibody targeting TIGIT and PVRIG, in patients with advanced solid tumors.

e14695 Background: PM1009 is an anti-TIGIT x PVRIG bispecific antibody containing a fully human anti-TIGIT IgG1 fused with a fully human anti-PVRIG scFv at the C terminus. PM1009 can potently block the TIGIT/CD155/CD112 and PVRIG/CD112 signaling pathways, and supports the depletion of TIGIT-positive Treg cells in the tumor microenvironment through FcγR engagement. This leads to the enhancement of T cell and NK cell activity towards the killing of tumor cells. PM1009 showed robust in vitro and in vivo efficacy with good safety in preclinical studies. Methods: This is the first-in-human study of PM1009, which includes a dose escalation stage (accelerated titration &amp; 3+3 design) followed by dose expansion. In the dose escalation stage, PM1009 was administered as flat doses of 120, 300, 600 and 1200 mg for DLT evaluation after 3 weeks followed by administration Q2W. Primary endpoints were safety and tolerability, and the secondary endpoints were PK, ORR and DCR (per RECIST 1.1). Results: As of February 1, 2024, a total of 12 patients were enrolled for dose escalation and received at least one dose of PM1009, with 3 patients in each of the 120, 300, 600 and 1200 mg dose-levels. Median number of prior therapies was 5 lines (range 1- 9). No DLTs were observed up to 1200 mg. Any-grade TRAEs occurred in 11 patients (91.7%), and ≥ Grade 3 TRAEs occurred in 2 patients (16.7%). Any-Grade irAEs occurred in 7 patients (58.3%), and ≥ Grade 3 irAEs occurred in 1 patient (8.3%). Treatment interruption due to TRAE occurred in 2 patients (16.7%), with infusion related reaction (the main symptom was nausea, and the single infusion was eventually completed), and neutrophil count decrease respectively. Treatment discontinuation due to TRAE occurred in 2 patients (16.7%), with acute myocardial infarction, and neutrophil count decrease respectively. The most common TRAEs were ALP elevation (33.3%) and AST elevation (25.0%). 12 patients completed at least one tumor evaluation. The DCR per RECIST 1.1 by investigator was 33.3% (4/12; 95% CI: 9.92 - 65.11), best overall response was SD. Pharmacokinetics were dose-proportional with a terminal half-life of 5.2-7.4 days across the dose range of 120-1200 mg. Conclusions: PM1009 was well-tolerated up to 1200 mg with signs of anti-tumor activity. These findings support further clinical investigation of PM1009 especially for the combination with chemotherapy or PD-1/L1-based checkpoint inhibitors. Clinical trial information: NCT05607563 .

Stereotactic body radiotherapy is an alternative to radiofrequency ablation for single HCC ≤5.0 cm

Background & AimsRadiation therapy has been refined with the increasing evidence of stereotactic body radiation therapy (SBRT) in treating hepatocellular carcinoma (HCC). In this study, we aimed to evaluate whether SBRT could serve as an alternative to radiofrequency ablation (RFA) for small HCC with a single lesion ≤ 5.0 cm. MethodsPatients with a single HCC lesion ≤ 5.0 cm who received RFA or SBRT were included. Cumulative local/distant recurrence rate (CLRR/CDRR), progression-free survival (PFS), overall survival (OS), adverse events (AEs) and subsequent treatments after recurrence were analyzed. ResultsA total of 288 patients received RFA (166) or SBRT (122) were enrolled. The baseline characteristics between the two groups were comparable. The CLRR in the SBRT group was significantly lower than that in the RFA group (HR = 0.30, 95%CI = 0.16 – 0.57, P < 0.001), especially for patients with tumors > 2.0 cm (HR = 0.20, 95% CI = 0.08 – 0.50, P < 0.001) or adjacent to major vessels (HR = 0.29, 95% CI = 0.13 – 0.66, P < 0.001). CDRR, PFS and OS showed no significant differences between the two groups (all P > 0.050). AEs were mild and easily reversible. However, more patients in the SBRT group suffered from Child-Pugh score and TB increase. More treatment options after recurrence or progression might be available for patients in the RFA group compared to those in the SBRT group (P < 0.001). ConclusionsBoth RFA and SBRT were effective and safe for HCC with a single lesion ≤ 5.0 cm. SBRT could be an alternative treatment to RFA, especially for tumors > 2.0 cm or adjacent to major vessels. Impact and implicationsStereotactic body radiation therapy (SBRT) may be used as an alternative therapy to thermal ablation for patients with BCLC stage A hepatocellular carcinoma (HCC) who are not candidates for surgical resection, including those with tumors > 3 cm and those with 1 to 3 tumors. This study focused on HCC patients with specific tumor burden, a single lesion ≤ 5.0 cm, demonstrating that SBRT could be an effective and safe alternative to radiofrequency ablation (RFA), especially for those with tumors > 2.0 cm or adjacent to major vessels. The findings of this study provided robust empirical evidence supporting for the utilization of SBRT in treating small HCC, while also establishing a solid foundation for future prospective clinical investigations.

The promising feeder-free allogenic NK cell therapy: Clinical outcomes of GIC-102 monotherapy (GIC-102101) and synergistic potential with GI-101 (CD80-IgG4 Fc-IL2v) in advanced solid tumors and hematologic malignancies.

e14526 Background: The allogeneic Natural Killer (NK) cell therapy derived from healthy donors may overcome the short lifespan and dysfunctional anti-tumor activity of current autologous approach. This limitation often restricts treatment efficacy and necessitating high dosages and frequent infusions. GIC-102, non-engineered / feeder-free, highly potent allogeneic NK cell derived from healthy donors, is a promising alternative. Here, we present the clinical outcomes from the Phase 1 study of GIC-102, along with nonclinical evidence demonstrating outstanding pharmacokinetics (PK) and pharmacodynamics (PD) when used in combination with a novel bi-specific Fc fusion protein, GI-101 (CD80-IgG4 Fc-IL2v/NCT04977453/KEYNOTE-B59). Methods: GIC-102101, a first-in-human study, evaluated GIC-102 monotherapy at doses of 1x109 QW and 3x109 QW in patients with advanced solid tumors or hematologic malignancies. A lympho-conditioning strategy using cyclophosphamide (300 mg/m2) and fludarabine (30 mg/m2) was implemented every two cycles before GIC-102 treatment. The study employed a conventional 3+3 dose escalation scheme. The primary endpoint was to determine the safety and tolerability of GIC-102, with tumor response assessed as secondary endpoints. Additionally, the PK/PD profile of GIC-102 in combination with GI-101 was evaluated in a mouse model. Results: As of December 31, 2023, six patients have been treated with GIC-102 monotherapy including two patients with Non-Hodgkin lymphoma (NHL), and four patients with metastatic colorectal cancer (CRC). The median number of prior treatments for patients with CRC and NHL was 4 and 6, respectively. No dose limiting toxicities (DLTs) were observed and maximum tolerated dose was not reached. Treatment-related adverse events (TRAEs) occurred in 5 patients (83%), with the majority being associated with the lympho-conditioning procedure; hyponatremia, neutropenia, lymphopenia and anemia. The best overall response was complete response (CR) in 1/6 patient (NHL) and stable disease (SD) in 4/6 patients (3 CRC, 1 NHL). Treatment for 1 CR (NHL) and 2 SD (CRC) is ongoing (for NHL, 215+ days/for CRC, 160+ days and 153+ days). The in-vivo study of GIC-102 in combination with GI-101 showed significantly enhanced anti-tumor activity and in-vivo NK cell proliferation lasting up to 4 weeks. Conclusions: The GIC-102, feeder-free allogeneic NK cell, was well tolerated without DLTs and demonstrated early promise in efficacy in patients for advanced solid tumors and hematologic malignancy. Further clinical investigation of GIC-102 in combination with GI-101, bi-specific Fc fusion protein, is currently ongoing. Clinical trial information: NCT05880043 .