bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-clinical evaluation of NT-112, an autologous T cell product engineered to express an HLA-C*08:02-restricted TCR targeting KRAS G12D and resistant to TGF-b inhibition.
Authors: Ma Jennifer , Tubb Vanessa , Mojadidi Michelle , Meade Kayla , Kong Xiangjun , Kroon Paula , Sareen Aastha , Stringer Bas , Krijgsman Oscar , Claasen Yvonne , Gadiot Jules , Buchner Karen , Eshuis Sander , Schumacher Ton , Linneman Carsten , Kuilman Thomas , van Heijst Jeroen , Bendle Gavin , Perez Arianne
Published: June 2024

e14533

Background: Adoptive transfer of T-cell receptor (TCR)-engineered T-cells to target shared cancer neoantigens is a promising new immunotherapy approach for patients harboring mutations in oncogenes such as KRAS. Activating mutations in KRAS are among the most prevalent oncogenic driver mutations in human cancers, with KRAS G12D being the most frequent KRAS mutation in colorectal carcinoma and pancreatic cancer. NT-112 is an autologous engineered T-cell product expressing an HLA-C*08:02-restricted TCR that specifically targets the KRAS G12D mutation. NT-112 is additionally engineered to lack TGF-β receptor II (TGFBR2) expression, rendering T-cells insensitive to TGF-b-mediated inhibition in the tumor microenvironment. Methods: For manufacturing of NT-112, CD4 and CD8 T-cells are enriched from leukapheresis material, activated in vitro and gene-edited to knock-out both endogenous TGFBR2 and TCR β constant 1/2 (TRBC1/2) and knock-in an HLA-C*08:02-restricted KRS G12D neoantigen-specific TCR at the TCR α constant (TRAC) locus using CRISPR-Cas9 technology. NT-112 product functionality was evaluated in both in vivo models and in vitro co-culture experiments with a panel of cell lines including those endogenously expressing the KRAS G12D mutation. T-cell reactivity was assessed by measuring cytotoxicity, proliferation, and cytokine production. For determination of NT-112 product safety, cross-reactivity and allo-reactivity assessments were carried out. A comprehensive analysis of potential off-target editing by CRISPR/Cas9 was performed to assess potential risk of genotoxicity in clinical grade NT-112. Results: High reactivity of the NT-112 TCR against KRAS G12D and HLA-C*08:02-expressing target cells was observed. T-cell activation and functionality was highly specific, as demonstrated by a lack of reactivity against KRAS WT, minimal cross-reactivity in Alanine and Glycine scans, and lack of T-cell activation in the absence of HLA-C*08:02. In vivo, NT-112 T-cells were able to induce tumor clearance in two independent models. Low frequency chromosomal translocation events (<0.1%) between on-target and off-target Cas9 cleavage sites were detectable in NT-112 T-cells. However importantly, these did not result in autonomous cytokine-independent growth. Conclusions: Non-clinical studies revealed a favorable safety and efficacy profile for NT-112 and supported further clinical development of a TGF-β-resistant TCR-edited T-cell product for mutant KRAS-targeted cancer immunotherapy.
Relationship between immune-inflammatory markers and clinical features and deepness of tumor response and prognosis of patients with PD-L1 ≥50% metastatic NSCLC receiving first-line immunotherapy.
Authors: Zheng Xixi , Zhou Lili , An Juan , Ding Xiaosheng , Hua Yichun , Shi Hui , Xu Weiran , Li Xiaoyan
Published: June 2024

e14547

Background: Patients with programmed cell death-ligand 1 (PD-L1) ≥50% metastatic non-small cell lung cancer (NSCLC) treated with first-line immunotherapy have heterogeneous clinical assessment and outcomes. In this study, we sought to identify features of patients with metastatic NSCLC who achieved high deepness of response (HDPR) to first-line immunotherapy, and how these might differ from features predictive of non-high deepness of response (NHDPR). The influence of clinical features on prognosis of patients with PD-L1 ≥50% were further clarified. Methods: This retrospective study analyzed patients with PD-L1≥50% metastatic NSCLC treated with first-line immunotherapy at Beijing Tiantan Hospital between July 2020 and December 2023. All the patients had at least one measurable lesion in lung according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. HDPR was defined as deepness of lung tumor response ≥50%, while NHDPR was defined as deepness of lung tumor response <50% or tumor enlargement. Tumor PD-L1 expression, target mutation, neutrophil-to-lymphocyte ratio (NLR), lactic dehydrogenase (LDH) level, and other prognostic variables were analyzed to identify characteristics enriched in patients achieving HDPR compared to NHDPR. We also investigated the effects of these variables on first-line progression-free survival (PFS) and overall survival (OS) of the patients. Results: A total of 17 patients were included in our retrospective analysis. Seven (41.2%) patients achieved HDPR (range: -50%, -72%) and ten (58.8%) patients achieved NHDPR (range: -13%, -45%). Seven (41.2%) patients had central nervous system (CNS) metastases at the first diagnosis of lung malignancy, and their CNS target lesions shrinkages were observed after therapy (range: -32%, -100%). Lower Th/Ts ratio ( P=0.01) and drug resistance mutations (TP53/KRAS/EGFR) ( P=0.001) were found enriched for NHDPR compared to HDPR. However, no differences were found in tumor PD-L1 expression, NLR, LDH, B lymphocyte subset, NK cell subset, pathological type, T-stage, smoking index, ECOG score, immunotherapeutic schemes, or CNS metastases between the two groups ( P>0.05). With a median follow-up of 26.0 months (range: 17.2-34.8 months), the median first-line PFS and OS were 9.0 months (95% CI: 5.0-13.0) and not reached (NR), respectively. The NLR was identified as an independent prognostic factor on first-line PFS. Patients with an NLR≥4 exhibited a worse median PFS (7.0 months vs. NR; P=0.033; 95%CI: 1.2-80.2) than those with an NLR<4 following first-line immunotherapy. Conclusions: Among patients with PD-L1≥50% metastatic NSCLC who received first-line immunotherapy, lower Th/Ts ratio and drug resistance mutations showed a diminished tumor response and higher NLR ratio exhibited a worse median PFS.
The prognostic impact of transforming growth factor beta 2 (TGFB2) mRNA levels, in conjunction with interferon-gamma receptor activation of interferon regulatory factor 5 (IRF5) and expression of CD276/B7-H3 in low-grade gliomas.
Authors: Trieu Vuong N. , Maida Anthony Ernest , Qazi Sanjive
Published: June 2024

e14564

Background: Low-grade glioma (LGG) tumors are characterized by a low infiltration of immune cells, requiring therapeutic interventions to boost the immune response. Methods: We analyzed mRNA expression datasets from the UCSC Xena web platform to compare normal brain tissue with LGG tumor samples to screen for upregulated genes. We also used cBioportal to determine the relationship between mRNA expression levels of 513 LGG patients and their overall survival (OS) outcomes. Results: Tumor-associated macrophage (TAM) markers, MSR1/CD204, CD86, and CD68, exhibited a 6-fold (P<0.0001), 8.9-fold (P<0.0001), and 15.6-fold increases in mRNA expression levels, respectively in LGG tumors. Both TGFB1 (4.1-fold increase, P<0.0001) and TGFB2 (2.2-fold increase, P<0.0001) were upregulated in brain tumors, suggesting that TGFB ligands are pivotal in establishing an immunosuppressive TME. In addition, mRNA upregulation of interferon-gamma receptors, IFNGR1 and IFNGR2, and signaling molecules STAT1, IRF1, and IRF5, pointed to an essential role for IFN-γ mediated remodeling of the TME. A tumor-associated antigen, CD276/B7-H3, mRNA expression showed a significant (P<0.0001) 4.03-fold increase in tumor tissue. Multivariate Cox proportional hazards models investigating the interaction of TGFB2 and activation of IFNGR2, STAT1, IRF1, or IRF5 showed that the prognostic impact of high mRNA levels (25 percentile cut-off) of TGFB2high was independent of IFNGR2, STAT1, IRF1, or IRF5 mRNA levels (TGFB2high HR (95% CI) = 4.07 (2.35-7.06), 6 (3.62-10.11), 4.38 (2.67-7.17), and 4.48 (2.82-7.12) for models with IFNGR2, STAT1, IRF1, or IRF5 respectively). Patients with high levels of TGFB2 were overrepresented by LGG patients with IDH wild-type mutation status. The prognostic impact of TGFB2high and IDH wild-type observed by the increases in hazard ratios for TGFB2 (HR (95% CI range) = 2.02 (1.05-3.89)) and IDH wild-type (HR (95% CI range) = 4.44 (1.9-10.4)) were independent predictors of survival requiring risk stratification of patients identify LGG patients with IDH wild-type and TGFB2high in the design of clinical trials. The ratio of TGFB1:TGFB2 expression levels was also a prognostic indicator for OS, whereby patients who exhibited a 2.5-fold greater level of TGFB1 compared to TGFB2 mRNA levels experienced improved survival outcomes. A 1.8-fold higher TGFB2 levels, the mRNA expression corresponded to worse OS. Conclusions: The specific abrogation of TGFB2 and not TGFB1 by OT101, a TGFB2-specific synthetic phosphorothioate antisense oligodeoxynucleotide, is a prerequisite to employing a strategy to target TGFB pathways. IRF5 and CD276/B7-H3 as prognostic markers are potential targets for combination therapies with TGFB2 inhibitors.
TROCEPT: An oncolytic virus platform engineered for αvß6 integrin targeted tumor-localised expression of an immune checkpoint inhibitor following intravenous delivery.
Authors: Krige David , Khanolkar Rahul C. , Davies James A. , Baker Alexander T. , Webb Thomas A. , Shahreza Somayeh , Uusi-Kerttula Hanni K. , Williams Lucy M. , Henderson Emma , Moore Samantha L. , Pentier Johanne M. , Jakobsen Bent K. , Parker Alan L. , Cole David K. , Gerry Andrew B.
Published: June 2024

e14579

Background: TROCEPT is a novel tumor-selective replicating, oncolytic adenovirus type 5 (Ad5) rationally engineered to remove all natural tissue tropisms. This engineering addresses the main limitation of other viral therapies which infect normal tissues and are rapidly removed by the liver and are therefore limited to local delivery. TROCEPT has been further engineered to specifically bind to αvβ6 integrin which is expressed at high frequency in the majority of epithelial cancers, so that following intravenous delivery the virus targets tumor tissue where it replicates and amplifies. In addition, the TROCEPT platform encodes transgenes which enables in-tumor production of powerful therapeutic drugs. The lead programme, TROCEPT-01, encodes a fully human, full length immune checkpoint inhibitor (ICI) antibody. TROCEPT-01 is currently undergoing IND-enabling studies and is expected to enter First in Human studies in 2024 in multiple solid tumor indications. Methods: Proof of concept studies, both in vitro and in vivo, to demonstrate TROCEPT-01’s tumor selectivity and toxicity profile have been performed. Results: In vitro experiments demonstrate that viral replication, transgene expression and oncolytic cell death following infection with TROCEPT-01 is highly selective for αvβ6 integrin positive tumor cells compared to a panel of normal human primary cells. Intravenous delivery in in vivo SKOV3 ovarian human tumor xenograft mouse models demonstrate virus delivery, replication, and transgene expression in the tumor. In comparison to the parental Ad5 virus, the engineering of TROCEPT-01 leads to more viral delivery to the tumour, less delivery to normal tissue including liver, reduced markers of liver toxicity and reduced inflammatory cytokine release, all of which validate the tumour selectivity and safety profile of the virus. Conclusions: We have demonstrated that TROCEPT engineering enables highly selective tumor targeting and significant tumor exposure following intravenous delivery. TROCEPT-01’s in-tumor selective expression of ICIs enables high local drug concentration in the tumor, potentially reducing systemic toxicity and increasing efficacy. TROCEPT-01 is currently undergoing IND-enabling studies and is expected to enter First in Human studies in 2024 in multiple solid tumor indications.
Preliminary safety, antitumor activity, and pharmacodynamics of intratumoral ABO2011 (IL-12 mRNA) in patients with advanced solid tumors.
Authors: Li Ning , Li Ning , Wang Yong , Cui Ningyi , Wang Xin , Tang Yu , Chu Yuting , Meng Qingwei , Lin Rui , Wu Yan , Ying Bo
Published: June 2024

e14583

Background: Interleukin (IL)-12 is a potent immunomodulatory cytokine demonstrating robust antitumor activity in multiple preclinical studies and potent immune-stimulating potential in humans. However, systemic delivery of IL-12 can result in life-threatening toxicity and therefore has shown limited efficacy at doses that can be safely administered. ABO2011 is a human IL-12 mRNA encapsulated in lipid nanoparticle and has been developed to be more effective and less toxic through the use of novel delivery technology and intratumoral injection. Methods: This phase I trial enrolled adults with advanced solid tumors who failed available standard treatments (NCT05392699). The trial was designed to primarily evaluate the safety of ABO2011 in single-dose cohorts and multiple-dose cohorts using “3+3” dose escalation approach. Patients (pts) would receive intratumoral ABO2011 at either a single dose, QW with 3 doses overall, every 3 weeks (Q3W) or QW followed by Q3W. Results: As of 09 December 2023, a total of 20 pts were enrolled and received at least one dose of ABO2011 at 4 μg single dose, 4 μg QW for 3 times, 12 μg single dose, 12 μg QW for 3 times followed by Q3W, 24 μg Q3W and 48 μg Q3W. Seventeen (85%) pts experienced treatment-related adverse events (TRAEs), and all were grade 1 or 2, including pyrexia (35%), pain (25%), and gamma-glutamyl transferase increased (25%). There were no dose-limiting toxicities or treatment-related SAEs reported and no TRAEs leading to treatment discontinuation. Of the 17 evaluable pts per RECISIT v1.1, 5 maintained stable disease, and the progression free survivals achieved 6.0 months, 5.6 months and 4.1 months for pts with colorectal cancer (6th line), non-small cell lung cancer (5th line) and pancreatic cancer (4th line), respectively. Peripheral blood IL-12 and IFN-γ levels increased and peaked at 24 hours and 48 hours after dosing, respectively, indicating expression of IL-12 and subsequent induction of IFN-γ after ABO2011 administration. Dose-dependent elevation of CXCL9, CXCL10, CXCL11 in peripheral blood was observed, consistent with the activation of downstream pathway of IFN-γ. CD8 T cells infiltration and PD-L1 expression were increased in tumor microenvironment (TME) at day 7, and further RNA sequencing analysis revealed increase of activated CD8 T cell and antigen processing and presentation after study treatment, suggesting the regulation of TME by ABO2011 and supporting the combination with PD-1(L1) inhibitor. Conclusions: Intratumoral ABO2011 was safe and well-tolerated in pts with advanced solid tumors. The pharmacodynamic changes were as expected. Promising preliminary antitumor activities of the single agent and the pharmacodynamic profiles support further investigation of ABO2011 in combination with immune checkpoint inhibitor. Clinical trial information: NCT05392699 .
Effect of TT-816, a novel immune response modifier targeting cannabinoid CB2 receptor, on antitumor immunity and cancer growth.
Authors: Fan Peidong , Elzein Elfatih , Yao Lina
Published: June 2024

e14595

Background: The endocannabinoid system is widely expressed in the human body, including the innate and adaptive immune system, where endocannabinoids, Δ9-tetrahydrocannabinol and synthetic ligands regulate immune suppression. The effects of endocannabinoids on immune regulation are primarily mediated by G-protein coupled cannabinoid CB2 receptors (CB2R) via several mechanisms, including immune cell development, migration, proliferation and T and NK cell effector functions. The upregulated expression of CB2R and elevated levels of endocannabinoids have been observed in a variety of tumor microenvironments and are associated with the aggressiveness of cancer. Methods: NK cell function was determined by co-culturing TT-816 pretreated NK cells with K562 cancer cells for 24 hours. The mixed lymphocyte reaction assay was conducted by co-culturing human CD4+ T cells with monocyte-derived dendritic cells. Cell viability was measured by FACS and IFN-g by MSD. The in vivo efficacy of TT-816 was determined in the murine syngeneic B16F10 melanoma and MC38 colorectal cancer models. Tumor-bearing C57BL/6 mice were randomized 6 days after inoculation and treated with vehicle (0.5% CMC, QD) or with TT-816 at 1, 4 or 10 mg/kg (QD) orally, or anti-PD1 (RMP1 14) at 5 mg/kg (Q3D), intraperitoneally. Tumor size and body weight were determined every 2 to 3 days. Data represent mean±SEM. Results: TT-816 concentration-dependently enhanced the functions of NK cells, dendritic cells and T cells. It increased NK cell killing of the human cancer cells and IFN-g production, significantly stimulated the expression of CD86, HLA-DR, IL-12 and TNF-a in monocyte-derived dendritic cells, and enhanced CD4+ T cell proliferation and IFN-g production in a mixed lymphocyte reaction assay. In B16F10 melanoma and MC38 colorectal cancer models, TT-816 dose-dependently inhibited the tumor growth. Furthermore, combination of TT-816 with anti-PD1 synergistically inhibited both tumor growth. In B16F10 model, treatment with TT 816 (4 mg/kg, QD) alone significantly inhibited the tumor growth by 45%. By contrast, anti-PD1 had little effect (TGI 5%). However, the combination of TT-816 with anti-PD1 resulted in a TGI of 72%. In the MC38 model, treatment with TT-816 (4 mg/kg, QD) and anti-PD1 alone, achieved TGI of 50% and 36%, respectively. When combined, TGI was increased to 88%. Conclusions: TT-816 is a novel, oral small molecule immune response modifier that selectively blocks CB2R on immune cells and cancer cells. Preclinical data have demonstrated that it stimulates antitumor immune response and inhibits cancer growth in both hot and cold tumor models. TT-816 is currently undergoing phase 1 clinical trials for the treatment of a broad range of solid tumors.
Possibilities of long-term atezolizumab immunotherapy in patients with metastatic urothelial cancer.
Authors: Kamishov Sergey , Tillyashaykhov Mirzagaleb , Boyko Elena , Niyozova Shakhnoza Khamoydinovna , Izrailbekova Kamila , Lipartiya Meri , Kobilov Odiljon , Rafiev Dilshod
Published: June 2024

e14628

Background: Results from various studies have indicated that atezolizumab can be an effective and well-tolerated treatment option for patients with advanced and metastatic urothelial cancer. However, the landscape of oncological practices in Uzbekistan reflects a scarcity of experience and data concerning the utilization of atezolizumab in the treatment of patients afflicted with urothelial cancer. This research endeavors to bridge this gap by contributing. Methods: In our retrospective study, a total of 44 patients were selected, with a mean age of 64.5±7.6 years, diagnosed with stage IV urothelial cancer and the presence of distant metastases in the lungs, bones, and liver. There were 28 (63.6%) males and 16 (36.4%) females. Group 1 included 18 (40.9%) patients with elevated PD-L1 levels SP142 – IC 2/3, receiving atezolizumab at 1200 mg intravenously (IV) on day 1 of each 21-day cycle + cisplatin at a dose of 70 mg/m2 body surface area (BSA), IV, on day 1 of each cycle, and gemcitabine at a dose of 1000 mg/m2 BSA, IV, on days 1 and 8 of each cycle. Group 2 included 26 (59.1%) patients receiving standard chemotherapy (cisplatin + gemcitabine) in the same regimens. Immunohistochemical analysis was performed using the Ventana Bench Mark Ultra automated stainer with Ventana PD-L1 SP142 monoclonal antibodies. Results: The research was conducted from September 2019 to May 2023, and the administered treatment was the first line for these patients. Treatment was administered until disease progression was registered or until the development of unacceptable toxicity. Grade I toxicity was not observed in both groups. Grade II toxicity in Group 1 was noted in 3 (16.7%), and in Group 2 - in 4 (15.4%). Grade III toxicity was identified in 9 patients (50.0%) in Group 1 and 14 patients (53.8%) in Group 2. Grade IV toxicity was encountered in 6 patients (33.3%) in Group 1 and 8 patients (30.8%) in Group 2. Hematological toxicity, regardless of atezolizumab use, predominated among the III and IV degrees of toxicity. The median overall survival in Group 1 was 14.8 months (95% CI: 12.8-16.2), while in Group 2, it was 11.9 months (95% CI: 9.3-13.5). Progression-free survival in Group 1 was 6.8 months (95% CI: 5.1-7.4), and in Group 2, it was 4.3 months (95% CI: 3.8-5.7). The objective response rate in Group 1 was 44.5%, and in Group 2, it was 38.5%. Conclusions: Atezolizumab, used in combination with standard platinum-based chemotherapy in the first line, improves treatment outcomes for metastatic urothelial cancer by increasing overall survival and progression-free survival without causing an increase in the toxicity of the administered therapy.
Alleviating lung injury and pulmonary fibrosis in radiotherapy-immunotherapy combination: The role of low-dose radiation therapy.
Authors: Wang Yu , Su Shengfa
Published: June 2024

e14632

Background: Lung cancer continues to be the primary cause of cancer-related mortality on a global scale. The integration of radiotherapy and immunotherapy has yielded significant advancements in the treatment of locally advanced non-small cell lung cancer. However, the occurrence of treatment-associated pneumonia remains the predominant adverse event necessitating treatment cessation and permanent medication discontinuation. The immune-modulating effects of radiation therapy on the body contribute to a complex interplay between radiation and inflammation. Low-dose radiotherapy (LD-RT) has historically been utilized for the management of benign inflammatory conditions. Recently, LD-RT was found to be effective in treating severe pneumonia in patients with severe COVID-19 as well as acute respiratory distress syndrome (ARDS). This investigation seeks to examine the impact of LD-RT on lung tissue morphology and the inflammatory immune microenvironment in preclinical models of lung injury induced by high-dose radiotherapy combined with programmed death-1(PD-1) inhibitor therapy. Methods: 6-8 week old C57BL/6 mice were treated with a single high-dose thoracic radiotherapy (15Gy) and the PD-1 inhibitor (once a week), with or without the low-dose radiotherapy (1.0/1.5Gy) four weeks later. Lung tissue was collected one and a half months and three months respectively after the initial high-dose radiotherapy for evaluation using HE and Masson staining, Image J software for analysis of collagen volume fraction (CVF), and immunohistochemical staining for CD3+ and CD8+ T lymphocytes. Cytokine transforming growth factor (TGF)-β1、interleukin (IL)-6 and tumor necrosis factor (TNF)-α level in lung tissue was detected by ELISA. Statistical analysis was performed using GraphPad Prism 9.5.0 software. Results: The radiotherapy-immunotherapy combination (iRT) group exhibits notable lung injury characterized by the proliferation of alveolar type II epithelial cells, thickening of alveolar septa, interstitial edema, pulmonary congestion and bleeding, increased infiltration of inflammatory cells, and significant deposition of interstitial collagen fibers. In contrast, the iRT+ LD-RT group demonstrates a significant decrease in lung tissue damage, interstitial fibrosis, collagen volume fraction (CVF), levels of IL-6 and TGF-β, as well as the infiltration of CD3+ and CD8+T cells compared to the iRT group. Conclusions: Low-dose radiation has the potential to ameliorate lung injury induced by the combination of radiotherapy and PD-1 inhibitors by modulating the inflammatory milieu, thereby potentially mitigating the development of pulmonary fibrosis.
The pan-cancer landscape of SMARCA4 and SMARCB1 alterations in a large cohort of Chinese patients.
Authors: Song Qingling , Xie Junjie , Guan Minxiao , Wu Huijia , Lv Yanling , Yuan Mengdi , Wang Yu , Zhao Jiaxing , Jiang Zeyu , Zhang Yafei , Pu Xingxiang
Published: June 2024

e14636

Background: Alterations of SMARCA4 or SMARCB1 (SMARCA4/B1) proteins have been identified in various aggressive cancers. Recent studies show that tumors harboring deleterious SMARCA4/B1 alterations express PD-L1 and respond to immune checkpoint inhibitor (ICI) therapies. Current ongoing immunotherapy-based clinical trials for cancers deficient in SMARCA4/B1 include combinations of atezolizumab and the TIGIT antibody tiragolumab (Phase II), as well as nivolumab and the CTLA-4 antibody ipilimumab (Phases II & III). Here we present a comprehensive analysis of the pan-cancer landscape of SMARCA4/B1 alterations, based on real-world data from a large cohort of Chinese patients. Methods: From 2021 to 2023, we collected genomic information from 16,113 cancer patients, spanning more than 40 different cancer types. These patients had undergone targeted next-generation sequencing (NGS) through the Med1CDx panel, which targets 601 cancer-associated genes. After excluding 1,034 samples of unidentified tumor origins, 15,079 samples were analyzed further. The analysis included somatic and germline pathogenic/likely pathogenic (P/LP) single-nucleotide variants, insertions/deletions, and copy number alteration in SMARCA4/B1. Results: We identified 421/15079 (2.8%) patients with SMARCA4/B1 alterations, with a median age of 63 years (range 13-90). Cancer types with a higher frequency of SMARCA4/CB1 mutations include: endometrial cancer (9.8%), thyroid cancer (6.9%), gastric cancer (6.2%), cholangiocarcinoma (5.7%), and lung cancer (4.4%). The predominant mutation type is variants of uncertain significance (VUS) gene mutations, constituting 72% (302/421) of the spectrum, with nearly all being missense mutations. These are mainly observed in lung cancer, thyroid cancer, and colorectal cancer. The frequency of pathogenic/likely pathogenic mutations is 28% (119/421), mainly distributed in lung cancer and liver cancer. Q201L, P222L, and E1364del are the most common mutations in SMARCA4, with a mutation rate of approximately 4.1%, occurring across over five cancer types. The most common co-mutations of SMARCA4/B1 were TP53 (47.3%), EGFR (25.4%), KRAS (15.9%), STK11 (7.1%) and CDKN2A (7.4%). Clinicopathological feature of age showed no significant differences between SMARCA4/B1 mutant and wild-type groups. Tissues with SMARCA4/B1 mutations exhibited a higher tumor mutational burden (TMB) (median=8.3) than wild-type tissues (median=4.2) (P < 0.001). Conclusions: Elevated TMB levels in patients with SMARCA4/B1 mutations suggest a significant potential benefit from immunotherapy. The presence of co-mutations may also aid in predicting the efficacy of combination immunotherapy treatments. Furthermore, the high prevalence of VUS emphasizes the need for additional research to determine their clinical relevance.
Effect of IL-15 on anti-tumor immune response to radio-immunotherapy through systemic immune activation.
Authors: Jin Peng , Meng Xue
Published: June 2024

e14641

Background: In this study, we propose to investigate the key role of IL-15 in radio-immunotherapy and its mechanism in regulating systemic immune activation by radio-immunotherapy. And further explore the potential of IL-15 combined with radio-immunotherapy. Methods: LLC5 and MC38 cells were used in this study. Mouse model and co-culture model were constructed to analyze the effect of IL-15 after radio-immunotherapy. Anti-IL-15 antibody was used to clarify the role of IL-15 on radio-immunotherapy. Flow cytometry and multiplex immunofluorescence were used to clarify IL-15Rα lever in macrophage after radio-immunotherapy. The effect of IL-15 in tumor and secondary lymphoid organ(SLO) was observed after macrophage removal. Macrophage IL-15 level were tested by ELISA. Tumor growth, TME, and memory effect after IL-15 combined with radio-immunotherapy were observed. In co-culture model, CD8+ T cell function were tested. Clearance macrophage of mice to determine the role of macrophage in combination therapy. After macrophages co-cultured with tumor cells, cytokine microarray was used to analyze the cytokine secretion of macrophages in combination treatment. Results: IL-15 secretion was significantly upregulated in TME after radio-immunotherapy. IL-15 and IL-15Rα were most enriched on macrophages and IL-15Rα was significantly increased after radio-immunotherapy. IL-15 inhibition significantly attenuated tumor killing and systemic immune activation and resulted in decreased IL-15Rα expression on macrophages. Removal of macrophages resulted in a significant reduction of IL-15 in tumor and spleen. Radio-immunotherapy in the co-culture model induced a significant increase of IL-15 secreted by macrophages.IL-15 combined with radio-immunotherapy can significantly controlled tumor growth, stimulated systemic immune activation, and CD8+ T cells and memory T cells were significantly increased in the circulation of long-term survival mice. In co-culture experiments, combination treatment stimulated proliferation and secretion of IFN-γ+CD8+ T cells. And it stimulated macrophages secrete more chemokines, especially CCL5, recruit more CD8+ T cells aggregate around macrophages. Macrophage clearance and co-culture experiments confirm that the synergistic effect of this combination therapy is mainly dependent on macrophages. Conclusions: IL-15 plays a critical role in systemic immune activation induced by radio-immunotherapy. Macrophages are the main cellular site of IL-15 effect in the microenvironment of tumor and SLO after radio-immunotherapy. IL-15 combined with radio-immunotherapy had a synergistic antitumor effect, and this combination treatment induced a further enhancement of memory T-cell-mediated systemic immune activation. Macrophage-secreted chemokines such as CCL5 played an important role in the antitumor effect of this combination therapy strategy.
Effect of a novel anti-PD-1-proIL-2 bifunctional fusion protein on potent anti-tumor activity via PD-1 checkpoint inhibition and conditional IL-2R agonism.
Authors: Zhou Harry , Li Zijuan , Zhang Feifei , Zhang Ze
Published: June 2024

e14697

Background: HD IL-2 was approved by FDA for metastatic melanoma (mM) and renal cell carcinoma (mRCC) but the treatment is associated with severe toxicities. PD-1 blockade has improved the overall survival, but only in 20-30% of cancer patients and many of them experience frequent relapses. Interestingly, HD IL-2 therapy displayed durable anti-tumor activity in mM and mRCC patients who progressed on anti-PD-1. Furthermore, combination therapy of IL-2 and pembrolizumab in mRCC has shown durable 70% response rate, while the ORR of monotherapy is 20% and 33% for IL-2 and pembrolizumab, respectively. Thus, combining IL-2 receptor activation and PD-1 blockade may represent a promising strategy in the post PD-1 era to overcome the resistance and improve the clinical efficacy. PTX-912 is a novel bifunctional PD-1-proIL-2v fusion protein designed to simultaneously harness PD-1 blockade and PD-1-cis directed IL-2R agonism conditionally in TME without the peripheral toxicities associated with IL-2. Methods: The biological functions were demonstrated in human PBMC assays. Anti-tumor efficacy and biomarker studies were evaluated in mouse / human PBMC xenograft models. Tox studies were performed in NHP. Results: PTX-912 shows dose-dependent inhibition of PD-1 pathway measured by GM-CSF and IFNgamma production in an MLR assay. Protease activated PTX-912, but not the intact drug, stimulates the phosphorylation of STAT5 of NK and T cells, the proliferation of CD8 T cells as well as the cytokine production in human whole blood. The potency of pSTAT5 by protease activated product is enhanced by > 10 folds on PD-1+ T cells than T cells without PD-1. When tested in mouse tumor models resistant to PD-1 blockade, PTX-912 demonstrated high potency of tumor inhibition at as low as 0.1 mg/kg dose. In contrast, non-targeted proIL-2v at molar equivalent or higher dose showed minimal antitumor effect in either monotherapy or combination with anti-PD-1. Analysis of PTX-912 treated mice showed increased tumor infiltrating CD4+ and CD8+ T cells, including PD-1+Tcf-1+ and PD-1+ IL-18Ra+TIM3- CD8+ T cells, referred to “stem-like” progenitor effector cells and “better” effector cells, respectively. Activation of the IL-2v in PTX-912 was observed in mouse tumor tissues but not in the plasma. In monkey GLP-compliant 4-week repeat-dose toxicity study, PTX-912 demonstrated excellent safety profiles without overt irAEs that are characteristic of IL-2. Conclusions: Our preclinical data demonstrated that PTX-912 effectively stimulated the expansion and reinvigoration of antigen specific T cells in the tumor tissue resulting in strong anti-tumor efficacy while it did not cause significant peripheral toxicity. Phase 1 clinical trial of PD-1-proIL-2v is planned to start in early 2024 to evaluate the safety, pharmacokinetics and anti-tumor activity in patients with advanced solid tumors.
Immune checkpoint inhibitor-associated gastrointestinal adverse events in patients with colorectal cancer.
Authors: Shatila Malek , Pizuorno Machado Antonio , Aujla Parvir , Huey Ryan W , Wang Yinghong , Thomas Anusha
Published: June 2024

e14708

Background: Immune checkpoint inhibitors (ICI) are successfully used to treat microsatellite instability-high (MSI-H) tumors. While immune checkpoint inhibitor related colitis is a frequent and devastating immune related adverse event (irAE) of these agents, the incidence and characteristics of this inflammatory toxicity in patients with MSI-H colorectal cancers has not been examined. We aimed to describe the characteristics and clinical profile of patients diagnosed with luminal gastrointestinal irAE in patients treated with ICI for colorectal cancer in a tertiary cancer care center. Methods: This is a retrospective analysis that included adult cancer patients diagnosed with colorectal cancer that received ICI between 6/1/2014 and 12/31/2022. We report data on those that developed colitis as an irAE up to 3 months after the last dose of ICI confirmed by laboratory and/or imaging report. We included patients’ demographic characteristics, oncologic profile and outcomes as well as clinical course, endoscopic features as well as treatment and outcomes in terms of luminal gastrointestinal irAEs. Results: Out of 474 patients with colorectal cancer on ICI in our study period, only 18 developed a gastrointestinal irAE with an incidence of 3.8%. Patients were primarily Caucasian (88.8%) males (61.1%) with a median age of 69.5 years. The majority of these patients received combination therapy with anti-PD1/L1 and CTLA-4 (50%). 66.6 % received ICI for MSI-H colorectal cancer. 11.1% of our sample were noted to have a second cancer-melanoma. The major-ity of patients had grade 1-2 colitis (61.2%) and grade 1-2 diarrhea (88.8%). Only 5 patients underwent endoscopic evaluation of whom, 2 had ulcerative inflammation necessitating use of selective immunosuppressive therapy with biologics. 61.1% had to withhold cancer treatment due toxicity. With regards to other gastrointestinal irAEs among this population, 41.4% and 5.8% were noted to have liver and pancreas toxicity respectively, with a median CTCAE grade of severity 2. The most common treatment for these toxicities were steroids. Conclusions: Luminal gastrointestinal irAEs seem to occur less frequently and at a lower severity among patients with MSI-H colorectal cancer after checkpoint inhibitors exposure compared to the overall incidence of the same among other cancers reported in literature. Larger prospective studies are necessary to determine the role of tumor biology and the gut microbiome in the disease profile and severity of immune related adverse events of the GI organ system. [Table: see text]
Immune-related adverse events in patients treated with immunotherapy according to corticosteroid exposure.
Authors: Meraz-Brenez Andres , Aranda-Gutierrez Alejandro , Soliz Dhylan Jael , Reyes-Vanegas Diego , Gonzalez-Sanchez Hector Raul , Martinez-Cannon Bertha Alejandra , Verduzco-Aguirre Haydee Cristina
Published: June 2024

e14709

Background: Patients with cancer require treatment with corticosteroids for multiple reasons, including prevention of chemotherapy-related side effects. Although corticosteroid use has been associated with lower efficacy of immune checkpoint inhibitors (ICI) in some studies, whether corticosteroid exposure affects the presence and severity of immune-related adverse events (irAEs) remains unclear. Methods: Retrospective single-center study of patients diagnosed with solid tumors treated with ICI. Eligible patients were those who received at least one cycle of ICI and had at least 1 month of follow-up post-ICI initiation. Patient data were extracted from electronic medical records. Comparisons between groups were made based on steroid exposure (defined as the administration of >10 mg of prednisone or its equivalent for >10 days within a 30-day period or at any point during ICI treatment, excluding steroid treatment for irAEs). Associations between variables were assessed using independent samples T-test, Chi-square, and Fisher’s exact tests. Results: We included 135 patients (mean age 61 years, SD 13); 72 (54%) were male. Forty-two (31%) had been exposed to steroids (mean prednisone equivalent of 427 mg, SD 298). Most patients received ICI as palliative treatment for advanced disease (105/135; 78%), primarily as first-line therapy (79/105; 75%). Patients exposed to corticosteroids were more likely to have received ICI with chemotherapy (76% vs 1%, p<0.001), were younger (56 vs. 63 years, p=0.009), more likely to be female (62% vs. 39, p=0.014), and had lower median Charlson Comorbidity Index scores (2 vs. 3, p=0.026). Steroid-exposed patients were more likely to have employed ICI in the neoadjuvant or adjuvant settings (36 vs. 16%, p=0.024) or as third or subsequent line therapy (26 vs. 8%, p=0.044). There were no statistically significant differences in the frequency of irAEs of any grade based on steroid exposure (31% vs 41%, p=0.252). However, patients who were exposed to steroids were significantly less likely to delay or suspend ICI (10% vs. 32%, p=0.005). No other parameters were associated with the rate or severity of irAEs. Conclusions: Our findings suggest that corticosteroid exposure does not increase the frequency of irAEs in patients treated with ICI, but it is associated with a reduced likelihood of discontinuing ICI due to irAEs. These observations suggest that corticosteroids may play a beneficial role in managing patients undergoing immunotherapy, particularly in sustaining treatment continuity despite irAEs. This study underscores the need for further investigation into optimal steroid use strategies to enhance patient outcomes with immunotherapy, especially in situations when they are commonly prescribed, such as premedication for chemotherapy.
FS-1502 in patients with HER2 high expression, locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma: An open-label, multicenter, phase II study.
Authors: Pan Hongming , Yuan Xiang-lin , Zheng Yu , Peng Hui , Qiu Hong , Wang Jufeng , Li Zhiwei , Gao Shegan , Niu Zuoxing , Yang Jianwei , He Yifu , Wu Guowu , Yu Yiyi , Jieer Ying , Wang Yusheng , Li Zhen , Bai Jun , Liu Huilong , Wu Zhuli , Wang Xingli
Published: June 2024

e15000

Background: FS-1502 is an antibody-drug conjugate composed of an anti-HER2 antibody, linker, and Monomethylauristatin F. In this study, we conducted an open-label, multicenter, two-cohort phase II trial to evaluate the efficacy and safety of FS-1502 in HER2- positive locally advanced or metastatic gastric or gastroesophageal junction cancer. Methods: Pts with HER2-positive (IHC 3+ or 2+/FISH+) who had received ≥1 prior treatment regimens were eligible and received FS-1502 2.3 mg/kg alone every 3 weeks. The study consists of Cohort 1 for pts received ≥2 lines of previous therapy and Cohort 2 for pts only received first-line of previous therapy, respectively. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression free survival (PFS), overall survival (OS), duration of response, disease control rate, and safety. Results: At data cutoff (Dec 24,2023), 46 pts were enrolled (intent-to-treat [ITT]), 35 pts were confirmed HER2-positive (IHC 3+ or IHC 2+/ISH+, Efficacy Evaluable Set [ES]) by central laboratory. In the ES, the median age was 58.3 years, 48.6% were IHC3+ and primary tumor location in 77.1% of pts was GC. 45.7% (16/35) pts had assigned to cohort 1 and 54.3% (19/35) pts had assigned to cohort 2. In cohort 1, median study follow-up time was 10.1 months, the investigator-assessed ORR was 37.5% (95% CI, 15.2-64.6), median PFS and OS were 4.3 months (95% CI, 1.5-5.8 months) and 10.0 months (95% CI,5.1-NA months), respectively. In cohort 2, median study follow-up time was 12.5 months, the investigator-assessed ORR was 52.6% (95% CI, 28.9-75.6). PFS and OS were 4.4 months (95% CI, 3.0-7.3 months) and 14.6 months (95% CI, 8.7-NA months), respectively. Grade≥3 treatment-related TEAEs were reported in 12 (26.1%) pts, ≥5% were hypokalemia (6.5%) and fatigue(6.5%). No adverse events leading to drug discontinuation or death. Efficacy and safety data are shown in table. Conclusions: FS-1502 showed promising activity with tolerable and manageable safety profile, which warrants further development in HER2-postive, advanced gastric or gastroesophageal junction adenocarcinoma who had received ≥1 prior treatment regimens. [Table: see text]
Disitamab vedotin combined with fruquintinib in patients with HER2-expressing or HER2 mutation/amplified metastatic colorectal cancer refractory to at least two standard regimens: A prospective, exploratory, single-arm study.
Authors: Xu Hui , Peng Jin , Wu Han , Yang Lei , Wang Wenbo , Wang You , Long Xin , He Linli , Zhou Fuxiang
Published: June 2024

e15003

Background: Human epidermal receptor growth factor 2 (HER2) -expressing or amplified has been identified in 2-6% of patients with stage 3/4 colorectal cancer (CRC), and is associated with poor prognosis, however there are currently no approved HER2-targeted therapies for CRC in China. Herein, we aimed to study the antitumor activity and safety of Disitamab vedotin (RC48), a novel humanized anti-HER2 antibody conjugated to MMAE via a cleavable linker, combined with fruquintinib in patients with HER2-expressing or -amplified metastatic colorectal cancer. Methods: In this prospective, exploratory, single-arm study, patients diagnosed pathologically with mCRC, 18-75 years old harboring HER2 expression or HER2 mutation/amplification, and received at least two lines of treatment. HER2 expression was defined as a score of 1+, 2+ or 3+ on immunohistochemical [IHC] analysis, or mutation/amplification by NGS. Patients received RC48 2.5mg/kg intravenously every 2 weeks. Meanwhile, fruquintinib 3mg was administered orally once daily on days until disease progression, death, intolerable toxicity, withdrawal of consent. The primary endpoint was objective response rate (ORR) per RECIST v1.1; the secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: A total of 12 patients were enrolled from November 25, 2022 to June 6, 2023. The results of baseline molecular profiling revealed 4 with IHC 1+, 4 with IHC 2+, 2 with IHC 3+, and 2 with HER2 amplification. In the metastatic setting, patients had received a median of 4 (range, 3-6) lines of prior systemic therapy. In the per-protocol set, the investigator-assessed ORR was 18.2% (2/11) and DCR was 90.9% (10/11). Median PFS was 5.5 months (95% CI: 2.7-8.2) and the median OS was 12.3 months (95% CI: 5.3-19.3). During the study process, 11 (91.7%) patients experienced adverse events (AEs), among which, 4 (33.3%) experienced grade 3 treatment-related AEs (TRAEs). The most common grade 3 TRAEs were neutropenia (25%), leukopenia (16.7%), and hypertension (8.3%). Moreover, no grade 4 or 5 TRAEs were observed. In addition, 4 (33.3%) patients experienced a dose reduction. No patients experienced dose interruption or discontinuation due to TRAEs. Conclusions: RC48 combined with fruquintinib has shown promising efficacy and a manageable safety profile for HER2-expressing or -amplified mCRC patients refractory to at least two standard treatment failures. Clinical trial information: NCT05661357 .
Phase 1 study of ZV0203, a first in class pertuzumab ADC, in patients with HER2 positive advanced solid tumors.
Authors: Miao Zhenwei , Lin Fengjuan , Rao Xi , Huang Yong , Wang Feng , LU Yao , Huang Xiuying , Huang Yunsheng
Published: June 2024

e15004

Background: ZV0203, a first in class (FIC) pertuzumab antibody-drug conjugate (ADC), targets HER2 positive tumor cells with tubulin inhibitor DUO5 as its payload via a stable and protease-cleavable valine-citrulline linker. In preclinical studies, ZV0203 demonstrated superior antitumor activity compared to Kadcyla in multiple tumor cell line xenograft models with no noticeable toxicity. GLP toxicity studies indicated that ZV0203 was well tolerated with an estimated therapeutic index of 35. Methods: This was an open-label, multicenter, phase 1, dose-escalation study in patients (pts) with HER2+ advanced solid tumors. Primary objectives were safety, tolerability and RP2D. Secondary objectives included PK, immunogenicity and preliminary clinical efficacy. ZV0203 was administered intravenously Q3W on a 21-day cycle. An accelerated titration design was used for the 0.3 and 0.6 mg/kg doses, followed by a 3+3 design for 1.2, 1.8, 2.7 and 3.6 mg/kg dose levels. Results: As of January 18, 2024, 15 pts with solid tumors (breast [11], colorectal [2], gastric [1], lung [1]) were enrolled across doses of 0.3-3.6 mg/kg with a median age of 52 years old (range 35-65), of which 9 pts received prior HER2-targeted therapy (trastuzumab ± pertuzumab) and 14 pts completed 21-day DLT assessment (0.3 mg/kg and 0.6 mg/kg [1 each], 1.2 mg/kg, 1.8 mg/kg, 2.7 mg/kg and 3.6mg/kg [3 each]) with no DLT incidence. Treatment-related adverse events (TRAE) occurred in 14 (93.3%) pts. The most frequent TRAEs were corneal epitheliopathy [9], elevated liver enzymes [6], dry eyes [6], neutropenia [4], anemia [4], leukopenia [3], and proteinuria [3], and most were grade 1-2 in severity. 5 pts experienced grade 3 TRAEs: lymphocytopenia (1.8mg/kg [1]) , corneal epitheliopathy (3.6 mg/kg [1]) and blurred vision (2.7 mg/kg [2], 3.6 mg/kg [1]), which were manageable during treatment. No unexpected safety signals were reported. TRAEs led to 13.3% (2/15) treatment discontinuation. Among 14 pts evaluated, 5 pts achieved a best tumor response of PR; 4 pts had SD; 1 pt had Non-CR/Non-PD per RECIST v1.1. Thus, disease control rate was 71.4% (10/14). PK results demonstrated that the PK profile of total antibody was similar to that of ZV0203 ADC, whose systematic exposure increased in a dose-dependent manner and remained stable after repeated administration. Concentration of DUO5 remained scarce, suggesting good stability of ZV0203. Conclusions: ZV0203 was well tolerated and showed clinically encouraging anti-tumor activity in heavily pretreated pts with HER2 positive cancer. Clinical trial information: NCT05423977 .