bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety study of a novel alpha-fetoprotein (AFP)-maytansine conjugate in an ovarian xenograft model.
Authors: Sherman Igor A. , Hill Wendy , Griffin Patricia , Andrews David , Boohaker Rebecca J , Stinson Karr , Gien Lilian Tran , Buzina Alla , Schormann Wiebke
Published: June 2023

e14570

Background: AFP receptor is an oncofetal antigen and a novel target for cancer therapeutics. It is highly expressed on the surfaces of many cancers and Myeloid Derived Suppressor Cells (MDSCs) but absent on normal tissues. By conjugating maytansine toxin to a recombinant human AFP, we selectively deliver toxin to cancer cells and MDSCs while sparing normal cells, enabling a combination of targeted and immune activating approaches. We previously reported high efficacy of AFP-maytansine conjugate in a xenograft model of colorectal cancer. Here we report the effect of this conjugate in an ovarian xenograft model and in 2 independent patient-derived 3D ovarian organoids, supporting the wider utility of this approach. Methods: Four dose regimens of AFP-maytansine conjugate were compared to control in a mouse A2780 ovarian xenograft model. The conjugate was administered IV 10 days after implantation, when tumor volumes reached ≈150 mm3. Mice were randomized into 4 treatment and 1 control group (10 mice/group, table below). Tumor growth, survival and clinical observations were assessed for 62 days post implantation. In addition, organoids were cultured from primary reprogrammed tumor cells from 2 separate patients with high-grade serous ovarian carcinoma. Conjugate, staurosporine, thapsigargin or DMSO (control) were added to the media. Cytotoxicity was assessed by staining for AnnexinV and TMRE. Results: A statistically significant dose-dependent reduction in tumor volume (p<0.001) and increase in survival (p<0.002) were seen in all treatment groups relative to control. All animals in Groups 1,3 and 4 survived to the end of the study and 6 of 10 mice survived in the lowest dose group. 100% of mice in Group 1, highest dose group had complete tumor regression with no regrowth seen by day 62. In the other treatment groups majority of animals had complete tumor regression with no regrowth. All control animals were dead by day 38 due to excessive tumor burden. No signs of toxicity, such as ocular toxicity or vascular scarring of the tail were seen. All mice gained weight during the study. Gross pathology at the time of sacrifice was unremarkable. In addition, in the 2 ovarian organoids the AFP-maytansine conjugate demonstrated a cytotoxic effect over 72 hours exposure similar to that of thapsigargin and staurosporine given at known effective concentrations. Conclusions: This ovarian xenograft study confirms high activity without obvious toxicity of the novel AFP-maytansine conjugate in a 2nd tumor type. The targeted cytotoxic activity is further confirmed by the effect of the conjugate in 2 different ovarian cancer organoids. These results support advancing this novel conjugate toward clinical use with a dose-dense regimen. [Table: see text]
Evaluation of THEO-260 as a novel oncolytic virus therapy for treating stromal rich tumours.
Authors: Krell Jonathan , Frost Sally , Negroni Caterina , Moriconi Chiara , Taverner William , Nicholls Brannon , Saunders Deanna , Cunnea Paula , Fotopoulou Christina , Lim Alfred , Bazan-Peregrino Miriam , Fisher Kerry , Duffy Margaret R
Published: June 2023

e14573

Background: Stromal rich tumours pose a significant challenge to the effectiveness of systemic anticancer therapies, including immunotherapies and oncolytic viruses. This is due to the abundance of cancer associated fibroblasts (CAFs) that suppress immune cells and limit drug penetration. THEO-260 is a potent, mechanistically novel oncolytic virus therapy intrinsically capable of lysing both cancer cells and CAFs, and is currently in development for late stage relapsed refractory ovarian cancer. Methods: The efficacy and safety of THEO-260 was assessed in multicellular spheroids, in patient-derived ex vivo fresh ovarian samples and in mouse models of human stromal tumours. Results: Unpassaged ascites and tumour samples collected from cytoreductive surgeries for advanced ovarian cancer (n=24 independent patients) were treated with a clinically-relevant dose of THEO-260. THEO-260 effectively killed the cancer cell (EpCAM+ EGFR+PDL1+ CA125+) and CAF (FAP+) populations, being efficacious in treatment-naive and platinum-resistant patient samples. Importantly, the T cell population in these patients, in addition to primary normal fibroblasts (including intestinal, pulmonary, dermal, cardiac, uterine fibroblasts) from healthy donors, were not damaged. Ex vivo studies show THEO-260 stimulates effector T cell responses upon tumour lysis as indicated by IFNγ release. Demonstrating suitability as an IV delivered agent, THEO-260 was active in pooled human serum and whole human blood (n = 10 donors). THEO-260 excels in low nutrient, low proliferative environments, typical of human solid tumours and has been developed with a view to persist in the tumour microenvironment without the need for repeated cycles of delivery. THEO-260 is well tolerated in vivo following a clinically relevant intravenous dosing regimen. In PARP inhibitor and platinum resistant ovarian cancer murine models containing human CAFs and cancer cells, THEO-260 shows antitumor efficacy, with a complete reduction in tumour volume in subcutaneous and intraperitoneal systems, and superiority to SOC. Virus activity is not restricted to ovarian cancer, with cell line data demonstrating killing in additional solid tumour types, including pancreatic, colorectal, lung, and breast cancer. THEO-260 exhibits genetic and temperature based stability, and GMP manufacturing to high yields is underway. Conclusions: Taken together, we present a preclinical data package for THEO-260 supporting progression to Phase I clinical trials.
Preliminary safety, efficacy, and pharmacokinetics (PK) results of the EP4 antagonist INV-1120 from a phase I study in Chinese patients with advanced solid tumors.
Authors: Liu Chang , Zhang Miao , Yuan Jiajia , Liu Dan , Gong Jifang , Zhu Yi , Lin Lishan , Sun Yongkui , Nippgen Johannes , Shen Lin
Published: June 2023

e14579

Background: INV-1120 is a highly selective, orally available inhibitor of PGE2-EP4, an immunosuppressive mediator in the TME. Objectives of this Phase I study in Chinese patients was to assess safety and pharmacokinetics and define a RP2D of INV-1120. Methods: Escalation was based on a 3+3 sequential design starting @ 60mg QD po as guided by the FIH trial in a Western population. DLT evaluation period was 4 weeks. Efficacy (RECIST 1.1) was evaluated every 8 weeks. Blood samples were collected for pharmacokinetics. Results: 9 patients were enrolled and treated with INV-1120 in 3 dose cohorts (60, 100, 150mg, n=3 each). All 9 patients had CRC. All 9 patients were evaluable for activity. Stable disease was observed in 3 of 9 (33.3%) patients. The median PFS (95% CI) was 55.0 days (range: 42.0-NE). The plasma exposure increased from 60 mg to 100 mg. Maximum concentrations were achieved approximately 2 hours post dose. The half-life was approximately 5-16 hours. No accumulation was noted after multiple doses. The PK profiles were similar to that in a Western population [NCT04443088, presented @ SITC 2022]. Conclusions: Single agent INV-1120 was generally well tolerated in the Chinese population and showed preliminary signs of antitumor activity in terms of stable disease. Data from this trial were in line with data in a Western population [NCT04443088, presented @ SITC 2022] and warrant further Global development. Due to the combined findings of this study and the above-mentioned sister study, the doses of 60, 100 and/or 150mg QD are proposed for further exploration in combination trials. Clinical trial information: ChiCTR20211872 . Clinical trial information: CTR20211872 . [Table: see text][Table: see text]
A phase I study of isunakinra, an IL-1 alfa/beta inhibitor, in combination with nivolumab for patients with solid tumors refractory to standard therapies.
Authors: Becerra Carlos Roberto , Paulson Andrew Scott , Kowalski Jan , Olivecrona Hans , de Chateau Maarten
Published: June 2023

e14580

Background: Interleukin-1 is a master cytokine produced by macrophages (IL-1 β) and released upon cell death (IL-1 α). IL-1 upregulates other cytokines in the tumor microenvironment (i.e. IL-6 and IL-8), drives chronic non-resolving inflammation in the tumor, induces cancer cell invasion and metastasis (EMT), has profound effects on immune cells and cancer associated fibroblasts and can attract granulocytic myeloid suppressor cells to the tumor (PMN-MDSC), that in turn inhibit cytotoxic T cell responses. Isunakinra is a small recombinant protein resembling IL-1Ra, with an inhibitory potency 10-20 times higher, that binds to the IL1-R1 and blocks activation of the receptor by both IL-1α and IL-1β. We conducted a phase I dose escalation study with isunakinra as monotherapy and in combination with a PD-1 inhibitor in patients with locally advanced or metastatic solid tumors that had exhausted all treatment options. Methods: Enrolled patients with refractory metastatic solid tumor, ECOG 0-2, on a 3 + 3 dose-escalation trial at three dose levels of isunakinra (15, 25 or 50 mg). Isunakinra was self-administered once daily SC for three weeks followed by 4 additional weeks in combination with nivolumab Q4W at 480 mg, flat dose to complete the DLT period of 7 weeks. Thereafter, isunakinra/nivolumab was continued until week 28. Primary endpoints: DLTs, safety, and pharmacokinetics. Secondary endpoints: tumor and immune monitoring. Results: Enrolled fifteen patients with metastatic or unresectable locally advanced solid tumors (colorectal, pancreatic, triple-negative BC, anal, prostatic, CCA, and appendix) that had received 2-5 prior lines of therapy. Seven SAE occurred in three rapidly deteriorating subjects, all disease related hospitalizations, leading to study withdrawal during the DLT period. No DLTs, irAE or predefined laboratory deviations occurred in any subject. The highest dose, 50 mg, was selected as RP2D. Twelve subjects completed visit week 8, six of them week 12, and four completed the trial. One patient with metastatic colon cancer (MSS, KRAS mut, high TMB) was granted extended treatment for PR and continued response at end of study. Isunakinra exposure totaled 1575 daily doses, 81% during combination with nivolumab, t 1/2 5 hours with no accumulation over time. At 50mg of isunakinra, plasma levels where well above 100 ng/mL, a target for complete IL-1 inhibition. Conclusions: Isunakinra is safe and well-tolerated in combination with standard dose nivolumab. Ongoing expansion cohorts and future studies will explore the safety and efficacy of isunakinra in specific tumors and with other immunotherapy combinations. Clinical trial information: NCT04121442 .
Role of immune checkpoint inhibitors in PDL1-negative, low TMB, stable MSI metastatic solid tumours: Single centre study.
Authors: Moorthy Vijay , T P Sharafudheen , Kumar Delvin , Dasgupta Roshni , Naseer Mohammed , B.J Srinivas , Tripathi Priyank , Radheshyam Naik , Patil Shekar , Thungappa Satheesh Chiradoni , Nagaraj Madhu , Munaf Sajad , Naidu Srinivas , Shah Mansi , Sanghavi Niyati Prakash , Thippeswamy Ravi , krishna S Adithya , Reddy Spoorthi , Kumar Goutham , Vithal Yergolkar Abhijna ,   HCG BENGALURU
Published: June 2023

e14603

Background: Immune check point inhibitors clearly play a part in malignancies with elevated PDL1 expression, high TMB or unstable MSI. There is no information on PDL1 negative, low TMB/MSI stable metastatic solid tumours, however several treatment trials advise using immune check point inhibitors regardless of tissue agnostic indicators. Detailed subset analysis was not performed, though. This study examines the effectiveness of immunotherapy in metastatic solid tumours with PDL1 negative/TMB low/MSI stability. Methods: Study was carried out from Jan-2020 to Dec- 2022 (retrospective data from 2019 also included for analysis). Inclusion criteria: Metastatic solid tumours in patients who received immunotherapy. Exclusion criteria: PDL1>1% ( Either TPS/ CPS >1) by sp263 or 22c3 platforms, TMB> 10, Unstable MSI by IHC or by genomics. Patients who were diagnosed with melanoma, hepatocellular cancer, renal cell carcinoma were also excluded from the study. Response was initially assessed after 3 to 6 cycles of immunotherapy, analysed by PET CT scan. Data were analysed using standard statistical method. Results: After carefully applying exclusion criteria, a total of 40 patients were enrolled in the research, with a male to female ratio of 1.5. Overall response rate in all tumours was 17.5% (7/ 40) Immune checkpoint inhibitors' ORRs at various tumour locations. Among the responders head and neck tumours 2/4 (50%) and lung cancers (37.5%) had higher ORR who also had greater depth of response, living more than 2 years from diagnosis. There is no response observed in gastroesophageal (0/8) gynaecological malignancies (clear cell ovary (0/2), endometrial and cervical (0/3). A patient with urothelial carcinoma who also had a BRCA mutation and was one out of seven responded to IO. Conclusions: Regardless of the presence of PDL1 expression, high TMB, or MSI, adding immune checkpoint inhibitors to the treatment regimen for metastatic head and neck malignancies and lung tumours that lack driver mutations is obviously advantageous. On the other hand, immunotherapy had no effect on gastrointestinal, gynaecological, or urothelial tumours. To validate these findings, more research with several centres and a sizable sample size is necessary. It's interesting that one patient responded to immunotherapy with positive BRCA mutation. Investigating immunotherapy in HRR deficient tumours may shed further insights. [Table: see text]
Use of tumor mutational burden as a predictive marker of response to immuno-oncology agents: Initial experience at an academic center in Venezuela.
Authors: Borga Guillermo , Sucre Santiago , Sucre Oscar , Vivas Liliam , Salazar Hector , Sucre Carlos Eduardo
Published: June 2023

e14613

Background: Tumor Genetic Profiling (TGP) is steadily becoming the mainstay of clinical practice, namely, the Tumor Mutational Burden (TMB) is believed to be a predictor of efficacy to treatment with Immune Checkpoint Inhibitors (ICI). Recent studies have demonstrated that a high-TMB score (TMB-H) is associated with higher response rates. In Venezuela, the evidence of mutational frequencies obtained by TGP is limited, herein we present our experience at a large educational institution. Methods: In this retrospective cohort, we included 80 subjects with different types of solid tumors to whom TGP was performed to determine TMB values, as well as other associated mutations, between January 2020 and December 2022. In a subgroup of subjects in which ICI therapy was formally indicated (n=21) we used the Objective Response Rate (ORR) as a primary endpoint, recorded as the percentage of patients who had a complete response (CR) or partial response (PR), based on the RECIST v1.1 criteria. Treatment options included Ipilimumab, Atezolizumab, Pembrolizumab and Nivolumab, as either monotherapy or in combination according to the corresponding NCCN guidelines. A TMB-H score was defined as greater than 10 mutations per megabase. Results: A TMB-H was found in 11 samples, subjects with lung cancer accounted for the majority of this finding (n=6). The most frequently reported mutations were BRCA 1-2 (n=9), KRAS (n=9), and EGFR (n=4). In the subgroup treated with ICI, the ORR of the group with TMB-H was 71.42%, while in those with low TMB it was 35.71%. The differences in response rates, with a 95% CI, yielded a p=0.122; which corresponds to a statistically non-significant outcome. Conclusions: This study constitutes the first country-level documentation of what is becoming a standardized practice, and contributes to the growing evidence regarding the use of TMB-H as a marker to predict response to treatment. Our small cohort demonstrated a high ORR to ICI when a TMB-H score is present, albeit to a non-statistically significant degree. We will continue to follow-up these patients, as well as to include newly sequenced samples for TGP, to give greater statistical power to these findings.
Effect of FAPα-expressing tumor cell vaccine with PD-1 mAb on its efficacy in mice colorectal cancer model.
Authors: Jia Hongyuan , Chen Meihua , Xiao Ling , Li Tao , Lang Jingyi
Published: June 2023

e14615

Background: Colorectal cancer (CRC) is the third prevalent malignant tumor all over the world, and many cases are metastatic at diagnosis. Immunotherapy emerges a promising treatment in CRC. However, anti-PD-1 monotherapy alone has not yielded a clinical benefit in majority of these patients. Therefore, combination therapy is necessary to overcome this limitation. Previously, we have developed a FAPα-expressing tumor vaccine and demonstrated its anti-tumor effects by reversing of immunosuppressive tumor microenvironment (TME). In the current study, we hypothesized that combination therapy could enhance the effect of anti-PD1 therapy. Methods: FAPα-expressing CT26 cells were produced as previously described. To establish xenograft tumor model, CT26 cells were injected into left flank of BALB/c mice. Anti-PD-1 monoclonal antibodies(mAb) were injected intraperitoneally twice weekly up to 5 injections. FAPα-vaccines were injected subcutaneously around tumors weekly up to 3 injections. Histological sections of tumours were analysed by H&E staining and immunofluorescence. Flow cytometric analysis was done using an FACSCalibur (BD) and analyzed using FlowJo software (TreeStar). Gene expression profile in TME was analyzed by bulk RNA sequencing. Results: In mice xenograft CT26 tumor model, either anti-PD-1 immunotherapy or FAPα tumor cell vaccine produced suppression of CT26 tumor growth compared with the control group. However, combining anti-PD-1 mAb and FAPα-expressing tumor cell vaccine elicited the most remarkable anti-tumor effect and induced the most pronounced tumor growth suppression among all groups. In combination therapy group of the vaccine and PD-1 mAb, there were significantly more infiltrated lymphocytes and less FAPα+ fibroblasts. Flow cytometry demonstrated that the combination therapy promoted M1 macrophage polarization with a reduction of M2-like tumor associated macrophages (TAMs) and an increase of M1-like TAMs. This polarization was in consistent with the reduced level of IL-10 that is predominant cytokine secreted by M2 macrophages. A reduction of myeloid-derived suppressor cells (MDSCs) in the TME were also observed. Using bulk RNAseq we observed a set of immune related genes upregulated following combination therapy, including innate immune response, antigen presentation, lymphatic cells and recruitment and T cells activation. Decreased secretion of immune inhibitory chemokines (eg, CXCL12, IL-10, TGFβ) was also found by ELISA in tumors from mice treated with combination therapy. Conclusions: Our preliminary results suggested that combination therapy of FAPα-expressing tumor vaccine and anti-PD-1 therapy is a promising way to improve the efficacy of immunotherapy through modulation of immunosuppressive TME. In the future, more research is needed to further elucidate mechanism and clinical value of this combination approach.
Atezolizumab plus bevacizumab combined with transarterial embolization plus hepatic arterial infusion-chemotherapy for unresectable hepatocellular carcinoma with a diameter larger than 8 cm: A retrospective study.
Authors: Guo Wenbo , Cai Hongjie , Chen Song , Wu Zhiqiang , Wang Fan , Chen Ludan , Tang Shuangyan , Zhuang Wenquan
Published: June 2023

e14617

Background: The combination of atezolizumab and bevacizumab (Atezo-Bev) has become the standard first-line therapeutic regimen for patients with unresectable hepatocellular carcinoma (uHCC), while the therapeutic effect is limited in patients with high-risk characteristics (vp3/vp4 portal vein tumor thrombus or high tumor burden). Locoregional therapy plays an important role in minishing tumor burden and synergistic antitumor effect with systemic therapy, including transarterial embolization (TAE) and hepatic arterial infusion chemotherapy (HAIC). Herein, this study aimed to assess the efficacy and safety of atezolizumab and bevacizumab combined with TAE and HAIC in unresectable hepatocellular carcinoma with high tumor burden. Methods: This retrospective study reviewed the medical records of patients who had primary uHCC with high tumor burden (maximum nodule diameter >8 cm) receiving Atezo-Bev plus TAE and HAIC from September 2019 to September 2022 in our medical center. HAIC involved oxaliplatin, fluorouracil and leucovorin (FOLFOX regimen). Progression-free survival (PFS), overall survival (OS), tumor response according to mRECIST, and treatment-related adverse events (AEs) were evaluated. Results: In total, 30 patients were included in this study with a median follow-up period of 11.4 months. Twelve patients (40%) died and all the remaining patients reached the end point of PFS at the cut-off follow-up time. The median PFS of the 30 evaluable patients was 6.8 months (95% CI, 2.6-11.1 months), and the survival rates at 3 months, 6 months, 9 months, and 12 months were 86.2%, 82.5%, 68.6%, and 60%, respectively, and the median OS was not estimated (NE). According to the mRECIST, the objective response rate (ORR) was 74.4% (95% CI, 59.3%-89.5%), and the disease control rate (DCR) was 93.3% (95%CI, 85.4%-98.6%) respectively. Extrahepatic metastasis was an independent risk factor associated with PFS.As for the safety, there was no treatment-related mortality throughout the study period. The most common AEs were fever (6.7%), and diarrhoea(6.7%), and grade 3/4 AEs occurred among 6 patients (20%). Conclusions: Atezo-Bev combined with TAE and HAIC may be safe and effective for uHCC patients with high tumor burden, while further prospectively clinical research is necessary to validate the efficacy and safety.
Immune checkpoint inhibitors-associated periodontitis: A propensity score-matched retrospective cohort study.
Authors: Hsia Yuanping , Chiang Cho Hsien , Chiang Cho Han , Chiang Cho Hung , Peng Cheng-Ming , Shiah Her-Shyong , Ma Kevin Sheng-Kai
Published: June 2023

e14618

Background: Immune checkpoint inhibitors (ICIs) have been associated with a wide spectrum of immune-related adverse events (irAE) including oral mucositis and xerostomia. Periodontitis is another form of common oral pathology characterized by severe gingival inflammation but has not been investigated in patients receiving ICIs. We aimed to evaluate the risk of periodontitis associated with the use of ICI and to determine the clinical outcome of ICI-associated periodontitis. Methods: We conducted a 1:1 propensity score-matched retrospective cohort study involving patients receiving ICIs between January 2010 and November 2021. The primary outcome was periodontitis and the secondary outcomes were overall survival (OS), progression-free survival (PFS), and objective response rates. The propensity score matching was performed using basic demographics, underlying comorbidities, cancer type, and cancer therapy. The risk of periodontitis and associations between periodontitis and survival were evaluated using Cox proportional hazard analysis and Kaplan-Meier survival analysis. Results: We matched 868 patients receiving ICIs to patients who did not receive ICIs. Among ICI users, 41 (4.7%) patients developed periodontitis. The incidence rate of periodontitis was about 2-fold higher in ICI users than non-users (55.3 vs 25.8 per 100 patient-years; incidence rate ratio: 2.1 [95% CI: 1.4-3.3], p < 0.001). In Cox regression analyses, the use of ICI was associated with an 80-90% increased risk of periodontitis. The presence of immune-related periodontitis was associated with improved OS (median not reached vs. 17.8 months, p < 0.001), PFS (median 14.9 vs. 5.6 months, p = 0.009), and objective response rates (complete or partial response, 55% vs. 27%, p < 0.001). In Cox regression analyses, ICI use was associated with a 30-60% lower risk of all-cause mortality or disease progression. Conclusions: ICIs were associated with an increased risk of periodontitis. ICI-related periodontitis was associated with better survival outcomes and treatment responses.[Table: see text]
Biliary intervention combined with lenvatinib+ PD-1 inhibitor of Klatskin tumor complicated with malignant obstructive jaundice.
Authors: Fu Xiaobo , Mu Maoyuan , Qi Han , Jiang Weiwei , Chen Zixiong , Gao Fei
Published: June 2023

e14620

Background: Hilar Cholangiocarcinoma (Klatskin tumor) is a rare and highly aggressive cancer that occurs at or near the junction of the right and left hepatic ducts. Gemcitabine + cisplatin has been established as an effective first-line treatment. However, this malignancy is commonly complicated by malignant biliary obstruction which may gradually damage patients’ liver function and may limit the chemotherapy. In addition, Cumulative clinical evidence showed that tyrosine kinase inhibitor (TKI) combined with immunotherapy is represented as a promising alternative. This study aimed to evaluate the clinical value of biliary intervention combined with the Lenvatinib+PD-1 inhibitor (Tislelizumab/Sintilimab) for the Klatskin tumor. Methods: From January 2020 to December 2022, 21 Klatskin tumor patients with malignant hilar biliary obstruction (MHBO) were included. All included patients received biliary decompression by metal stent + Iodine-125 seed strand (ISS) implantation. The number of 125I seeds to be implanted was determined according to the plan of the preoperative computerized treatment planning system (TPS). The procedure-related outcomes were evaluated regarding successful drainage and complications. In addition, the survival of patients who received successful biliary drainage and patients who received sequential systemic anticancer treatment were analyzed. Successful biliary drainage was defined as the serum total bilirubin level dropped by 75% of the preoperative value within 4 weeks. Major complications referred to those that result in death or serious adverse effects including sepsis, uncontrollable biliary or intestinal bleeding, and acute renal failure. The time between stent insertion and death was defined as patient survival. Results: 71.4% achieved successful drainage, significant improvements were observed from before to one month after the procedure in liver function values, including total bilirubin (TBIL), and direct bilirubin (DBIL) (all P<0.001). Minor complications occurred in 5 patients (23.8%) in all patients, including 1 patient (4.8%) who experienced cholangitis, and 4 patients (19%) who suffered abdominal pain. No major procedure-related complication was observed. The median overall survival(mOS) of 21 patients was 6.1 months. Patients who received successful biliary drainage (n=15) had longer mOS than those who received unsuccessful biliary drainage(n=6) [7.4 months vs. 3.5 months, respectively, P<0.001]. Patients who received sequential Lenvatinib+ Pembrolizumab after effective drainage(n=9) had longer mOS than those who only received palliative therapy(n=6) [7.4 months vs. 5.2 months, respectively, P=0.028]. Conclusions: Biliary intervention + ISS combined with the following Lenvatinib+ PD-1 inhibitor is safe and feasible for cholangiocarcinoma patients complicated with obstructive jaundice.
TIPS combined with lenvatinib and PD-1 inhibitor in patients with advanced HCC with symptomatic portal hypertension: A retrospective study.
Authors: Mu Maoyuan , Fu Xiaobo , Qi Han , Jiang Weiwei , Chen Zixiong , Gao Fei
Published: June 2023

e14628

Background: Symptomatic portal hypertension (SPH) leads to a poor prognosis as a common complication in advanced hepatocellular carcinoma (HCC) patients due to cirrhosis or portal vein tumor thrombus. Although combined therapy including Lenvatinib and PD-1 inhibitors has shown valuable advantages in advanced HCC, the above strategy is limited by liver function impairment due to SPH complications such as variceal bleeding and refractory ascites. Transjugular intrahepatic portosystemic shunt (TIPS) directly relieves portal hypertension which may create a chance for advanced HCC patients with SPH to receive systemic therapy. Thus, TIPS plus following Lenvatinib and PD-1 inhibitor may serve as an effective anticancer modality. This study aimed to evaluate the efficacy and safety of TIPS combined with Lenvatinib and PD-1 inhibitor for advanced HCC patients with SPH. Methods: This retrospective study included thirteen advanced HCC with SPH patients who received TIPS combined with Lenvatinib and PD-1 inhibitor (Tislelizumab/Sintilimab) between January 2020 and January 2023. Main inclusion criteria: a confirmed HCC (BCLC stage C) based on the AASLD with either pathological or imaging findings; no previous systemic anticancer treatment; Child-Pugh score ≤10; ECOG status: 0-1. Portal hypertension with complications (variceal bleeding, refractory ascites). The outcome measures included objective response rate (ORR) (assessed with mRECIST v1.1), disease control rates (DCR), progression-free survival (PFS), overall survival (OS), SPH recurrence rate, and safety. Drug safety was investigated according to CTCAE (version 5.0). Results: With a median follow-up of 6.5 months (range 2.3-19.0), 13 patients with a median age of 57 years (range: 33-70) were evaluable for response and toxicity. 3 (23.1%) patients with Tislelizumab and 10 (76.9%) with Sintilimab. 7 (53.8%) patients were classified as Child-Pugh A class. According to mRECIST v1.1, ORR was 38.5% (95%CI, 11.8%-61.6%) with 1CR and 4 PR, and the DCR was 53.8% (95%CI, 21.3%-73.4%). The median overall survival (OS) was 16.5 months (95%CI,16.1-17.0). The prevalence of rebleeding, ascites and hepatic encephalopathy, was 7.7 %, 15.4%, and 7.7%, respectively. Treatment-related adverse events were confined to grades 1-2 occurring in 3/13 (23.1%) patients as rash (2, 15.4%) and fatigue (1, 7.7%). There were no treatment-related serious adverse events. Conclusions: TIPS combined with Lenvatinib and PD-1 inhibitor demonstrated a valuable anti-cancer strategy for advanced HCC patients with SPH based on the low recurrence rate of SPH and acceptable side effects.
Comparison of two ICI-based microtubule antagonist therapies for high-risk, non-muscle-invasive bladder cancer.
Authors: Niu Yuanjie , Hu Hailong , Li Hong Zheng , Shen Chong , An Zesheng , Wu Zhouliang , Zhang Zhe , Huang Shiwang , Zhao Gangjian , Guo Shizheng , Chen Houyuan , Jia Kaipeng
Published: June 2023

e14629

Background: Patients with highly extensive non-muscle-invasive bladder cancer (NMIBC) whose invasion area is too vast to be removed through TURBT should receive radical cystectomy in clinical practice. Clinical practice showed that nab-paclitaxel (Nab-P) or RC48-ADC (Disitamab Vedotin, DV) in combination with tislelizumab (BGB-A317, immune checkpoint inhibitor, ICI) had good effects on these patients with acceptable adverse events (AEs). This study was to compare the efficacy and safety of these two regimens. Methods: Retrospectively collected and analyzed data from two single-center clinical trials. Eligible patients were aged 18 years or older with unresectable NMIBC who received their first dose of Nab-P/ICI or DV/ICI between July 2020 and December 2022. The primary outcome was the pathological complete response (pCR) rate in a propensity score matching (PSM) population that was performed matching using a 1:4 ratio for the DV/ICI and Nab-P/ICI groups by propensity score. The main secondary outcome was treatment-related adverse events (trAEs), assessed in all eligible populations. Results: The eligible population was 12 for DV/ICI and 69 for the control group (Nab-P/ICI). The PSM population was 12 for DV/ICI and 48 for Nab-P/ICI. pCR was 66.7% (39.1%-86.2%) for DV/ICI and 60.4% (46.3%-72.9%) for the Nab-P/ICI group (OR: 0.76; 95% CI: 0.23–2.78; Fisher's exact test P = 0.75) in the PSM population. The most common trAE in the Nab-P/ICI group was alopecia, and the incidence was significantly lower in DV/ICI (Fisher's exact test, P < 0.05). Grade 3–4 trAEs were observed at 8.70% and 8.33% in Nab-P/ICI and DV/ICI, respectively. No trAE-related deaths were reported. Conclusions: The pooled results of the two studies with the efficacy and safety data showed promising ICI-based microtubule antagonist regimens in pts with highly extensive non-muscle-invasive bladder cancer (NMIBC), and DV/ICI may be preferred by pts for the low incidence of alopecia in clinical practice.
Atypical response patterns in Chinese patients with cancer with immune checkpoint blockade.
Authors: Cui Yu , Guan Yaping , Han Xinyue , Xie Hong , Chen Yingcui , Nie Weiwei , Wang Jun
Published: June 2023

e14631

Background: As specific patterns of progression, atypical responses, including pseudoprogression (PsPD) and dissociated response (DR), have been recently described. The purpose of the present study was to evaluate the frequency and prognosis of PsPD and DR in Chinese cancer patients treated with immune checkpoint inhibitors. Methods: We retrospectively reviewed patients with advanced cancer who received PD-1/PD-L1 inhibitor alone or combination therapy in a single center between December 2019 and January 2022. We evaluated all measurable lesions in each organ to identify PsPD and DR independently of RECIST 1.1. PsPD was defined as RECIST-defined progression followed by stabilization or decrease at the next imaging, and DR as concomitant decrease in some lesions and increase in others or emerging new lesions at a same timepoint. Progression‐free survival (PFS) and overall survival (OS) was compared between patients with atypical responses and those with true response (CR/PR) or nonresponse (SD/PD) using Cox proportional hazards models. Results: The present study included 178 patients aged 18-81 years (median: 63 years). The overall response rate was 18.5%. PsPD and DR were observed in 12 (6.7%) and 7 (3.9%) patients, respectively, and were not associated with any patient’s baseline characteristics. Median PFS (10.9 vs. 5.3 months; p=0.041) and OS (24.1 vs. 13.2 months; p=0.010) was significantly longer in patients with atypical response versus nonresponse, but shorter versus true responses (PFS: 10.9 vs. 35.4 months; p=0.009; OS: 24.1 vs. NR months; p=0.047). Patients with DR had a longer median PFS (10.1 vs. 1.5 months; p<0.0001) and OS (23.9 vs. 5.6 months; p=0.0001) than those with true PD. All patients with PsPD or DR were administrated with continuing ICIs. Among patients who experienced an initial progression (excluding patients with PsPD and DR), the continuing ICIs treatment cohort (n=20) still had a significantly longer median OS (7.5 vs. 3.1 months; p=0.004) than discontinuing ICIs treatment cohort (n=11). Conclusions: PsPD and DR are uncommon patterns of disease progression. Patients with DR exhibited a relatively favorable clinical outcome. Prognosis or biomarkers are needed to identify early patients with atypical responses who will benefit from immunotherapy.
Effect of trametinib and anti-PD-1 combo on tumor growth and survival of KRAS-mutant lung cancer by ID1 downregulation.
Authors: Puyalto Calvo Ander , Rodríguez-Remírez María , Lopez Ines , Olmedo Maria , Vilalta Anna , Macaya Irati , Welch Connor , Vicent Silvestre , Calvo Alfonso , Ajona Daniel , Gil-Bazo Ignacio
Published: June 2023

e14633

Background: Although anti-PD-1/PD-L1 antibodies represent a major breakthrough in NSCLC patients’ survival, this treatment efficacy is highly dependent on tumor PD-L1 expression. We reported the role of ID1 and the efficacy of a combined blockade of PD-1-ID1 in a KRAS mutant NSCLC mouse model (Baraibar et al; Cancers 2020). Trametinib, which is an oral MEK1/2 inhibitor, acts downstream of KRAS. Here we evaluate trametinib as an ID1 inhibitor able to enhance immunotherapy efficacy through PD-L1 overexpression. Methods: To explore whether MEK1/2 inhibition reduces ID1 expression in vitro and in vivo, experiments in NSCLC cells (human and murine) and in murine models were performed. RNAseq analysis was conducted to elucidate the pathways implicated in ID1 inhibition. Trametinib resistant (TR) cells were generated to analyze the effect of ID1 in the acquired resistance to treatment. Apoptosis was measured by flow cytometry. PD-L1 expression was evaluated by flow cytometry in control, ID1 silenced, ID1-overexpressing and TR cell lines. Treatment of trametinib combined with anti-PD1 was performed in KRAS-mutant LUAD models. Results: In vitro experiments in NSCLC cells showed ID1 inhibition at protein level after MEK1/2 blockade. However, we observe an increase in ID1 mRNA levels following treatment. In vivo experiments performed in C57BL6J and in ID1-deficient mice showed no significant differences in tumor growth between ID1 knock-out and ID1 wild-type mice treated with trametinib. IHC analysis of those tumor samples showed reduced ID1 levels (LLC p<0.001; CMT-167 p<0.0001). RNAseq analysis revealed an enrichment of ubiquitin-proteasome pathway after trametinib exposure. Blockade of proteasome activity with a specific inhibitor, restored ID1 levels. TR cells did not show MEKi induced ID1 inhibition, moreover, ID1 blockade rescued the sensitivity to trametinib in human and murine NSCLC TR cells (p<0.001). Flow cytometry analysis showed increased PD-L1 expression (p<0.001) in human and murine NSCLC cell lines after trametinib administration. In contrast, ID1-overexpressing cells and TR cells did not show PD-L1 upregulation after MEK inhibition. In vivo experiments confirmed the therapeutic efficacy of trametinib and anti-PD-1 combo, reducing tumor growth (p<0.05) and increasing mice survival (p<0.05), compared with trametinib monotherapy or immunotherapy alone. Conclusions: Pharmacological inhibition of MEK1/2 decreased ID1 expression in vitro and in vivo, replicating the effect of a specific shRNA against ID1, through proteasome activation. PD-L1 upregulation induced by ID1 blockade after trametinib treatment sensitized KRAS-mutant NSCLC cells to PD-1/PD-L1 immunotherapy, blocking tumor growth and improving overall survival.
Meta-analysis of gastrointestinal adverse effects in patients with non-small cell lung cancer treated with a combination therapy of pembrolizumab and chemotherapy versus chemotherapy alone.
Authors: Khosla Akshita , Mukherjee Samiran , Koka Jean Marie , Shore Stephen Arthur
Published: June 2023

e14634

Background: Pembrolizumab combined with chemotherapy has transformed the treatment of non-small cell lung cancer (NSCLC) and is now the standard of care. It has unique immune-related adverse events (irAE) that have been well defined. There is limited literature reporting its effect on the occurrence of common chemotherapy related AEs such as gastrointestinal adverse effects (GIAEs) (nausea, vomiting and diarrhea). We performed a meta-analysis to evaluate the GIAEs of pembrolizumab in non-small cell lung cancer patients treated with pembrolizumab and chemotherapy (P+C) and drew a comparison with those treated with chemotherapy alone (C). Methods: A literature search was performed in the MEDLINE database for randomized clinical trials of non-small cell lung cancer treated with pembrolizumab reporting gastrointestinal adverse effects. Articles were screened in concordance with PRISMA guidelines. Funnel plots were generated to assess publication bias. The pooled odds ratios (OR) for occurrence of GIAEs with 95% confidence intervals (CI) using random-effects models was calculated. Results: 9 studies (including data from KEYNOTE-021, 407, 189, 604, PROLUNG trial) were included in our analyses (n = 3157 patients). A clear increment in certain GIAEs (constipation (OR 1.16 (0.99- 1.37)), diarrhea (OR 1.51 (1.28- 1.78)), colitis (OR 4.39 (1.81- 10.62)), hepatitis (OR 4.67(1.79-12.18)) was noted the Pembrolizumab plus chemotherapy arm versus chemotherapy alone. No significant differences were noted in the occurrence of nausea, vomiting and pancreatitis. Conclusions: Pembrolizumab plus chemotherapy compared with chemotherapy alone has been studied extensively to highlight the survival advantages of the former therapeutic strategy. The risk of certain GIAEs (constipation, diarrhea, colitis, hepatitis) with pembrolizumab combination therapy for non-small cell lung cancer is significantly higher in comparison to chemotherapy alone. This alludes to the superadded effect of pembrolizumab on the existing AEs of chemotherapy. [Table: see text]
TIGIT transcriptomic expression and high levels of multiple checkpoints across diverse cancers.
Authors: Adashek Jacob J. , Kato Shumei , Pabla Sarabjot , Nesline Mary K , Conroy Jeffrey M. , DePietro Paul , Kurzrock Razelle
Published: June 2023

e14637

Background: The T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is an immune inhibitory receptor present on some T- and natural killer (NK) cells. It plays an important role in restricting innate and adaptive immunity. Given this, studies to combine other checkpoint inhibitors with anti-TIGIT therapies are currently in development. Methods: The RNA expression levels of 397 genes in various types of solid tumors from 514 patients seen at the UCSD Moores Cancer Center were analyzed at a CLIA-licensed laboratory, (OmniSeq (https://www.omniseq.com/)). Transcript abundance was normalized to internal housekeeping gene profiles and ranked (0-100 percentile) in a standardized manner to a reference population of 735 tumors spanning 35 histologies. Odds ratio for high TIGIT expression (≥75 percentile rank) was calculated and Bonferroni corrected for multiple genes and cancer histologies with > 10 samples. Results: Of 514 tumors, 99 (19%) tumors had high TIGIT expression (32 different histologies). Cancers with the greatest proportion of high TIGIT expression were small intestine (33%; 4/12) pancreatic (31%; 17/55), lung (25%; 5/20), stomach (20%; 5/25), breast (20%; 10/49), colorectal (18%; 25/140), head and neck (17%; 2/12), sarcoma (13%; 3/24), and uterine (13%; 3/23), though there were no statistically significant associations between these histologies and high TIGIT. There were significant associations between high TIGIT and high PD-L1 (P < 0.0021), PD-1 (P < 0.0021), PD-L2 (P < 0.0021), CTLA-4 (P < 0.0021), OX40 (P < 0.0021), LAG3 (P < 0.0021), FOXP3 (P < 0.0021) expressions (p values Bonferroni adjusted for multiple comparisons). However, there was no significant association between tumor mutation burden ≥10 mutations/mb and high TIGIT. Conclusions: High TIGIT expression was found in 19% of 514 tumors (pan-cancer) and significantly associated with high RNA expression of other immune checkpoints (PD-L1, PD-1, PD-L2, CTLA-4, OX40, LAG3, FOXP3), many of which can be targeted by FDA-approved drugs or drugs in clinical trials. Ongoing studies combining TIGIT inhibitors and specific immune checkpoint inhibitors may yield more clinical benefit after personalized tumor immune profiling.
Correlation between biomarkers and treatment outcomes in diverse cancers: A meta-analysis of phase I and II immunotherapy clinical trials.
Authors: Fountzilas Elena , Vo Henry Hiep , Müller Peter , Kurzrock Razelle , Tsimberidou Apostolia Maria
Published: June 2023

e14638

Background: Many immuno-oncology (IO) trials are conducted without biomarker selection. We performed a meta-analysis of phase I/II clinical trials evaluating immune checkpoint inhibitors (ICIs) to determine the association between biomarkers and clinical outcomes, if any. Methods: We searched PubMed for phase I/II clinical trials of drugs approved by the Food and Drug Administration (labeled, off-label, or combined with investigational ICIs or other treatment modalities) from 2018 to 2020. We compared the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) between biomarker-positive and biomarker-negative groups, using data from correlative studies. Results: Overall, 174 clinical studies that included 19,178 patients were identified and 131 studies investigated >30 correlative biomarkers, that included PD-L1 expression (≥1%, 111 studies), tumor mutational burden (20 studies), and microsatellite instability/mismatch repair deficiency (10 studies). Overall, 123, 46, and 30 cohorts (drugs, tumor types, or biomarkers) with 11,692, 3,065, and 2,256 patient outcomes for ORR, PFS, and OS, respectively, were analyzed in correlation with biomarkers. Meta-analyses demonstrated that ICIs in patients with biomarker-positive tumors were associated with higher ORR (odds ratio 2.15 [95% CI, 1.79-2.58], p<0.0001); and longer PFS (hazard ratio [HR] 0.55 [95% CI, 0.45-0.67], p<0.0001), and OS (HR 0.65 [95% CI, 0.53-0.80], p<0.0001) compared with those with biomarker-negative tumors. Significance for ORR and PFS was retained in multivariate analysis (p<0.001) (OS, not included owing to the small number of trials reporting OS). Conclusions: Our data suggest that IO biomarkers should be used in patient selection for ICIs. Prospective studies are warranted.
PD-L1 expression in Chinese patients with solid tumor and its correlation with gene alternations.
Authors: Zhang Xin , Liu Jiayu , Zhao Xin , Sun Li , Liu Chuang , Zhang Yaxuan , Du Pengyao , Meng Fanfan , Li Ling
Published: June 2023

e14640

Background: Immune checkpoint blockade are recommended in more and more solid tumors for first-line or posterior treatment, and PD-L1 expression is a crucial predictive biomarker for immunotherapy. However, the expression can be influenced by many factors. Methods: A total of 1743 Chinese patients with solid tumor was retrospectively identified. The Dako PD-L1 IHC 22C3 pharmDx assay was used to detect PD-L1 protein expression. And Tumor Proportion Score (TPS) ≥ 1% was defined as positive expression, TPS ≥ 50% was defined as high expression. Genomic profiling was performed on tumor tissue and matched peripheral blood samples. Only the tumor subtypes with sufficient sample size were used for correlation analysis. Results: PD-L1 positive expression occurred in 45.6% patients and high expression occurred in 8.1% patients. The highest expression incidences occurred in cervical cancer as of 78.8%, followed by lung cancer (53.8%), esophageal cancer (53.7%) and gastric cancer (42.7%). The PD-L1 expression assessed by TPS was consistent with that assessed by Combined Positive Score (CPS) in multiple tumors. However, it was significantly different in gastrointestinal tumors, especially in colorectal cancer (TPS>1%: 30.4% vs. CPS>1: 80.6%). In addition, gene alternations including TP53, CDKN2A, LRP1B, KRAS and PIK3CA apparently occurred in patients with high PD-L1 expression. Moreover, high tumor mutation burden (TMB-H) was associated with PD-L1 positive expression in these Chinese patients. Besides, no correlation was found between microsatellite instability (MSI) and PD-L1 expression. Conclusions: Our results illustrated genomic correlates of PD-L1 expression in Chinese solid tumor patients. These findings may broaden the application of immune checkpoint blockade to patients harboring specific molecular characteristics.