Combination Of Antiangiogenic Therapy Research Articles

Abstract PO2-05-12: Retrospective analysis on therapeutic efficacy and predictive indicators of eribulin plus anti-angiogenic drugs for metastatic breast cancer

Abstract Background: Eribulin has been widely used for the treatment of metastatic breast cancer (MBC). It has been found that eribulin can work in synergy with Bevacizumab or Anlotinib to achieve anti-angiogenic effects and possible synergistic enhancement. To optimize the efficacy of eribulin usage in late-line MBC patients, it is essential to delve deeper into the effects of combined treatments and gather more real-world clinical outcomes. Therefore, we evaluated the efficacy and safety of eribulin plus the anti-angiogenic drugs in late-line MBC patients. Objective: This study aims to retrospectively analyze the therapeutic efficacy and safety of eribulin plus anti-angiogenic drugs in treating metastatic breast cancer and explore predictive indicators of the therapeutic efficacy of eribulin in treating MBC. Methods: A retrospective review study was performed. 40 Patients diagnosed with MBC and treated with eribulin in Xi’an international medical center hospital from May 2020 to May 2021 were enrolled in this study. Patients were evaluable for this study and divided into two groups based on whether they received eribulin monotherapy or combined therapy. 22 patients were treated with eribulin monotherapy, and 18 were treated with eribulin and anti-angiogenic drugs (Bevacizumab and Anlotinib). Patients’ treatment parameters and characteristics were recorded. The Kaplan-Meier method was used to calculate the median PFS and corresponding 95% confidence interval (CI), and the Cox regression model was used for multivariate analysis of predictive indicators. The Fisher exact probability test was used to compare the difference in adverse reactions between the two groups, with a level of significance set at p-value < 0.05. Results: All study patients have an average of 5 treatment lines and a median progression-free survival (mPFS) of 4.2 months. The eribulin plus anti-angiogenic drug treatment group had a significantly prolonged mPFS compared to the group without anti-angiogenic drug treatment (7.0 months vs 2.0 months, p < 0.001, log-rank). Multivariate analysis identified that the combination of anti-angiogenic therapy (HR = 0.043, p = 0.004) and the occurrence of grade 3-4 neutropenia after treatment were two predictive factors for longer PFS (HR = 0.322, p = 0.009). In contrast, prior resistance to taxanes was predictive of shorter PFS (HR = 4.583, p = 0.019). Other factors, including age, Eastern Cooperative Oncology Group (ECOG) performance status, hormone receptor (HR) type, expression status, human epidermal growth factor receptor-2 (HER-2) expression status, Ki-67 level, number of metastatic lesions, and number of prior lines of Eribulin therapy, were not significantly associated with PFS. The results of Fisher’s exact test show that there was no significant increase in treatment-related adverse events (all grades) after combination with anti-angiogenic drugs. Conclusion: A combination of eribulin and anti-angiogenic therapy has significantly prolonged mPFS in the treatment of MBC patients. Other factors such as prior non-taxane resistance, grade 3-4 neutropenia occurrence after treatment, and combined anti-angiogenic therapy can be used as biomarkers for predicting treatment efficacy. The adverse events are manageable and the safety of combined therapy can be guaranteed. Therefore, the eribulin plus anti-angiogenic combination may act as a potential therapy for late-line MBC patients with clinically beneficial therapeutic effects. Keywords: metastatic breast cancer, eribulin, anti-angiogenic therapy, retrospective analysis Citation Format: Junmei Zhang, Xuezheng Wang, Hongjuan Du, Yan Xue. Retrospective analysis on therapeutic efficacy and predictive indicators of eribulin plus anti-angiogenic drugs for metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-05-12.

Plasma sPD-L1 and VEGF levels are associated with the prognosis of NSCLC patients treated with combination immunotherapy.

The clinical significance of plasma soluble programmed cell death ligand 1 (sPD-L1) and vascular endothelial growth factor (VEGF) for non-small cell lung cancer (NSCLC) treated with the combination of anti-angiogenic therapy and anti-PD-L1 antibody (Ab) remain unknown. This study aimed to explore the association between plasma sPD-L1 and VEGF levels and the prognosis of NSCLC patients treated with the combination of Envafolimab and Endostar. Peripheral blood samples were collected from 24 NSCLC patients at baseline and after 6 weeks of treatment and were detected for sPD-L1 and VEGF levels. Both baseline and posttreatment sPD-L1 were significantly higher in progressive disease (PD) group than in controlled disease (CD) group (median: 77.5 pg/ml vs. 64.6 pg/ml, P = 0.036, median: 8451 pg/ml vs. 5563 pg/ml, P = 0.012). In multivariate analysis, lower baseline sPD-L1 levels were significantly associated with longer progression-free survival (PFS) (HR = 6.834, 95% CI: 1.350-34.592, P = 0.020). There were significantly higher posttreatment VEGF levels in PD group compared with CD group (median: 323.7 pg/ml vs. 178.5 pg/ml, P = 0.009). Higher posttreatment VEGF levels were significantly associated with shorter PFS in multivariate analysis (HR = 5.911, 95% CI: 1.391-25.122, P = 0.016). Plasma sPD-L1 and VEGF levels are associated with the clinical response and prognosis of NSCLC patients treated with the combination of PD-L1 inhibitors and anti-angiogenetic therapy.

Clinical Potential of YY1-Hypoxia Axis for Vascular Normalization and to Improve Immunotherapy

Abnormal vasculature in solid tumors causes poor blood perfusion, hypoxia, low pH, and immune evasion. It also shapes the tumor microenvironment and affects response to immunotherapy. The combination of antiangiogenic therapy and immunotherapy has emerged as a promising approach to normalize vasculature and unlock the full potential of immunotherapy. However, the unpredictable and redundant mechanisms of vascularization and immune suppression triggered by tumor-specific hypoxic microenvironments indicate that such combination therapies need to be further evaluated to improve patient outcomes. Here, we provide an overview of the interplay between tumor angiogenesis and immune modulation and review the function and mechanism of the YY1-HIF axis that regulates the vascular and immune tumor microenvironment. Furthermore, we discuss the potential of targeting YY1 and other strategies, such as nanocarrier delivery systems and engineered immune cells (CAR-T), to normalize tumor vascularization and re-establish an immune-permissive microenvironment to enhance the efficacy of cancer therapy.

Антиангиогенная терапия в сочетании с ферментным тромболизисом – новый перспективный способ лечения тромбоза вен сетчатки

Сentral retinal vein occlusion (CRVO), the first mention of which was made more than 200 years ago, today is characterized by a sufficiently fully and in detail studied pathogenesis and a detailed clinical picture [1]. It should be noted that currently, when studying certain aspects of the pathogenesis of this disease, preference is given to studying the role of various angiogenic factors, in particular, vascular endothelial growth factor (VEGF) [2, 3]. At the same time, the assessment of the influence of coagulation, hemodynamic and immune-inflammatory factors of retinal vein occlusion to a certain extent fades into the background. However, it is a holistic understanding of the pathogenesis of CRVO based on the principles of systemic methodology that is the basis for the development of effective, pathogenetically substantiated methods of treating this disease. Purpose. To study the effectiveness of anti-angiogenic therapy in combination with epiretinal thrombolysis in the treatment of «fresh» CRVO. Methods. A clinical study was conducted among 106 patients with retinal vein occlusion with a disease development period up to 7 days, divided depending on the method of treatment into 2 groups: the main one – 56 patients (56 eyes), who were intravitreally injected with the anti-VEGF drug aflibercept with simultaneous epiretinal injection of recombinant prourokinase, and a comparison group – 50 patients (50 eyes) who received monotherapy with an angiogenesis inhibitor. All patients were matched for age and gender. Ophthalmological examination included: visometry, pneumotonometry, ophthalmoscopy, optical coherence tomography of the macular retina. Statistical processing of the obtained results was carried out using the IBM SPSS Statistics 27 program. Differences were considered statistically significant at p<0.05. Results. The use of a new combined method for thrombosis treatment, including intravitreal injection of an antiVEGF drug in combination with epiretinal injection of prourokinase, provides high and stable clinical and functional results in the postoperative period with an increase in visual acuity by 1.8 times, as well as an acceleration of hemorrhage lysis and resorption of macular edema by 2.0 times. Key words: central retinal vein occlusion; branch central retinal vein occlusion; anti-VEGF therapy; thrombolytics; prourokinase.

Radiation Therapy With Combination Therapy of Immune Checkpoint Inhibitors and Antiangiogenic Therapy for Hepatocellular Carcinoma

Immune checkpoint inhibitors (ICIs) combined with antiangiogenic therapy have limited efficacy in treating advanced hepatocellular carcinoma (HCC). The synergistic effect of systemic therapy and radiation therapy (RT) might resolve this problem. We aimed to investigate the effect of RT on the treatment outcomes of ICIs and antiangiogenic combination therapy in patients with advanced-stage HCC. This retrospective observational study analyzed the medical records of 194 patients with Barcelona Clinic Liver Cancer stage C HCC who were admitted to our center from August 2018 to June 2022 and received ICIs combined with antiangiogenic therapy as the first-line treatment. Patients who were administered RT for tumor thrombus or symptomatic metastases within 8 weeks of the commencement of combination therapy were allocated to the RT group, whereas those who did not receive RT were assigned to the non-radiation therapy (NRT) group. Propensity score matching was used to mitigate selection bias. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints included objective response rate, disease control rate (DCR), local PFS, out-of-field PFS, and treatment-related adverse events. A total of 76 patients diagnosed with advanced-stage HCC and treated with ICIs and antiangiogenic therapy were included in the study, with 33 patients in the RT group and 43 patients in the non-RT group. After propensity score matching, 29 matched patient pairs were generated. The median follow-up was 15.5 months, and the RT sites were mainly located on the tumor thrombus (55.2%) and extrahepatic metastatic lesions (48.3%). The median PFS was 8.3 months (95% CI, 5.4-11.3) in the RT group and 4.2 months (95% CI, 3.4-5.0) in the NRT group (P < .001). The median OS was not reached in the RT group and was 9.7 months (95% CI, 4.1-15.3) in the NRT group (P = .002). The objective response rate was 75.9% (95% CI, 56.5-89.7) in the RT group and 24.1% (95% CI, 10.3-43.5) in the NRT group (P < .001). The DCR was 100% in the RT group and 75.9% (95% CI, 56.5-89.7) in the NRT group (P = .005). The median local PFS and out-of-field PFS were 13.2 months (95% CI, 6.3-20.1) and 10.8 months (95% CI, 7.0-14.7), respectively. RT was an independent prognostic factor for PFS (hazard ratio = 0.33; 95% CI, 0.17-0.64; P < .001) and OS (hazard ratio = 0.28; 95% CI, 0.11-0.68; P = .005), respectively. The rates of any grade treatment-related adverse events were similar between the 2 groups. In comparison to the combination of ICIs and antiangiogenic therapy, the inclusion of RT has been observed to improve the DCR and survival outcomes in patients with advanced-stage HCC. The safety profile of this triple therapy was satisfactory.

Combined Treatment of Post-Thrombotic Macular Edema with Navigation Laser Coagulation and Intravitreal Administration of Angiogenesis Inhibitors

At present about 16.4 million people in the world suffer from retinal venous occlusions (RVO). The pathophysiology of RVO includes changes in the vascular wall, blood flow, blood clotting. The key role in the pathogenesis of this group of diseases is played by ischemia and retinal hypoxia, leading to neovascularization. Macular edema (ME) is the most common complication of retinal vein occlusions. Optical coherence tomography-angiography (OCTA) is considered as an informative and highly sensitive method for diagnosing macular edema (ME) and ischemic zones in RVO. Intravitreal administration of glucocorticosteroids and/or angiogenesis inhibitors is the priority treatment method for macular edema in RVO. The combination of antiangiogenic therapy and laser treatment is promising. The navigation treatment technology is implemented under the conditions of the Navilas 577 system. The Navilas 577 laser navigation system is a laser coagulator with a tracking system and a fundus camera. The possibility of planning the operation, superimposing the results of OCTA on a fundus image makes the treatment faster, more accurate, and minimizes damage to healthy tissues.Purpose: to evaluate the results of target topographically oriented threshold laser coagulation in the treatment of post-thrombotic ME using theNavilas 577 laser navigation system following intravitreal administration of angiogenesis inhibitors.Materials and methods. There was performed a prospective study of the results of navigation laser treatment on the Navilas 577 device after intravitreal injections of angiogenesis inhibitors in 14 patients (14 eyes), aged 51 to 83 years, with macular edema up to 390 μm due to the branch central retinal vein occlusion. Laser treatment was performed within 2 weeks to 1 month following the last injection of angiogenesis inhibitors. The zones of ischemia in the macula were determined according to OCT-A data, imported into the Navilas 577 navigation system and superimposed on a color fundus image. Then the treatment was planned — the position of the future coagulates was marked.Results. In 3 months, there was a decrease in the height of edema from 366.5 (323;390) to 280 (270;300) μm, an increase in light sensitivity in the central retinal zone from 17 to 21.2 dB and an increase in visual acuity from 0.4 (0.3;0.5) to 0.5 (0.45;0.6).Conclusion. The combination of navigation retinal laser coagulation and angiogenesis inhibitors in the treatment of low post-thrombotic edema (less than 390 μm) gives good results; therefore, it can be justified and advisable in real clinical practice.

Resistance to Antiangiogenic Therapy in Hepatocellular Carcinoma: From Molecular Mechanisms to Clinical Impact.

Antiangiogenic drugs were the only mainstay of advanced hepatocellular carcinoma (HCC) treatment from 2007 to 2017. However, primary or secondary resistance hampered their efficacy. Primary resistance could be due to different molecular and/or genetic characteristics of HCC and their knowledge would clarify the optimal treatment approach in each patient. Several molecular mechanisms responsible for secondary resistance have been discovered over the last few years; they represent potential targets for new specific drugs. In this light, the advent of checkpoint inhibitors (ICIs) has been a new opportunity; however, their use has highlighted other issues: the vascular normalization compared to a vessel pruning to promote the delivery of an active cancer immunotherapy and the development of resistance to immunotherapy which leads to a better selection of patients as candidates for ICIs. Nevertheless, the combination of antiangiogenic therapy plus ICIs represents an intriguing approach with high potential to improve the survival of these patients. Waiting for results from ongoing clinical trials, this review depicts the current knowledge about the resistance to antiangiogenic drugs in HCC. It could also provide updated information to clinicians focusing on the most effective combinations or sequential approaches in this regard, based on molecular mechanisms.

324P Efficacy and safety analysis of anlotinib combined with immunotherapy as second-line therapy for advanced non-small cell lung cancer (NSCLC)

No standard treatment exists for non-small cell lung cancer (NSCLC) with failure of first-line therapies. Combination of antiangiogenic therapy and immune checkpoint inhibitor therapy is reported as an effective antitumor strategy. Anlotinib is a novel multi-target tyrosine kinase inhibitor, inhibiting tumour angiogenesis and proliferative signalling.We aimed to assess the activity and safety of anlotinib combined with immunotherapy as second-line therapy for advanced NSCLC.

Advances in Engineered Biomaterials Targeting Angiogenesis and Cell Proliferation for Cancer Therapy.

Antiangiogenic therapy in combination with chemotherapeutic agents is an effective strategy for cancer treatment. However, this combination therapy is associated with several challenges including non-specific biodistribution leading to systemic toxicity. Biomaterial-mediated codelivery of chemotherapeutic and anti-angiogenic agents can exploit their passive and active targeting abilities, leading to improved drug accumulation at the tumor site and therapeutic outcomes. In this review, we present the progress made in the field of engineered biomaterials for codelivery of chemotherapeutic and antiangiogenic agents. We present advances in engineering of liposome/hydrogel/micelle-based biomaterials for delivery of combination of anticancer and anti-angiogenesis drugs, or combination of anticancer and siRNA targeting angiogenesis, and targeted nanoparticles. We then present our perspective on developing strategies for targeting angiogenesis and cell proliferation for cancer therapy.

Abstract 5087: KDR mutation as novel biomarker for immune checkpoint inhibitors in pan-cancer

Abstract Purpose: Immune Checkpoint Inhibitors (ICIs) have marked important milestones in cancer treatment, while few patients experience clinical benefits from them. Therefore, reliable predictive markers for ICIs are urgently needed. Nowadays, the combination of antiangiogenic therapy and ICIs exhibits encouraging efficacy. As a key protein of VEGFR signaling, KDR may also function to regulate immune responses beyond its role in angiogenesis. Experimental Design: Pan-cancer immunotherapeutic patients from public cohorts including genomic data and clinical data were analyzed. Further analysis was performed on an internal validation data set including 67 non-small cell lung cancer (NSCLC). Investigation on underlying mechanism was performed in The Cancer Genome Atlas (TCGA) data via bioinformatics analysis. Results: We found better responses to ICIs in patients who harbored KDR mutation from pan-cancer public datasets (discovery cohort: n=662; validation cohort: n=1333). Our NSCLC cohort verified the value of KDR mutation in predicting better ICI outcomes, including objective response rate (70.0% vs 22.81%, P=0.0057) and progression-free survival (HR=0.158, 95% CI, 0.045-0.773; P=0.007). KDR mutation was associated with increased TMB level, neoantigen burden, immune cellular activities, and decreased VEGFR signaling. Meanwhile, KDR mutation was indicative of an immune-hot status, characterized by higher expression of PD-L1 and abundance of cytotoxic lymphocytes. Conclusions: Our work demonstrates that KDR mutation has the potential to become a predictive biomarker for ICIs. Citation Format: Renhua Guo, Yanan Cui, Pengpeng Zhang, Xiao Liang, Jiali Xu, Xinyin Liu, Yuemin Wu, Wei Wang, Fang Zhang, Junling Zhang, Mengli Huang. KDR mutation as novel biomarker for immune checkpoint inhibitors in pan-cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5087.

Augmenting Experimental Gastric Cancer Activity of Irinotecan through Liposomal Formulation and Antiangiogenic Combination Therapy.

Gastric adenocarcinoma (GAC) is the third most common cause of cancer-related deaths worldwide. Combination chemotherapy remains the standard treatment for advanced GAC. Liposomal irinotecan (nal-IRI) has improved pharmacokinetics (PK) and drug biodistribution compared with irinotecan (IRI, CPT-11). Angiogenesis plays a crucial role in the progression and metastasis of GAC. We evaluated the antitumor efficacy of nal-IRI in combination with novel antiangiogenic agents in GAC mouse models. Animal survival studies were performed in peritoneal dissemination xenografts. Tumor growth and PK studies were performed in subcutaneous xenografts. Compared with controls, extension in animal survival by nal-IRI and IRI was >156% and >94%, respectively. The addition of nintedanib or DC101 extended nal-IRI response by 13% and 15%, and IRI response by 37% and 31% (MKN-45 xenografts); nal-IRI response by 11% and 3%, and IRI response by 16% and 40% (KATO-III xenografts). Retardation of tumor growth was greater with nal-IRI (92%) than IRI (71%). Nintedanib and DC101 addition tend to augment nal-IRI or IRI response in this model. The addition of antiangiogenic agents enhanced tumor cell proliferation inhibition effects of nal-IRI or IRI. The tumor vasculature was decreased by nintedanib (65%) and DC101 (58%), while nal-IRI and IRI alone showed no effect. PK characterization in GAC xenografts demonstrated that compared with IRI, nal-IRI treatment groups had higher retention, circulation time, and tumor levels of CPT-11 and its active metabolite SN-38. These findings indicate that nal-IRI, alone and in combination with antiangiogenic agents, has the potential for improving clinical GAC therapy.

Anti-angiogenesis revisited: reshaping the treatment landscape of advanced non-small cell lung cancer.

Although anti-angiogenic agents have been of limited use in the treatment of non-small cell lung cancer (NSCLC) until recently, further roles for the use of angiogenesis inhibition have emerged in the era of targeted therapy and immune checkpoint blockade. Given the shared common downstream signals of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) with their complementary roles in tumorigenesis and tumor angiogenesis, the dual inhibition of EGFR and VEGF pathways represents a rational strategy to maximize clinical efficacy and overcome resistance in the treatment of EGFR-mutant NSCLC. VEGF-driven angiogenesis is a potent driver of immunosuppressive tumor microenvironment (TME), with the recruited immunosuppressive cells driving angiogenesis, highlighting the interplay between the tumor vasculature and the anticancer immunity. Anti-angiogenic therapy can normalize the tumor vasculature and reprogram the TME from immunosuppressive into immunosupportive. Intensive research is under way to utilize the anti-angiogenic combination therapy to its full potential in diverse clinical settings in urgent unmet needs for the treatment of NSCLC. In this review, we present an overview of tumor angiogenesis and summarize the scientific background and preclinical and clinical evidence of anti-angiogenic therapy in combination with target therapy and immunotherapy for the treatment of NSCLC.

Оценка эффективности и безопасности навигационного комбинированного лазерного лечения в сочетании с антиангиогенной терапией при макулярном отеке вследствие окклюзии ветви центральной вены сетчатки

Purpose. To study methods of using antiangiogenic therapy in combination with combined navigational laser treatment in patients with MO due to BRVO. Material and methods. The study included 99 patients with ME due to BRVO, the main group (n=54) consisted of patients treated using the combined technique, the control group – patients treated with ranibizumab monotherapy (n=45). The combined method for the treatment of ME due to BRVO included the initial intravitreal injection of ranibizumab. 2 weeks after the injection, the patients carry out OCT, in the presence of central retinal thickness (CRT) more than 350 μm, 1 month after injection, one or more injections of ranibizumab were performed until the CRT reached 350 μm or less, when the «target» level was reached, combined navigation laser treatment was performed. Results. 1 month after the combined laser treatment, the best corrected visual acuity (BCVA) was 0.67±0.14 (on average), the CRT, on the average for the group, was 311.9 114.5 μm, the central retinal sensitivity was 22.3±1.6 dB. After 3 months, BCVA was 0.71±0.14, CRT was 289.9±110.5 μm, central retinal sensitivity was 22.8±1.6 dB. After 6 months, BCVA was 0.74±0.14, CRT was 236.5±107.6 μm, central retinal sensitivity was 23.1±1.5 dB. At follow-up period of 1 year in the main group was required on average, 3.47±1.58 injections of ranibizumab for stabilization, in the control group, on average, 4.36±1.58 injections were required, the average indicators of BCVA and CRT significantly did not differ. Conclusion. Navigational combined laser treatment in combination with antiangiogenic therapy has shown its effectiveness and safety in the treatment of macular edema due to the branch retinal vein occlusion. The effectiveness of the combined laser technology is expressed in positive dynamics in all functional and morphometric parameters. The safety of the proposed technology is expressed in the absence of clinically significant intra- and postoperative complications. Key words: navigation laser technology, micropulse mode, retinal vein occlusion, macular edema, antiangiogenic therapy

Docetaxel and 5-FU enhanced the inhibitory effects of apatinib and ramucirumab on growth and migration of gastric cancer

BackgroundGastric cancer (GC) is one of the most common malignant tumors in the world. The clinical benefit of anti-angiogenic strategy as a single drug is limited. Some studies showed that the combination of anti-angiogenic therapy and chemotherapy exhibited synergistic effect and reduced the side effects of chemotherapy drugs. We investigated the combined effects of these two types of drugs in gastric cancer cells in vitro and in vivo. Methodscell viability, migration, invasion, and apoptosis were evaluated by CCK-8, wound-healing, transwell, and Annexin V-FITC/PI assay, respectively. In vivo anti-cancer efficacy was tested for the cell proliferation and metastasis in cell line derived tumor xenograft (CDX) model and patient derived tumor xenografted (PDX) model based on Tg (fli-1: EGFP) zebrafish embryos; ResultsIn the cell experiments, the combination of the two types of drugs could inhibit the proliferation and metastasis of gastric cancer cells and promote apoptosis through VEGFR-2/AKT/ERK1/2 signal. In the zebrafish CDX (zCDX) model and zebrafish PDX (zPDX) model, the combination of the two treatment also showed a synergistic effect in inhibiting gastric cancer cell metastasis and cell proliferation. ConclusionsApatinib/ramucirumab targeted therapy combined with docetaxel or 5-fluorouracil (5-FU) may serve as an effective treatment strategy for patients with advanced gastric cancer.

Efficacy and Safety Associated With Immune Checkpoint Inhibitors in Unresectable Hepatocellular Carcinoma

Immune checkpoint inhibitors (ICIs) have yielded conflicting results in hepatocellular carcinoma (HCC). The overall effect of ICIs compared with standard therapies in unresectable HCC requires more research. To estimate the efficacy and safety associated with ICIs compared with standard therapies in patients with unresectable HCC. PubMed, Cochrane Library, Web of Science, Latin American and Caribbean Health Sciences Literature, and American Society of Clinical Oncology and European Society of Medical Oncology meeting proceedings were systematically searched. Reference lists from studies selected by electronic searching were manually searched to identify additional relevant studies. The search included literature published or presented from February 2010 to February 2020. From December 2019 to February 2020, independent reviewers evaluated each database, scanning the title, abstract, and keywords of every record retrieved. Full articles were further assessed if the information given suggested that the study was a randomized clinical trial (RCT) comparing ICIs vs standard therapies in the treatment of unresectable HCC. The full text of the resulting studies and extracted data were reviewed independently according to PRISMA guidelines. Summary hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS) were calculated by a random-effects model. The likelihood of ICIs being associated with overall response rate (ORR) and treatment-related adverse events (TRAEs) was expressed by odds ratios (ORs) using a random-effects model. The main outcomes were OS, PFS, ORR, and TRAEs. Of 1836 studies yielded by the search, 3 were retained, totaling 1657 patients (985 treated with ICIs vs 672 receiving standard treatment). Two studies evaluated ICIs as monotherapy, and 1 study investigated the combination of ICIs with bevacizumab. Compared with standard therapies (sorafenib in first-line therapy or placebo in second-line therapy), ICIs were associated with significantly improved OS (HR, 0.75; 95% CI, 0.62-0.92; P = .006), PFS (HR, 0.74; 95% CI, 0.56-0.97; P = .03), and ORR (OR, 2.82; 95% CI 2.02-3.93; P < .001). The probability of grade 3 or 4 TRAEs was lower with ICIs than with sorafenib (OR, 0.44; 95% CI, 0.20-0.96; P = .04). This meta-analysis found superior efficacy and safety associated with ICIs compared with standard therapies and highlights the survival benefit associated with the combination of antiangiogenic therapy with ICIs in first-line systemic therapy of unresectable HCC.

TAMI-31. GLIOBLASTOMA GENETIC DRIVERS DICTATE THE FUNCTION OF TUMOR-ASSOCIATED MACROPHAGES/MICROGLIA AND RESPONSES TO CSF1R INHIBITION

Abstract Tumor-associated macrophages/microglia (TAMs) are prominent microenvironment components in human glioblastoma (GBM) that are potential targets for anti-tumor therapy. However, TAM depletion by CSF1R inhibition showed mixed results in clinical trials. We hypothesized that GBM subtype-specific tumor microenvironment convey distinct sensitivities to TAM targeting. We generated syngeneic PDGFB-driven and RAS-driven GBM models that resemble proneural-like and mesenchymal-like gliomas, and determined the effect of TAM targeting by CSF1R inhibitor PLX3397 on glioma growth and progression. We also investigated the co-targeting of TAMs and angiogenesis on PLX3397-resistant RAS-driven GBM. Using single-cell transcriptomic profiling, we further explored differences in tumor microenvironment compositions and functions between the proneural-like and mesenchymal-like glioma models. We found that the growth of PDGFB-driven tumors was markedly inhibited by PLX3397. In contrast, depletion of TAMs at the early phase accelerated RAS-driven tumor growth and had no effects on other proneural and mesenchymal human GBM models. In addition, PLX3397-resistant RAS-driven tumors did not respond to PI3K signaling inhibition. Single-cell transcriptomic profiling revealed that PDGFB-driven gliomas induced expansion and activation of pro-tumor microglia, whereas mesenchymal RAS-driven gliomas elicited TAMs enriched in pro-inflammatory and angiogenic signaling. Co-targeting of TAMs and angiogenesis decreased cell proliferation and tumor mass in RAS-driven gliomas. Our work identifies functionally distinct TAM subpopulations in the growth of different glioma subtypes. Notably, we uncover a potential responsiveness of resistant mesenchymal-like gliomas to combined anti-angiogenic therapy and CSF1R inhibition. These data highlight the importance of microenvironment landscape characterization to optimally stratify glioma patients for TAM-targeted therapy.

RARE CASE OF PAZOPANIB-ASSOCIATED BILATERAL PNEUMOTHORACES IN A PATIENT WITH METASTATIC SYNOVIAL SARCOMA

TOPIC: Lung Cancer TYPE: Medical Student/Resident Case Reports INTRODUCTION: Bilateral pneumothoraces are a rare occurrence, comprising 1.4% to 7.6% of cases [1]. Secondary causes of pneumothorax include bullous emphysema, cystic parenchymal lung disease and tuberculous lung disease [2]. Malignancy is a rare cause of pneumothorax, yet sarcomas have been associated with pneumothorax in 2% of patients [3]. Pazopanib, a tyrosine kinase inhibitor used in the treatment of metastasized sarcoma, has been shown to have a 3.3% risk of developing pneumothorax [4]. CASE PRESENTATION: A 24-year-old previously healthy Yemeni female initially presented with left-sided groin pain and swelling. Computed tomography of the pelvis showed a large heterogeneous mass in the proximal left thigh. Biopsy was consistent with synovial sarcoma. Staging via chest computed tomography showed multiple pulmonary nodules concerning for metastasis. Over the course of two years, she failed multiple lines of chemotherapy and had progression of disease with new and enlarging bilateral pulmonary nodules. She was started on fourth-line chemotherapy with pazopanib (Votrient) 400 mg daily. Two months later, she presented with shortness of breath, found to be tachypneic, tachycardic and hypoxemic. Chest x-ray revealed bilateral pneumothoraces with left mediastinal shift concerning for tension pneumothorax. Two tube thoracostomies were placed; however, course was complicated by persistent air leak bilaterally, requiring video-assisted thoracoscopic surgery with bullectomy and surgical talc pleurodesis. Patient had a slow resolution of pneumothorax and subsequently discharged home without recurrence. DISCUSSION: Bilateral pneumothoraces can be life-threatening and are associated with poor long term prognosis, especially in patients with poor underlying lung function [5]. Pneumothorax is seen in approximately 2% of sarcoma patients with pulmonary metastases. In patients with sarcoma and pulmonary metastases, 41.6% of pneumothoraces were bilateral, and typically associated with multiple lung nodules, cystic or cavitary lesions, or presence of pleural nodules or thickening [3]. Additionally, cytotoxic agents have been shown to induce cavitation in pulmonary lesions and increase the risk of pneumothorax development [6]. Per the PALETTE trial which led to the approval of pazopanib for use in sarcoma, there was a 3.3% risk for pneumothorax development [4], comparable to the baseline rate of pneumothorax development in patients with sarcoma. Nevertheless, bilateral pneumothoraces carry potentially fatal consequences. CONCLUSIONS: In patients with sarcoma undergoing treatment with pazopanib, a bilateral pneumothorax, though rare, may be life threatening and should be acutely suspected. REFERENCE #1: TG Rim, JS Bae, YS Yuk. Life-Threatening Simulatenous Bilateral Spontaneous Tension Pneumothorax - A case report. Korean J Thorac Cardiovasc Surg. 2011 Jun; 44(3): 253-256.2. Mason RJ, Braoddus VC, Murray JF, Nadel JA. Murray and Nadel's Textbook of Respiratory Medicine. 4th ed. Elsevier Saunders (2005); Vol 2, Chapter 81. Philadelphia, PA. REFERENCE #2: Hoag JB, Sherman M, Fasihuddin Q, Lund ME. A comprehensive review of spontaneous pneumothorax complicating sarcoma. CHEST. 2010 Sep; 138(3);510-8.4. Van der Graaf WT, Blay JY, Chawla SP, Kim DW, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012 May 19; 379(9829):1879-86. REFERENCE #3: Graf-Deuel E, Knoblauch, A. Simultaneous bilateral spontaneous pneumothorax. CHEST. 1994 Apr; 105(4):1142-6.6. Interiano RB, McCarville MB, Wu J, Davidoff AM, Sandoval J, Navid F. Pneumothorax as a complication of combination antiangiogenic therapy in children and young adults with refractory/recurrent solid tumors. J Pediatr Surg. 2015 Sep; 50(9):1484-9. DISCLOSURES: No relevant relationships by Sally Askar, source=Web Response No relevant relationships by Owais Nadeem, source=Web Response

A Sampling of Highlights from the Literature: Article Recommendations from Our Deputy and Senior Editors.

ILC3–T cell interactions regulate the gut microbiota (from Fig. 1C of Hakozaki et al., Cancer Immunol Res 2020)Group 3 innate lymphoid cells (ILC3) regulate host–microbe interactions in the intestines, but whether they have a role in colorectal cancer (CRC) is not known. Goc et al. show that ILC3s in human and mouse CRC are dysregulated. In mice, this reduces ILC3 interactions with CD4+ T cells, which decreases gut colonization by microbiota that induce type-1 immunity and thereby promotes CRC progression and resistance to PD-1 blockade. Patients with inflammatory bowel disease have dysregulated ILC3s and microbiota that do not induce type-1 immunity when transferred to mice, but rather promote CRC resistance to PD-1 blockade. The data identify new avenues for immunotherapeutic intervention.Goc J, …, Sonnenberg GF. Cell 2021 Aug 17. DOI: 10.1016/j.cell.2021.07.029.Autologous TIL ACT is effective and safe (by Shyamal via Wikimedia Commons)Adoptive cell therapy (ACT) for metastatic non–small cell lung cancer (NSCLC) has not yet been evaluated. Creelan et al. report on a phase I clinical trial testing ACT using autologous tumor-infiltrating lymphocytes (TIL) in patients with metastatic NSCLC that progressed despite nivolumab treatment. Autologous TIL ACT is effective and safe, and assessment after TIL treatment shows tumor-specific T cells are elevated in responding patients. The data highlight a potential new therapy option for patients with metastatic NSCLC.Creelan BC, …, Antonia SJ. Nat Med 2021 Aug 12;27:1410–8.HBV-specific CD8+ T cells infiltrate HCC (from GrahamColm at English Wikipedia via Wikimedia Commons)Hepatocellular carcinoma (HCC) is often associated with chronic hepatitis B virus (HBV) infection, but whether HBV-specific T cells can control HCC growth is not known. Through comprehensive analysis of CD8+ T cells in samples from 46 patients with HCC, Cheng et al. show that HCC infiltration with HBV-specific CD8+ T cells associates with improved relapse-free survival. Intratumoral HBV-specific CD8+ T cells are enriched in two of five detectable subsets of tissue-resident memory T cells (Trm): CD103+CD57+ Trm and CD103+CD57− Trm. These cells are clonally expanded and lack gene signatures of terminally exhausted T cells, suggesting they could be harnessed therapeutically.Cheng Y, …, Newell EW. Immunity 2021 Aug 10;54:1825–40.e7.Overcoming treatment resistance in NSCLC can be achieved (from Librepath via Wikimedia Commons)Strategies to overcome resistance to anti–PD-1 immune checkpoint blockade in patients with cancer are much needed. By using genetically engineered models of non–small cell lung cancer (NSCLC), Martinez-Usatorre et al. identify mechanisms behind resistance to PD-1 blockade, antiangiogenic therapy, and the combination thereof. Tumor-associated macrophages of monocyte origin and alveolar origin contribute to resistance, and targeting these cells using a CSF1R inhibitor and cisplatin, respectively, improves responses to combination antiangiogenic therapy and PD-1 blockade. The data provide insight into the potential for targeting macrophages to overcome resistance to PD-1 blockade in patients with NSCLC.Martinez-Usatorre A, …, De Palma M. Sci Transl Med 2021 Aug 11;13:eabd1616.Improved CAR design improves performance (by Chris Phutully via Wikimedia Commons)Improving the antigen sensitivity of chimeric antigen receptor (CAR) T cells has the potential to improve responses in patients with tumors having low target antigen expression. Salter et al. compare T-cell receptor and CAR signaling in primary human T cells and show that multiple CD3 chains are not or are only weakly phosphorylated after CAR stimulation, indicating lower antigen sensitivity. Modifying the CAR construct to improve CD3 engagement increases CAR T-cell activation and efficacy in low antigen settings. The data highlight how understanding receptor signaling events can guide therapy design and provide potential construct alterations to improve CAR T-cell efficacy.Salter AI, …, Riddell SR. Sci Signal 2021 Aug 24;14:eabe2606.Immune profiling reveals inter- and intratumoral immune heterogeneity in PDAC (from Fig. 4C of Liudahl et al., Cancer Discov 2021)A deeper understanding of the pancreatic ductal adenocarcinoma (PDAC) tumor immune microenvironment is needed if effective immunotherapies are to be developed for this cancer. By analyzing 135 human PDAC samples using a single-cell multiplexed immunohistochemistry platform, Liudahl et al. provide insight into the inter- and intrapatient heterogeneity in density, complexity, phenotype, and spatial relationships of myeloid and lymphoid cells in PDAC. The data provide a comprehensive immune atlas of PDAC that can serve as a resource to stimulate further investigations.Liudahl SM, …, Coussens LM. Cancer Discov 2021 Aug 1;11:2014–31.

Glioblastoma genetic drivers dictate the function of tumor-associated macrophages/microglia and responses to CSF1R inhibition.

Tumor-associated macrophages/microglia (TAMs) are prominent microenvironment components in human glioblastoma (GBM) that are potential targets for anti-tumor therapy. However, TAM depletion by CSF1R inhibition showed mixed results in clinical trials. We hypothesized that GBM subtype-specific tumor microenvironment (TME) conveys distinct sensitivities to TAM targeting. We generated syngeneic PDGFB- and RAS-driven GBM models that resemble proneural-like and mesenchymal-like gliomas, and determined the effect of TAM targeting by CSF1R inhibitor PLX3397 on glioma growth. We also investigated the co-targeting of TAMs and angiogenesis on PLX3397-resistant RAS-driven GBM. Using single-cell transcriptomic profiling, we further explored differences in TME cellular compositions and functions in PDGFB- and RAS-driven gliomas. We found that growth of PDGFB-driven tumors was markedly inhibited by PLX3397. In contrast, depletion of TAMs at the early phase accelerated RAS-driven tumor growth and had no effects on other proneural and mesenchymal GBM models. In addition, PLX3397-resistant RAS-driven tumors did not respond to PI3K signaling inhibition. Single-cell transcriptomic profiling revealed that PDGFB-driven gliomas induced expansion and activation of pro-tumor microglia, whereas TAMs in mesenchymal RAS-driven GBM were enriched in pro-inflammatory and angiogenic signaling. Co-targeting of TAMs and angiogenesis decreased cell proliferation and changed the morphology of RAS-driven gliomas. Our work identifies functionally distinct TAM subpopulations in the growth of different glioma subtypes. Notably, we uncover a potential responsiveness of resistant mesenchymal-like gliomas to combined anti-angiogenic therapy and CSF1R inhibition. These data highlight the importance of characterization of the microenvironment landscape in order to optimally stratify patients for TAM-targeted therapy.

Abstract 5: Experimentally-driven mathematical model of tumor angiogenesis mediated by multiple angiogenic factors

Abstract Tumor angiogenesis is regulated by multiple pro- and anti-angiogenic factors. Anti-angiogenic drugs target the interconnected network of these angiogenic factors to inhibit neovascularization and tumor growth. However, current anti-angiogenic therapeutics targeting a single angiogenic factor show limited clinical success, prompting the development of combination anti-angiogenic therapy targeting multiple angiogenic factors simultaneously. In cases where anti-angiogenic therapy may be effective, tumors display a wide range of responses, which is not fully understood. In this work, we use an integrative in vitro imaging and mathematical modeling approach to investigate how tumor angiogenesis is systematically regulated by multiple angiogenic factors and to study the effects of anti-angiogenic therapy. We particularly focus on two pro-angiogenic factors, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF2), and two anti-angiogenic factors, thrombospondin-1 (TSP1) and platelet factor 4 (PF4). In our in vitro experimental setting human endothelial cells are cultured in a microfluidic organ-on-chip chip platform exposed to angiogenic factors or in the presence of cancer cells to mimic the tumor microenvironment. The cellular responses induced by various concentrations of angiogenic factors are measured through a high content screening (HCS) confocal imaging system to quantify the cell counts, morphological features and vessel characteristics. These data are used to construct a novel mathematical model to capture how the angiogenic factors mediate cross-talk between tumor cells and endothelial cells. By fitting the model to the experimental measurements, we are able to predict the temporal dynamics of cell numbers and concentrations of the angiogenic factors. Using the model, we generate insights into the effects of angiogenic factors and various anti-angiogenic treatments on tumor cells and endothelial cells. Excitingly, the model can also be applied to investigate how the effect of anti-angiogenic therapy is influenced by inter-tumor heterogeneity. For example, we identified that tumors with lower tumor cell growth rate and higher carrying capacity have a stronger response to anti-VEGF treatment, which indicates that variation in tumor cell growth rates can be a main reason for the observed heterogenous response to anti-VEGF therapy. In addition, we investigate a novel hypothesis regarding synergy between anti-angiogenic and chemotherapeutic agents with the model. Our simulated results suggest a new mechanism in which the chemotherapeutic agent enhances anti-angiogenic therapy simply through reducing the tumor cell growth rate. Overall, this work generates novel insights into the function of multiple angiogenic factors in tumor angiogenesis, providing a tool that can be further used to test and optimize anticancer therapy. Citation Format: Ding Li, Danielle D. Hixon, Shannon M. Mumenthaler, Stacey D. Finley. Experimentally-driven mathematical model of tumor angiogenesis mediated by multiple angiogenic factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 5.