Antiangiogenic Monoclonal Antibody Research Articles

Rational design of polyelectrolyte complexes based on bevacizumab and gellan gum with a surface modified with chitosan

Bevacizumab (BVZ) is an anti-angiogenic monoclonal antibody used to treat diseases such as various types of cancer. However, its parenteral administration causes several side effects and oral administration is limited due to the integrity of these macromolecules in the face of the extreme conditions of the gastrointestinal tract. To overcome these limitations, the study of drug delivery systems becomes a promising strategy to increase the efficiency of BVZ therapeutic delivery. Therefore, it is important that drug delivery systems are meticulously designed and that their physicochemical properties are understood. The objective of the present study was to develop nanoparticles through polyelectrolytic complexation between polysaccharides and polyampholytes, without the use of organic solvents, and to evaluate the influence of pH and molecular weight on particle formation. Different proportions of polymers were tested to obtain the nanoparticles, exhibiting average diameters in the range of 222.6–412.1 nm, zeta potential of −16.3 to −40 mV, and polydispersity index of ∼0.16–0.53. Complexation with chitosan promoted charge inversion (> +40 mV), in addition to increasing particle diameter and association efficiency, ranging from 29 % to approximately 60 %.

Systemic treatment options for non-small cell lung cancer after failure of previous immune checkpoint inhibitors: a bayesian network meta-analysis based on randomized controlled trials

BackgroundAlthough immune checkpoint inhibitors (ICIs) have brought survival benefits to non-small cell lung cancer (NSCLC), disease progression still occurs, and there is no consensus on the treatment options for these patients. We designed a network meta-analysis (NMA) to evaluate systemic treatment options for NSCLC after failure of ICIs.MethodsPubMed, Embase, Web of Science and Cochrane Library databases were searched, then literature screening was followed by NMA. We included all Phase II and III randomized controlled trials (RCTs). Progression-free survival (PFS) and overall survival (OS) used hazard ratio (HR) for evaluation. Objective response rate (ORR) and adverse events (AEs) used odds ratio (OR) and relative risk (RR) effect sizes, respectively. R software was applied to compare the Bayesian NMA results.ResultsWe finally included 6 studies. 1322 patients received ICI plus Chemotherapy (ICI + Chemo), ICI plus Anti-angiogenic monoclonal antibody (ICI + Antiangio-Ab), ICI plus Tyrosine kinase inhibitor (ICI + TKI), Tyrosine kinase inhibitor plus Chemotherapy (TKI + Chemo), Standard of Care (SOC), Chemotherapy (Chemo). TKI + Chemo is associated with longer PFS, higher ORR (surface under cumulative ranking curve [SUCRA], 99.7%, 88.2%), ICI + TKI achieved the longest OS (SUCRA, 82.7%). ICI + Antiangio-Ab was granted the highest safety rating for adverse events (AEs) of any grade, AEs greater than or equal to grade 3 and AEs of any grade leading to discontinuation of treatment (SUCRA, 95%, 82%, 93%).ConclusionsFor NSCLC after failure of ICIs, TKI + Chemo was associated with longer PFS and higher ORR, while ICI + TKI was associated with the longest OS. In terms of safety, ICI + Antiangio-Ab was the highest.

Camrelizumab plus apatinib for previously treated advanced adrenocortical carcinoma: A single-arm, open-label, phase 2 trial.

4511 Background: Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with dismal prognosis. Therapeutic options for patients with advanced ACC after failure of standard treatments are limited. The clinical benefit of single-agent immunotherapy as second-line therapy was still unsatisfactory. Methods: This was an investigator-initiated, prospective, single-arm, open-label, phase 2 trial and conducted at a single medical center. Patients were eligible for inclusion if they were aged at least 18 years; were pathologically diagnosed as unresectable or metastatic ACC; had failed first-line therapy; had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; had at least one measurable lesion; and had adequate organ function. The key exclusion criteria included a history of treatment with immunotherapy, anti-angiogenic small molecule TKIs, or anti-angiogenic monoclonal antibodies; a history of uncontrolled hypertension; and a history of an autoimmune condition requiring systemic therapy. All study participants received camrelizumab 200 mg intravenously on the first day of each 3 week cycle, combined with apatinib 250 mg orally once per day until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate (ORR), defined as the proportion of participants with complete response (CR) or partial response (PR) per RECIST (version 1.1). Results: A total of 21 patients with advanced ACC received at least one dose of camrelizumab and apatinib. ORR was 52% (95% CI, 30 to 74), and the disease control rate was 95% (95% CI, 84 to 100), superior to PD-1 inhibitor monotherapy and first-line standard therapy. The median PFS was 12.6 months (95% CI, 8.4 to 20.9), and the median OS was 20.9 months (95% CI, 11.0 to 20.9). The most common grade 3—4 treatment-related adverse events were alanine aminotransferase elevation (28.6%), aspartate aminotransferase elevation (23.8%) and lymphopenia (23.8%). Our exploratory analysis showed higher peripheral blood CXCR3+CD8+ T cell abundance, lower immunosuppressive CD4+ T cell abundance, and higher overlap of clonotypes between tumor-infiltrating T cells and circulating T cells, likely related to preferable response to camrelizumab plus apatinib therapy. Conclusions: In conclusion, the combination of camrelizumab with apatinib showed promising activity and acceptable toxicity in advanced ACC patients who failed previous lines of therapy. Pre-treatment peripheral blood immune cell subsets could be regarded as potential predictors of efficacy. Given the promising clinical activity, the potential of camrelizumab with apatinib as first-line therapy for advanced ACC need further evaluated. Clinical trial information: NCT04318730 .

The efficacy and safety of anlotinib combined with bevacizumab in treatment of recurrent isocitrate dehydrogenase wildtype glioblastoma: A retrospective analysis.

e14028 Background: Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor with a 5-year survival rate of 5%. There is no standard and effective treatment for recurrent GBM. Angiogenesis is recognized as a key event in the progression of GBM. Bevacizumab as an anti-angiogenic monoclonal antibody has been recommended by NCCN guidelines for recurrent GBM. Anlotinib is a small-molecule multi-target tyrosine kinase inhibitor (TKI) which has different function mechanisms and targets with bevacizumab. Therefore, we investigated the clinical efficacy and safety of anlotinib combined with bevacizumab in patients with recurrent IDH-wide type (wt) GBM on the basis of TMZ treatment. Methods: We retrospectively analyzed the clinical data of 18 patients with IDH-wt GBM in Shandong Cancer Hospital and Institute from 2019 to 2022. The primary endpoint was progression-free survival (PFS) and overall survival (OS) for combination treatment. The secondary endpoint was 6-months PFS rate, 1-year OS rate, objective response rate (ORR), disease control rate (DCR), OS and safety and toxicity profile. Results: All patients were diagnosed as WHO grade IV IDH-wt GBM and the median age of all patients was 55 years (range 39-76). Patients with recurrent GBM were first treated with anlotinib, followed by bevacizumab when patients developed progression or cerebral edema. In the overall population, the median OS for overall patients is 27 months, and the median survival time after first recurrence is 13.3 months. The median survival time of anlotinib treatment and combination treatment is 15.6 months and 12 months, respectively and the median PFS is 14.3 months and 9.1 months, respectively. The ORR for combination treatment was 27.8%, and 6-months DCR was 77.8%. The last follow-up date was October 15, 2022. By the last follow-up date, 3 patients were continuing anlotinib combined with bevacizumab treatment with no disease progression. The 6-months PFS rate was 78.9%, and the 1-year OS rate was 44.4%. The treatment-related adverse events (AEs) were shown in Table 3. The main AEs was bone marrow suppression (83.3%, 15/18), most of which were grade I and II (50%, 9). The AEs were relieved by adjusting the drug dose and symptomatic treatment. There were no treatment related deaths. Conclusions: Our study reported the clinical effect of anlotinib combined with bevacizumab treatment in recurrent GBM patients on the basis of TMZ treatment in a real-world setting. This is the first attempt to conduct dual antiangiogenic treatment in GBM patients. We demonstrate a promising result and suggest that this combination treatment may be a novel and safety treatment option for recurrent IDH-wt GBM patients.

Sustained Ocular Delivery of Bevacizumab Using Densomeres in Rabbits: Effects on Molecular Integrity and Bioactivity.

To demonstrate that a single administration of an anti-angiogenic monoclonal antibody, when integrated into a novel biodegradable Densomere composed only of the active pharmaceutical ingredient and polymer, maintains molecular integrity, sustained release, and prolonged bioactivity in vitro and in vivo for up to 12 months. Bevacizumab, a high-molecular-weight antibody (140,000-150,000 Da) was incorporated at 5% loading into Densomere microparticle carriers (DMCs) for injection to observe in vitro release over time from an aqueous suspension. The molecular integrity of the released bevacizumab was assessed by enzyme-linked immunosorbent assay (ELISA) and size-exclusion chromatography-high-performance liquid chromatography (SEC-HPLC). Anti-angiogenic bioactivity in vivo was assessed using the rabbit corneal suture model for suppression of neovascular encroachment from the limbus following a single subconjunctival administration. Continuous release of bevacizumab in vitro was observed in serial samples over a period of 12 months. ELISA and SEC-HPLC yielded profiles from aqueous supernatant samples indistinguishable from the reference bevacizumab. A single subconjunctival administration in rabbit eyes significantly suppressed corneal neovascularization in vivo compared to control eyes for 12 months. The Densomere carrier platform maintained the molecular integrity of bevacizumab with a prolonged release profile in vitro and demonstrated sustained in vivo drug delivery with continuous bioactivity in the rabbit cornea eye model for 12 months. The Densomere platform provides a significant opportunity for prolonged delivery of biologics in ocular and other tissues.

Long term outcomes of bevacizumab-associated kidney adverse effects

Bevacizumab is an anti-angiogenic monoclonal antibody against vascular endothelial growth factor (VEGF) and has multiple indications with known renal adverse effects, notably proteinuria, and acute kidney injury (AKI). There is insufficient knowledge about the long-term outcomes of its renal adverse effects. In this retrospective study, we reviewed the clinical course of all patients who received bevacizumab and developed therapy associated AKI, chronic kidney disease (CKD), or proteinuria. Among the 1,506 patients who received bevacizumab, the renal events attributed to bevacizumab were: 125 episodes of AKI (8.3%), 110 new-onset proteinuria events (7.3%), and new onset CKD in 112 patients (7.4%). All patients with bevacizumab-associated AKI recovered without requiring renal replacement therapy and in most patients (59%), the renal function returned to baseline. In conclusion, bevacizumab associated renal adverse effects were a common occurrence but with minimal long term adverse outcomes considering that this population is significantly impacted by their cancer prognosis. These results are helpful during counseling regarding risks and benefits of therapy discontinuation in patients who develop bevacizumab-associated adverse effects.

Blocking CD47 Shows Superior Anti-tumor Therapeutic Effects of Bevacizumab in Gastric Cancer.

Background: Bevacizumab (Avastin®), a humanized antiangiogenic monoclonal antibody, is widely used in the clinical treatment of tumour diseases. However, recent research has shown that the beneficial antiangiogenic effects of these agents have been limited in a number of patients due to complex immunosuppressive mechanisms. Here, we report a synergistic antitumour strategy through simultaneous blockade of VEGF and CD47 signalling to enhance the curative effect of advanced gastric cancer. Method: A BGC-823 gastric tumour model was chosen to evaluate antitumour efficacy. Macrophage migration and phagocytosis were evaluated to determine immune-related resistance to bevacizumab therapy. Synergistic antitumour activity was observed on the basis of tumour volume, tumour weight, tumour inhibition rate, tumour angiogenesis and tumour metastasis when bevacizumab was combined with an anti-CD47 monoclonal antibody. Results: Our study demonstrated that synergistic therapy targeting CD47 and VEGF reversed macrophage migration and phagocytosis, which were inhibited by antiangiogenic therapy and enhanced antitumour effects. Moreover, blockade of CD47 induced by antiangiogenic therapy inhibited tumour metastasis. Conclusion: Our data provide an effective strategy to attenuate resistance to bevacizumab therapy, promoting clinical cancer treatment with antiangiogenic drugs in combination with CD47-targeting inhibitors.

Maintenance endocrine therapy plus bevacizumab for advanced or metastatic breast cancer.

Endocrine therapy is the preferred option for patients with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer. 1 Gennari A André F Barrios CH et al. ESMO clinical practice guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021; 32: 1475-1495 Summary Full Text Full Text PDF PubMed Scopus (33) Google Scholar However, first-line chemotherapy is used in approximately half of this patient population, notably in the context of organ failure or resistance to endocrine therapy. 2 Werutsky G Reinert T Rosa ML Barrios CH Real-world data on first-line systemic therapy for hormone receptor-positive HER2-negative metastatic breast cancer: a trend shift in the era of CDK 4/6 inhibitors. Clin Breast Cancer. 2021; 21: e688-e692 Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar , 3 Jacquet E Lardy-Cléaud A Pistilli B et al. Endocrine therapy or chemotherapy as first-line therapy in hormone receptor-positive HER2-negative metastatic breast cancer patients. Eur J Cancer. 2018; 95: 93-101 Summary Full Text Full Text PDF PubMed Scopus (30) Google Scholar In these patients, chemotherapy is frequently stopped, despite disease stabilisation, because of acute and cumulative toxic effects. 4 Giuliano M Schettini F Rognoni C et al. Endocrine treatment versus chemotherapy in postmenopausal women with hormone receptor-positive, HER2-negative, metastatic breast cancer: a systematic review and network meta-analysis. Lancet Oncol. 2019; 20: 1360-1369 Summary Full Text Full Text PDF PubMed Scopus (66) Google Scholar Switching to maintenance endocrine therapy after first-line induction chemotherapy has been proposed to improve disease control and to maintain quality of life (QOL). Switch maintenance therapy is regularly used in clinical practice, 1 Gennari A André F Barrios CH et al. ESMO clinical practice guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021; 32: 1475-1495 Summary Full Text Full Text PDF PubMed Scopus (33) Google Scholar , 3 Jacquet E Lardy-Cléaud A Pistilli B et al. Endocrine therapy or chemotherapy as first-line therapy in hormone receptor-positive HER2-negative metastatic breast cancer patients. Eur J Cancer. 2018; 95: 93-101 Summary Full Text Full Text PDF PubMed Scopus (30) Google Scholar although clinical trials attesting to its relevance are scarce. 5 Ren W Yu Y Hong H et al. Clinical evidence of chemotherapy or endocrine therapy maintenance in patients with metastatic breast cancer: meta-analysis from randomized clinical trials and propensity score matching of multicentre cohort study. Cancer Res Treat. 2022; (published online Feb 4.)https://doi.org/10.4143/crt.2021.698 Crossref PubMed Google Scholar Moreover, the first-line combination of bevacizumab (an anti-angiogenic monoclonal antibody) plus chemotherapy has been shown in clinical trials to improve progression-free survival, although its effect on overall survival remains controversial. 6 Miyashita M Hattori M Takano T Toyama T Iwata H Risks and benefits of bevacizumab combined with chemotherapy for advanced or metastatic breast cancer: a meta-analysis of randomized controlled trials. Breast Cancer. 2020; 27: 347-354 Crossref PubMed Scopus (7) Google Scholar These results have led to the consideration of this combination as an acceptable first-line strategy. 1 Gennari A André F Barrios CH et al. ESMO clinical practice guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021; 32: 1475-1495 Summary Full Text Full Text PDF PubMed Scopus (33) Google Scholar Similarly, bevacizumab plus endocrine therapy is efficacious in improving progression-free survival and overall survival while being well tolerated as a first-line treatment for advanced or metastatic breast cancer. 7 Martín M Loibl S Hyslop T et al. Evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for hormone receptor-positive metastatic breast cancer: a pooled analysis from the LEA (GEICAM/2006–11_GBG51) and CALGB 40503 (Alliance) trials. Eur J Cancer. 2019; 117: 91-98 Summary Full Text Full Text PDF PubMed Scopus (10) Google Scholar Switch maintenance endocrine therapy plus bevacizumab after bevacizumab plus paclitaxel in advanced or metastatic oestrogen receptor-positive, HER2-negative breast cancer (BOOSTER): a randomised, open-label, phase 2 trialSwitch to maintenance endocrine therapy plus bevacizumab with the possibility of weekly paclitaxel reinduction if needed is an efficacious alternative, with a better safety profile, to continuing weekly paclitaxel plus bevacizumab in patients with ER-positive, HER2-negative advanced or metastatic breast cancer who have responded to induction therapy. Full-Text PDF

AAV-Vectored Expression of the Vascular Normalizing Agents 3TSR and Fc3TSR, and the Anti-Angiogenic Bevacizumab Extends Survival in a Murine Model of End-Stage Epithelial Ovarian Carcinoma.

Epithelial ovarian cancer is the deadliest gynecological malignancy. The lack of effective treatments highlights the need for novel therapeutic interventions. The aim of this study was to investigate whether sustained adeno-associated virus (AAV) vector-mediated expression of vascular normalizing agents 3TSR and Fc3TSR and the antiangiogenic monoclonal antibody, Bevacizumab, with or without oncolytic virus treatment would improve survival in an orthotopic syngeneic mouse model of epithelial ovarian carcinoma. AAV vectors were administered 40 days post-tumor implantation and combined with oncolytic avian orthoavulavirus-1 (AOaV-1) 20 days later, at the peak of AAV-transgene expression, to ascertain whether survival could be extended. Flow cytometry conducted on blood samples, taken at an acute time point post-AOaV-1 administration (36 h), revealed a significant increase in activated NK cells in the blood of all mice that received AOaV-1. T cell analysis revealed a significant increase in CD8+ tumor specific T cells in the blood of AAV-Bevacizumab+AOaV-1 treated mice compared to control mice 10 days post AOaV-1 administration. Immunohistochemical staining of primary tumors harvested from a subset of mice euthanized 90 days post tumor implantation, when mice typically have large primary tumors, secondary peritoneal lesions, and extensive ascites fluid production, revealed that AAV-3TSR, AAV-Fc3TSR+AOaV-1, or AAV-Bevacizumab+AOaV-1 treated mice had significantly more tumor-infiltrating CD8+ T cells than PBS controls. Despite AAV-mediated transgene expression waning faster in tumor-bearing mice than in non-tumor bearing mice, all three of the AAV therapies significantly extended survival compared to control mice; with AAV-Bevacizumab performing the best in this model. However, combining AAV therapies with a single dose of AOaV-1 did not lead to significant extensions in survival compared to AAV therapies on their own, suggesting that additional doses of AOaV-1 may be required to improve efficacy in this model. These results suggest that vectorizing anti-angiogenic and vascular normalizing agents is a viable therapeutic option that warrants further investigation, including optimizing combination therapies.

Meta-analysis of surrogate endpoints for survival in patients with unresectable hepatocellular carcinoma treated with immune checkpoint inhibitor-based regimens.

483 Background: Overall survival (OS) remains the gold standard for demonstrating clinical benefit in advanced hepatocellular carcinoma (HCC). While surrogate radiology-based endpoints for OS, such as progression-free survival (PFS) and objective response rate (ORR) are commonly used in the field of oncology, they remain controversial in the setting of HCC where antiangiogenic agents were the mainstay of treatment until recently. Immune checkpoint inhibitors (CPIs) as monotherapy or in combination have shifted the treatment paradigm in HCC. We investigated the surrogacy of radiology-based endpoints from CPI clinical trials in advanced HCC. Methods: Study level data were collected for disclosures published in EMBASE, PubMed, Clinicaltrials.gov and conference abstracts. Keywords used included (abbreviated here): immune CPIs, advanced or metastatic HCC and ORR, PFS and OS. Key inclusion criteria included: Phase I, II and III trial data, and patients with advanced or metastatic HCC who received CPI monotherapy or in a combination regimen. The endpoints investigated were median OS (mOS), median PFS (mPFS) and ORR (RECIST v1.1). A weighted Pearson correlation coefficient, with weights corresponding to the number of patients in the different treatment arms of the trials, was calculated between ORR/mOS, ORR/mPFS and mPFS/mOS in all arms, arms that included only patients with Child-Pugh A liver function, and arms in the first-line therapy setting. 95% confidence intervals (CIs) based on the empirical bootstrap re-sampling method are also reported. Results: Eighteen clinical trials (8 randomized trials and 10 multi-cohort trials) published between 2017 and 2021, including 3,246 patients across 32 treatment arms, were selected for inclusion in this meta-analysis. Ten trials included CPI monotherapy arms, 5 trials included CPI + TKI arms, 4 trials included CPI + anti-angiogenic monoclonal antibody arms, and 2 trials included CPI + CPI arms. There was 1 CPI + chemotherapy arm and 1 CPI + CPI + TKI arm in separate trials. Weighted Pearson correlation coefficients and corresponding 95% CIs are presented in the table. Conclusions: Our analysis suggests ORR/mOS, ORR/mPFS, and mPFS/mOS are positively correlated, with ORR/mPFS more strongly correlated compared to the other pairs, in patients with advanced HCC who were treated with CPI-based regimens. [Table: see text]

The role of antiangiogenic monoclonal antibodies combined to EGFR-TKIs in the treatment of advanced non-small cell lung cancer with activating EGFR mutations: acquired resistance mechanisms and strategies to overcome them.

As of today, only two antiangiogenic monoclonal antibodies plus epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) combinations are FDA and EMA-approved and are recommended by American Society of Clinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network for the first-line treatment of EGFR+ advanced non-small cell lung cancer patients: erlotinib plus bevacizumab and erlotinib plus ramucirumab. However, all treated patients eventually become unresponsive to such drugs, due to several different acquired resistance mechanisms, mainly represented by T790M substitutions and MET amplifications. While osimertinib treatment in T790M+ patients still represents the only approved treatment, MET-TKIs will likely change this status quo in the near future. In fact, existing clinical data strongly support a role for MET-TKI-based combinations in EGFR+ MET-amplified patients, possibly revolutionizing our current treatment algorithm. Chemotherapy plus immunotherapy plus antiangiogenic therapy combinations could also represent another useful addition.

Cerebral amyloid angiopathy-related inflammation during bevacizumab treatment for metastatic cervical cancer

Bevacizumab is an anti-angiogenic monoclonal antibody targeting Vascular Endothelial Growth Factor (VEGF). Bevacizumab inhibits cancer angiogenesis fundamental for either cancer development, its exponential growth, or metastatic spread.

1242P Anlotinib with gefitinib as first-line therapy in advanced non-small cell lung cancer harboring EGFR mutations: A phase II study

Anti-angiogenic monoclonal antibodies combined with EGFR-TKI has shown excellent efficacy and prolong PFS in patients(pts) with EGFR mutations. Anlotinib, an oral and multi-target tyrosine kinase inhibitor, has significantly improved OS and PFS in advanced NSCLC pts in the ALTER0303 study. This is the first trial evaluating anlotinib plus gefitinib in treatment-naive advanced NSCLC pts.

Case Report: Probable Cerebral Amyloid Angiopathy-Related Inflammation During Bevacizumab Treatment for Metastatic Cervical Cancer

Bevacizumab is an anti-angiogenic monoclonal antibody targeting Vascular Endothelial Growth Factor (VEGF) that induces the proliferation and migration of vascular endothelial cells thus, promoting vasculogenesis. Bevacizumab inhibits cancer angiogenesis, which is fundamental for either tumor development, exponential growth, or metastatic spread by supplying nutrients and oxygen. We report a new possible adverse event of bevacizumab, a Cerebral Amyloid Angiopathy-Related Inflammation (CAARI), in a 72-year-old woman with metastatic cervical cancer. After six cycles every three weeks of chemotherapy (cisplatin, paclitaxel, bevacizumab) and following two maintenance bevacizumab administrations, the patient presented a worsening confusional state. The MRI scan showed bilateral asymmetric temporo-parieto-occipital hyperintensity with numerous cortical microbleeds indicative of a CAARI. After stopping bevacizumab treatment, steroid therapy was administered resulting in rapid clinical improvement. The subsequent neurological and oncological follow-up was negative for recurrence. The patient was a heterozygote carrier for apolipoprotein-E ε4 that increases the risk of sporadic Cerebral Amyloid Angiopathy (CAA), which is characterized by beta-amyloid accumulation and fibrinoid necrosis in cerebral vasculature leading to micro/macrohemorrhages and dementia. Moreover, CAA is present in 30% of people aged over 60 years without dementia. In the brains of CAA patients, there is a proinflammatory state with cerebrovascular endothelial cell alteration and elevated levels of either adhesion molecules or inflammatory interleukins that increase the blood–brain barrier permeability. Moreover, CAARI is an inflammatory form of CAA. Inhibition of VEGF, which has anti-apoptotic, anti-inflammatory, and pro-survival effects on endothelial cells, impairs their regenerative capacity and increases expression of proinflammatory genes leading to weakened supporting layers of blood vessels and, hence, to damaged vascular integrity. In our patient, bevacizumab administration may have further increased permeability of cerebral microvasculature likely impaired by an underlying, asymptomatic CAA. To our knowledge, this is the first case reporting on the development of probable CAARI during bevacizumab treatment, which should alert the clinicians in case of neurological symptom onset in older patients under anti-angiogenic therapy.

Further Understanding of High-Grade Serous Ovarian Carcinogenesis: Potential Therapeutic Targets.

High-grade serous ovarian carcinoma (HGSOC) is the most common type of ovarian cancer and the most lethal gynecologic malignancy due to advanced stage at presentation. Recent years have witnessed progress in the therapy of HGSOC with the introduction of PARP (poly-adenosine diphosphate ribose polymerase) inhibitors and the anti-angiogenic monoclonal antibody bevacizumab to the backbone of chemotherapy or as maintenance therapy after chemotherapy. The improved molecular understanding of ovarian cancer pathogenesis, which has brought these therapies into the clinic, aspires to extend the boundaries of therapies through elucidation of other molecular aspects of ovarian carcinogenesis. This accumulating knowledge has started to be translated to additional targeted therapies that are in various stages of development. These include inhibitors of the function of other proteins involved in homologous recombination deficiency (HRD), such as WEE1 kinase, ATM/ATR kinases and CDK12 inhibitors. Despite disappointing results with immune checkpoint inhibitors monotherapy, harnessing the immune system in HGSOC with combination therapies that promote antigen production and immune cell activation is an avenue being explored. This paper examines arising HGSOC therapies based on molecular understanding of pathogenesis.

Abstract CT166: TRX-E-002-1 in treatment-refractory ovarian cancer - 3-month follow-up results from a phase I study dose escalation phase

Abstract Introduction: The poor outcomes associated with current therapies for recurrent epithelial ovarian cancer (EOC) are thought to reflect the existence of drug-resistant ovarian cancer stem cells (OCSCs). The introduction of emerging therapies such as anti-angiogenic monoclonal antibodies and PARP inhibitors have added to the treatment armamentarium but have generated new resistance mechanisms to contend with. TRX-E-002-1 is a novel, 3rd generation benzopyran molecule that induces caspase-dependent and -independent apoptosis in CD44 +ve ovarian cancer stem-like cells and CD44 -ve ovarian somatic cancer cells. The dose escalation phase of a progressive design trial investigating intraperitoneal (IP)-administered TRX-E-002-1 monotherapy and in combination with standard of care for recurrent EOC (NCT02903771) has been completed with a Maximum Tolerated Dose (MTD) of 5 mg/kg established. Methods: Women with platinum-resistant relapsed disease, platinum refractory disease, or documented intolerance to platinum therapy were enrolled into the study. Patients had completed at least 2 or more prior regimens (including adjuvant therapy) prior to enrolment. Patients were dosed weekly with single agent TRX-E-002-1 IP for the first 2 cycles after which addition of pre-defined standard intravenous chemotherapy regimens was allowed cycles 3-8. Patients were followed up for 3 months after the end of treatment. Assessments included disease response, based on CA-125 and Response Evaluation Criteria in Solid Tumours or GCIG criteria along with circulating epithelial tumour cells (CETC) and stem cell markers. Results: For the 11 evaluable patients, on average, 4 prior lines of therapy, across a range of current and emerging treatments were completed. A total of 9 subjects were evaluable for MTD analysis with 5 patients showing stable disease on monotherapy per RECIST 1.1 criteria and 4 completing 8 cycles (6 months) of treatment; 2 remained progression-free at the 3-month endpoint post-treatment. Preliminary data on activity includes 2 partial responses (PR) per RECIST 1.1 criteria observed at follow-up. With no measurable disease per RECIST 1.1 criteria, 1 patient demonstrated a complete response (CR) during combination treatment which was maintained through-out follow-up, as per GCIG criteria in patients without initial measurable disease. Median progression free survival shown to be 5.5 months. CETC data for responders shows growth of circulating cancer stem cells no longer detected during cultivation of epithelial-antigen +ve cells indicating that the epithelial antigen cells present are not capable of clonal expansion. Conclusion: IP administered TRX-E-002-1 as a first-in-class, dual acting, anti-cancer therapy has preliminary activity for the treatment of platinum resistant ovarian cancer for patients who have demonstrated resistance to a range of prior treatments. Citation Format: Jermaine Coward, Ganessan Kichenadasse, Paul Harnett, Kathleen Moore, Minal Barve, Daniel Berg, James Garner, Don Dizon. TRX-E-002-1 in treatment-refractory ovarian cancer - 3-month follow-up results from a phase I study dose escalation phase [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT166.

Phase II trial of bevacizumab and temozolomide for treatment of elderly patients with newly diagnosed glioblastoma.

2540 Background: Glioblastoma (GBM) in elderly patients differ molecularly as compared to younger patients, and may have increased angiogenic activity. Bevacizumab (BV) is an anti-angiogenic monoclonal antibody against vascular endothelial growth factor. We conducted a clinical trial to evaluate the efficacy and safety of BV and temozolomide (TMZ) for elderly patients with a new diagnosis of GBM, while deferring radiotherapy. Methods: This is a phase II, single-arm, multicenter, open label trial. Eligible patients have a tissue diagnosis of GBM with no treatment other than surgery, age ≥ 70, KPS ≥ 60, and adequate organ function. TMZ was initiated within 2 weeks of surgery and BV was initiated within 4 weeks thereafter. TMZ was administered at 150-200 mg/m2/day for 5 days every 4 weeks and BV at 10mg/kg every 2 weeks. A historical control group of 42 patients with similar criteria who received concurrent TMZ and RT followed by adjuvant TMZ, was derived for comparison from an institutional patient database. The primary endpoint is overall survival (OS) and secondary endpoints are progression-free-survival and safety. Results: 50 patients were enrolled from June 2010 to January 2016. Median age is 75 (range 70-87), and median KPS is 80 (range 60-100). 17 patients had a biopsy only, 26 patients have MGMT promoter methylation, and all patients are IDH wildtype. The study and control group are well matched in terms of age and molecular markers, however, the study patients had worse initial KPS and higher baseline tumor volume. At time of analysis, all but 2 patients were deceased. The median OS was 12.6 months for study patients (95% CI, 10.9-15.9 months) and 16.3 months for control patients (95% CI, 12.9-22.4 months). In a multivariate Cox analysis, baseline tumor volume (HR = 2.6, p = 0.0001) and MGMT promoter methylation (HR = 0.49, p = 0.004) were significant prognostic markers. Treatment type did not have a significant impact on OS (HR = 1.5, p = 0.14). Treatment-related serious adverse events included: pulmonary embolism (5), cerebral hemorrhage (3), pneumonia (1), intestinal perforation (1), deep venous thrombosis (6), hypertension (2), atrial fibrillation (1), congestive heart failure (1), cardio-respiratory arrest (1), lymphopenia (2), thrombocytopenia (8), and neutropenia (5). Conclusions: The results of this study suggest for patients with newly diagnosed GBM age ≥70 and KPS ≥60, treatment with BV and TMZ is equivalent to standard chemoradiotherapy, and has tolerable side effects. Complete endpoint analysis will be presented with the poster. Clinical trial information: NCT01149850 .

Study of anlotinib combined with icotinib as the first-line treatment in non-small cell lung cancer (NSCLC) patients harboring activating EGFR mutations (ALTER-L004).

9573 Background: Anti-angiogenic monoclonal antibodies plus EGFR TKIs have previously shown to prolong PFS in patients with EGFR-mutated NSCLC (JO25567 and NEJ026). Unlike bevacizumab, anlotinib is more convenient with orally administered and can inhibit more targets. Monotherapy using anlotinib has significantly prolonged median PFS and OS compared with the placebo values for third-line treatment or beyond in advanced NSCLC. We conducted a study to investigate the activity of anlotinb combined with icotinib, an oral EGFR TKI. Methods: This is a prospective, single-arm, multicenter clinical trial. Patients with locally advanced and/or metastatic IIIB, IIIC or IV non-squamous NSCLC are enrolled. Patients with EGFR exon 19 deletion and/or exon 21 L858R mutation who have not received prior therapies are eligible. The regimen consists of anlotinib (12 mg p.o, qd, day 1 to 14 every 21-day cycle) and icotinib (125mg p.o, tid). The primary endpoint is PFS. Secondary endpoints are OS, ORR, DCR and safety. Results: Between Jul 2018 and Dec 2019, 35 patients were enrolled in five centers and treated with anlotinb and icotinib. At data cutoff (Jan 7, 2020), patients were followed up for a median of 6.01 months.32 tumors were analyzed with 30 evaluable. Preliminary efficacy results: ORR was 59% (0 CR, 19 PR), DCR was 88% (0 CR, 19 PR, 9 SD). 26 patients are still receiving treatment and the longest exposure was 14 cycles. 10 (67%) of 15 patients with exon 19 deletions and 9 (53%) of 17 patients with L858R mutations achieved an objective response. 18 patients harbored aberrations in additional oncogenic drivers (PIK3CA or AKT1) and/or tumor suppressors (TP53, RB1, and PTEN) with an ORR of 72%. Upon analyses, AEs were observed in 97% (34/35) of patients. No Gr 5 AEs were reported. The most common Grade 3 AEs were hypertension (6 [ 17% ]), hypertriglyceridemia (2 [6% ]), diarrhea (1 [ 3% ]), hyperuricemia (1 [ 3% ]), hand and foot skin reaction (1 [3%]), asthenia (1 [3%]), and acute coronary syndrome (1 [ 3% ]). Hypertriglyceridemia was the only grade 4 AE (2 [ 6% ]). Three patients had to adjust treatment dosage. Conclusions: The strategy of anlotinib plus icotinib showed encouraging efficacy for previously untreated, EGFR-mutated advanced NSCLC patients. The combination was well tolerated and the AEs were manageable. The follow-up time is not sufficient and the PFS and OS outcomes need further evaluation. Clinical trial information: NCT03736837 .

Gastrointestinal Adverse Effects of Immunotherapeutic Agents: A Systematic Review

The utilization of immunotherapy is increasing to the point of becoming the fifth pillar of management alongside surgical intervention, chemotherapy, radiotherapy and targeted therapy. However, gastrointestinal adverse effects and toxicities have been frequently cited with its use. As per literature, the most common adverse effect of immune checkpoint inhibitors is watery and non-bloody diarrhea. Adoptive cell therapy can lead to delayed, on-target but off-tumor adverse effects which are unknown and may be life-threatening. The use of anti-angiogenic monoclonal antibodies can lead to bowel perforations, whereas epidermal growth factor receptor inhibitors and anti-HER2 agents are frequently associated with diarrhea. Minimal adverse effects have been associated with therapeutic cancer vaccines; however, additional studies are needed to determine their efficacy and potential toxicities. To provide an in-depth review of the gastrointestinal side effects of immunotherapeutic agents, we performed a thorough literature search using multiple online search engines such as PubMed, Google Scholar and Ovid MEDLINE, along with a review of the guidelines from the United States Food and Drug Administration (FDA) and the Cancer Research Institute on immunotherapy. In this systematic review, we detail the gastrointestinal adverse effects of immunotherapy and describe their management. With the advent of newer immunotherapeutic agents and the consistent approval of current agents by FDA for a wide spectrum of cancers, it is vital for physicians to familiarize themselves with their adverse effects for prompt diagnosis and early intervention to decrease adverse outcomes.

The Tumor Microenvironment in Colorectal Cancer Therapy.

The current standard-of-care for metastatic colorectal cancer (mCRC) includes chemotherapy and anti-angiogenic or anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, even though the addition of anti-angiogenic agents to backbone chemotherapy provides little benefit for overall survival. Since the approval of anti-angiogenic monoclonal antibodies bevacizumab and aflibercept, for the management of mCRC over a decade ago, extensive efforts have been devoted to discovering predictive factors of the anti-angiogenic response, unsuccessfully. Recent evidence has suggested a potential correlation between angiogenesis and immune phenotypes associated with colorectal cancer. Here, we review evidence of interactions between tumor angiogenesis, the immune microenvironment, and metabolic reprogramming. More specifically, we will highlight such interactions as inferred from our novel immune-metabolic (IM) signature, which groups mCRC into three distinct clusters, namely inflamed-stromal-dependent (IM Cluster 1), inflamed-non stromal-dependent (IM Cluster 2), and non-inflamed or cold (IM Cluster 3), and discuss the merits of the IM classification as a guide to new immune-metabolic combinatorial therapeutic strategies in mCRC.