Combination VEGFR/immune checkpoint inhibitor therapy: a promising new treatment for renal cell carcinoma.
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ABSTRACT:
SUBMITTER: Lee CH
PROVIDER: S-EPMC6203729 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:The outcome of patients who progress on front-line immune-based combination regimens (IC) including immune checkpoint inhibitors (CPI) and receive subsequent systemic therapy is unknown. METHODS:Retrospective analysis of consecutive patients with clear-cell mRCC who progressed on one of seven clinical trials investigating an IC and received ≥1 line of subsequent VEGFR TKI therapy. RESULTS:Thirty-three patients [median age 57 (37-77), 85% male, 73% ECOG 0] were included. For evaluable patients (N = 28), the best response to first subsequent therapy was 29% partial response, 54% stable disease, and 18% progressive disease. The median PFS (mPFS) for first subsequent therapy was 6.4 months (95% CI, 4.4-8.4); no difference in mPFS by prior type of IC (VEGFR TKI-CPI vs. CPI-CPI) was noted (p = 0.310). Significant AEs were observed in 30% of patients, more frequently transaminitis (9%). CONCLUSIONS:VEGFR TKIs have clinical activity in mRCC refractory to IC therapy, possibly impacted by the mechanism of prior combination therapy.
| S-EPMC6048048 | biostudies-literature
Project description:Gastric cancer is one of the most common types of cancer; notably, gastric cancer is one of the top five malignancies with regards to incidence and mortality rates. The symptoms of early gastric cancer are not typical, exhibiting only slight upper abdominal discomfort. When the symptoms become more obvious, the lesion has usually progressed to an advanced stage. Notably, >90% of inpatients already have locally advanced or metastatic gastric cancer at the time of initial diagnosis, with limited treatment options for advanced gastric cancer. These options include chemotherapy, targeted therapy and immune checkpoint inhibitors (ICIs). With regards to ICIs, the clinical benefit of monotherapy for advanced gastric cancer is limited; however, combinations of ICIs and other therapies may have clinical benefit. Relevant clinical studies have demonstrated that combinations of ICIs with chemotherapy, anti-vascular targeted therapy or other molecular targeted therapies, and the use of two ICIs, improve outcomes for patients with advanced gastric cancer. This article is a review of progress in the use of ICIs in combination with other therapies for the treatment of gastric cancer. The purpose of this article was to advance gastric cancer immunotherapy and to improve the overall therapeutic benefit for patients with advanced gastric cancer.
| S-EPMC7412728 | biostudies-literature
Project description:BackgroundImmune checkpoint inhibitor (ICI)-based combination therapy modalities for hepatocellular carcinoma (HCC) have achieved significant efficacy in clinical research and practice and have become the mainstay for the treatment of unresectable HCC.SummaryTo better help clinicians use combination immunotherapy drugs and regimens rationally, effectively, and safely, the editorial board facilitated a discussion with multidisciplinary experts in the field, adopted the "Delphi" consensus formation method, and finally revised and completed the "Chinese Multidisciplinary Expert Consensus on the Immune Checkpoint Inhibitors (ICIs)-Based Combination Therapy for Hepatocellular Carcinoma (2023 Edition)" on the basis of the 2021 edition.Key messagesThis consensus primarily focuses on the principles and methods of clinical practice of combination therapy based on ICIs, aiming to summarize the recommendations for clinical application based on the latest research and expert experience and provide application guidance for clinicians.
| S-EPMC11305662 | biostudies-literature
Project description:The B-raf gene is mutated in up to 66% of human malignant melanomas, and its protein product, BRAF kinase, is a key part of RAS-RAF-MEK-ERK (MAPK) pathway of cancer cell proliferation. BRAF-targeted therapy induces significant responses in the majority of patients, and the combination BRAF/MEK inhibitor enhances clinical efficacy, but the response to BRAF inhibitor and to BRAF/MEK inhibitor is short lived. On the other hand, treatment of melanoma with an immune checkpoint inhibitor, such as anti-PD-1, has lower response rate but the response is much more durable, lasting for years. For this reason, it was suggested that combination of BRAF/MEK and PD-1 inhibitors will significantly improve overall survival time.This paper develops a mathematical model to address the question of the correlation between BRAF/MEK inhibitor and PD-1 inhibitor in melanoma therapy. The model includes dendritic and cancer cells, CD 4+ and CD 8+ T cells, MDSC cells, interleukins IL-12, IL-2, IL-6, IL-10 and TGF- β, PD-1 and PD-L1, and the two drugs: BRAF/MEK inhibitor (with concentration γ B ) and PD-1 inhibitor (with concentration γ A ). The model is represented by a system of partial differential equations, and is used to develop an efficacy map for the combined concentrations (γ B ,γ A ). It is shown that the two drugs are positively correlated if γ B and γ A are at low doses, that is, the growth of the tumor volume decreases if either γ B or γ A is increased. On the other hand, the two drugs are antagonistic at some high doses, that is, there are zones of (γ B ,γ A ) where an increase in one of the two drugs will increase the tumor volume growth, rather than decrease it.It will be important to identify, by animal experiments or by early clinical trials, the zones of (γ B ,γ A ) where antagonism occurs, in order to avoid these zones in more advanced clinical trials.
| S-EPMC5517842 | biostudies-other
Project description:Hepatocellular carcinoma (HCC) is estimated to be the fourth leading cause of cancer-related deaths globally, and its overall prognosis is dismal because most cases are diagnosed at a late stage and are unamenable to curative treatment. The emergence of immune checkpoint inhibitors (ICIs) has dramatically improved the therapeutic efficacy for advanced hepatocellular carcinoma; however, their response rates remain unsatisfactory, partly because >50% of HCC exhibit an ICI-nonresponsive tumor microenvironment characterized by a paucity of cytotoxic T cells (immune-cold), as well as difficulty in their infiltration into tumor sites (immune excluded). To overcome this limitation, combination therapies with locoregional therapies, including ablation, transarterial embolization, and radiotherapy, which are usually used for early stage HCCs, have been actively explored to enhance ICI efficacy by promoting the release of tumor-associated antigens and cytokines, and eventually accelerating the so-called cancer-immunity cycle. Various combination therapies have been investigated in early- to late-phase clinical trials, and some have shown promising results. This comprehensive article provides an overview of the immune landscape for HCC to understand ICI efficacy and its limitations and, subsequently, reviews the status of combinatorial therapies of ICIs with locoregional therapy for HCC.
| S-EPMC10605879 | biostudies-literature
Project description:BackgroundAlthough immune checkpoint inhibitors (ICIs) combined with vascular endothelial growth factor receptor (VEGFR)-targeted therapy and sunitinib monotherapy have been widely applied to metastatic renal cell carcinoma (mRCC), effectiveness and safety data are still lacking. To optimize clinical decision-making, we conducted a systematic review and meta-analysis of published randomized clinical trials to characterize the efficacy and the risk of adverse events (AEs) in patients treated with ICIs plus anti-VEGF therapy.Materials and methodsWe used PubMed, EMBASE, and the Cochrane Library to retrieve randomized controlled trials (RCTs) published before March 27, 2021. The efficacy outcomes were progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). The pooled risk ratio (RR) and 95% confidence intervals (CI) of AEs were calculated in the safety analysis.ResultsSix RCTs involving 4,227 patients were identified after a systematic search. For OS, ICI and anti-VEGF combination therapy decreased mortality approximately 30% in the intention-to-treat population (ITT) (hazard ratio (HR) = 0.70, 95% CI: 0.57-0.87), but there was no statistical difference in patients evaluated as "favorable" by the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) criteria compared with monotherapy (HR = 0.90, 95% CI: 0.55-1.46, p = 0.66). In terms of PFS, the progression risk for all participants declined 35% (HR = 0.65, 95% CI: 0.50-0.83) and patients evaluated as "poor" by IMDC benefited further (HR = 0.46, 95% CI: 0.36-0.58). No evident divergence was found in age and sex subgroups. The RRs of all-grade hypertension, arthralgia, rash, proteinuria, high-grade (grades 3-5) arthralgia, and proteinuria developed after combination therapy were increased compared with sunitinib. The risk of high-grade hypertension and rash showed no statistical difference. However, the risk of hand-foot skin reaction (HFSR), stomatitis, and dysgeusia decreased in combination therapy groups.ConclusionsCompared with sunitinib, OS, PFS, and ORR were significantly improved in patients receiving ICI and anti-VEGF combination therapy at the expense of increased specific AEs. More attention should be paid to individualized application of these combination therapies to achieve the best benefit-risk ratio in the clinic.Systematic review registration[https://inplasy.com/] INPLASY: 202130104.
| S-EPMC8552014 | biostudies-literature
Project description:Recently, immune checkpoint inhibitors (ICIs) therapy has become a promising therapeutic strategy with encouraging therapeutic outcomes due to their durable anti-tumor effects. Though, tumor inherent or acquired resistance to ICIs accompanied with treatment-related toxicities hamper their clinical utility. Overall, about 60-70% of patients (e.g., melanoma and lung cancer) who received ICIs show no objective response to intervention. The resistance to ICIs mainly caused by alterations in the tumor microenvironment (TME), which in turn, supports angiogenesis and also blocks immune cell antitumor activities, facilitating tumor cells' evasion from host immunosurveillance. Thereby, it has been supposed and also validated that combination therapy with ICIs and other therapeutic means, ranging from chemoradiotherapy to targeted therapies as well as cancer vaccines, can capably compromise tumor resistance to immune checkpoint blocked therapy. Herein, we have focused on the therapeutic benefits of ICIs as a groundbreaking approach in the context of tumor immunotherapy and also deliver an overview concerning the therapeutic influences of the addition of ICIs to other modalities to circumvent tumor resistance to ICIs.
| S-EPMC8725311 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is the most frequent primary liver tumor. As a result of advanced disease being often present at diagnosis, only a small percentage of patients are amenable to curative-intent treatment options such as surgical resection and liver transplantation. Systemic therapy consisting of tyrosine kinase inhibitors such as sorafenib had been used for over a decade with limited efficacy. More recently, treatment with immune checkpoint inhibitors has revolutionized the treatment landscape of various malignant tumors. With this shifting paradigm, recent data have demonstrated encouraging outcomes among patients with HCC. In particular, several trials have investigated the safety and efficacy of various immune checkpoint inhibitors (ICI) either as monotherapy or in the form of combined treatments. We sought to provide an overview of recent clinical trials among patients with advanced HCC as well as to highlight predictors of response and immune-related adverse events and to review the evidence on perioperative administration of ICI in patients with resectable HCC.
| S-EPMC9025403 | biostudies-literature
Project description:BackgroundImmune checkpoint inhibitors and vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors are the most commonly used medications in metastatic renal cell carcinoma (mRCC). Recently, large clinical trials have shown favorable outcomes in patients treated with combined immune checkpoint plus VEGFR inhibition compared with VEGFR inhibition alone. However, the benefit among favorable risk (based on International Metastatic Renal Cell Carcinoma Database Consortium score) and elderly (age > 65 years) patients was not clear, leading to a discrepancy between United States Food and Drug Administration and European Association of Urology recommendations.Materials and methodsWe searched available literature for phase III randomized clinical trials evaluating the efficacy of combining immunotherapy plus VEGF/VEGFR inhibitors versus standard of care in patients with previously untreated mRCC. Combinations that were included in United States Food and Drug Administration recommendations or European Association of Urology guidelines were used for analysis. We performed a meta-analysis with a random effects model to evaluate the efficacy of immunotherapy-VEGFR inhibitor combinations compared with sunitinib in favorable risk and elderly patients.ResultsOur analysis demonstrated that progression-free survival (PFS) was significantly prolonged with combination therapy compared with sunitinib in patients with age > 65 years (hazard ratio, 0.66; 95% confidence interval, 0.52-0.84; P = .001). The PFS in favorable risk disease was improved with combination therapy compared with sunitinib, but the difference was not statistically significant (hazard ratio, 0.68; 95% confidence interval, 0.46-1.01; P = .055).ConclusionOur meta-analysis strengthens the trend of beneficial effect in prolonging PFS in both subgroups compared with each trial alone, indicating that favorable risk and elderly patients with mRCC likely benefit from combining programmed cell death 1 or programmed cell death-ligand 1 and VEGFR inhibition.
| S-EPMC7875559 | biostudies-literature
Project description:BackgroundImmune checkpoint therapies have led to significant breakthroughs in cancer patient treatment in recent years. However, their efficiency is variable, and resistance to immunotherapies is common. VISTA is an immune-suppressive checkpoint inhibitor of T cell response belonging to the B7 family and a promising novel therapeutic target. VISTA is expressed in the immuno-suppressive tumor microenvironment, primarily by myeloid lineage cells, and its genetic knockout or antibody blockade restores an efficient antitumor immune response.MethodsFully human monoclonal antibodies directed against VISTA were produced after immunizing humanized Trianni mice and single B cell sequencing. Anti-VISTA antibodies were evaluated for specificity, cross-reactivity, monocyte and T cell activation, Fc-effector functions, and antitumor efficacy using in vitro and in vivo models to select the KVA12123 antibody lead candidate. The pharmacokinetics and safety profiles of KVA12123 were evaluated in cynomolgus monkeys.ResultsHere, we report the development of a clinical candidate anti-VISTA monoclonal antibody, KVA12123. KVA12123 showed high affinity binding to VISTA through a unique epitope distinct from other clinical-stage anti-VISTA monoclonal antibodies. This clinical candidate demonstrated high specificity against VISTA with no cross-reactivity detected against other members of the B7 family. KVA12123 blocked VISTA binding to its binding partners. KVA12123 induced T cell activation and demonstrated NK-mediated monocyte activation. KVA12123 treatment mediated strong single-agent antitumor activity in several syngeneic tumor models and showed enhanced efficacy in combination with anti-PD-1 treatment. This clinical candidate was engineered to improve its pharmacokinetic characteristics and reduce Fc-effector functions. It was well-tolerated in preclinical toxicology studies in cynomolgus monkeys, where hematology, clinical chemistry evaluations, and clinical observations revealed no indicators of toxicity. No cytokines associated with cytokine release syndrome were elevated.ConclusionThese results establish that KVA12123 is a promising drug candidate with a distinct but complementary mechanism of action of the first generation of immune checkpoint inhibitors. This antibody is currently evaluated alone and in combination with pembrolizumab in a Phase 1/2 open-label clinical trial in patients with advanced solid tumors.
| S-EPMC10751915 | biostudies-literature