Immunotherapy has emerged as a major therapeutic modality in oncology. Currently, however, the majority of patients with cancer do not derive benefit from these treatments. Vascular abnormalities are ...a hallmark of most solid tumours and facilitate immune evasion. These abnormalities stem from elevated levels of proangiogenic factors, such as VEGF and angiopoietin 2 (ANG2); judicious use of drugs targeting these molecules can improve therapeutic responsiveness, partially owing to normalization of the abnormal tumour vasculature that can, in turn, increase the infiltration of immune effector cells into tumours and convert the intrinsically immunosuppressive tumour microenvironment (TME) to an immunosupportive one. Immunotherapy relies on the accumulation and activity of immune effector cells within the TME, and immune responses and vascular normalization seem to be reciprocally regulated. Thus, combining antiangiogenic therapies and immunotherapies might increase the effectiveness of immunotherapy and diminish the risk of immune-related adverse effects. In this Perspective, we outline the roles of VEGF and ANG2 in tumour immune evasion and progression, and discuss the evidence indicating that antiangiogenic agents can normalize the TME. We also suggest ways that antiangiogenic agents can be combined with immune-checkpoint inhibitors to potentially improve patient outcomes, and highlight avenues of future research.
For more than a decade, sorafenib has been the only systemic treatment option for patients with advanced hepatocellular carcinoma (HCC). However, rapid progress over the past few years led to ...approval of other angiogenesis inhibitors and several immune checkpoint blockers (ICBs) that have been added to the treatment armamentarium for advanced HCC. Moreover, the recent success of a combination of bevacizumab with atezolizumab signals an important change in the front-line treatment of HCC.
This review summarizes rapidly emerging clinical data on the promise and challenges of implementing ICBs in HCC and discusses the unmet need of biomarkers to predict response or resistance to therapy. Two strategies to target immunosuppression in tumors are also discussed: one proven (vascular endothelial growth factor pathway inhibition) and one currently under investigation (transforming growth factor-β pathway inhibition). The rationale and preliminary evidence on how their inhibition may reprogram the immunosuppressive milieu and enhance the efficacy of ICBs in HCC are reviewed.
The recent successes and failures of angiogenesis inhibitors and ICBs, alone and in combination, have provided important insights into how to implement this novel systemic therapy in HCC and led to new avenues to enhance immunotherapy efficacy in this disease.
The recent approval of Provenge has brought new hope for anticancer vaccine therapies. However, the immunosuppressive tumor microenvironment seems to impair the efficacy of vaccine therapies. The ...abnormal tumor vasculature creates a hypoxic microenvironment that polarizes inflammatory cells toward immune suppression. Moreover, tumors systemically alter immune cells' proliferation, differentiation, and function via secretion of growth factors and cytokines. For example, VEGF, a major proangiogenic cytokine induced by hypoxia, plays a critical role in immunosuppression via these mechanisms. Hence, antiangiogenic treatment may be an effective modality to potentiate immunotherapy. Here, we discuss the local and systemic effects of VEGF on tumor immunity and propose a potentially translatable strategy to re-engineer the tumor-immune microenvironment and improve cancer immunotherapy by using lower "vascular normalizing" doses of antiangiogenic agents.
Surgical treatments offer the chance for cure in primary or metastatic liver cancers. However, many patients experience disease progression after surgical interventions, or cannot undergo surgery as ...they present with unresectable disease at diagnosis. In such cases, available treatment options (local and systemic) have been limited in efficacy, which led to dismal survival rates in advanced hepatocellular carcinoma (HCC), intrahepatic colangiocarcinoma (ICC) or metastatic pancreatic ductal adenocarcinoma (PDAC). More recent developments in oncology have offered renewed hope for advanced liver cancer patients. Hypofractionated radiation has shown feasibility and promise in unresectable setting, and is now being tested in a randomized phase III trial in HCC (clinicaltrials.gov identifier NCT03186898). Antiangiogenic agents have strongly impacted the management of advanced HCC, with multiple drug options in first line setting (sorafenib, lenvatinib) and second line setting (regorafenib, cabozantinib, ramucirumab). Chemotherapy based regimens are standard of care in ICC and PDAC. Immunotherapy with anti-PD-1/PD-L1 or anti-CTLA4 antibodies has shown real potential to transform advanced HCC therapy, both in first line and second line settings. Finally, combinations of these new strategies are very attractive approaches, as they promise durable and profound responses in advanced HCC. But in order to achieve this promise more broadly, these concepts require greater understanding based on mechanistic preclinical studies and validation in correlative studies in clinical trials as a basis to establish optimal combinatorial strategies. The insights gained from this “bench to the bedside and back” approach raise the hope for a more efficient development of targeted agents in combination, and in earlier stages of the disease, with the goal of increasing survival in patients afflicted with this aggressive and deadly diseases. (Presented at the 2001st Meeting, July 4, 2022)
Angiogenesis is defined as the formation of new blood vessels from preexisting vessels and has been characterized as an essential process for tumor cell proliferation and viability. This has led to ...the development of pharmacological agents for anti-angiogenesis to disrupt the vascular supply and starve tumor of nutrients and oxygen, primarily through blockade of VEGF/VEGFR signaling. This effort has resulted in 11 anti-VEGF drugs approved for certain advanced cancers, alone or in combination with chemotherapy or other targeted therapies. But this success had only limited impact on overall survival of cancer patients and rarely resulted in durable responses. Given the recent success of immunotherapies, combinations of anti-angiogenics with immune checkpoint blockers have become an attractive strategy. However, implementing such combinations will require a better mechanistic understanding of their interaction. Due to overexpression of pro-angiogenic factors in tumors, their vasculature is often tortuous and disorganized, with excessively branched leaky vessels. This enhances vascular permeability, which in turn is associated with high interstitial fluid pressure, and a reduction in blood perfusion and oxygenation. Judicious dosing of anti-angiogenic treatment can transiently normalize the tumor vasculature by decreasing vascular permeability and improving tumor perfusion and blood flow, and synergize with immunotherapy in this time window. However, anti-angiogenics may also excessively prune tumor vessels in a dose and time-dependent manner, which induces hypoxia and immunosuppression, including increased expression of the immune checkpoint programmed death receptor ligand (PD-L1). This review focuses on revisiting the concept of anti-angiogenesis in combination with immunotherapy as a strategy for cancer treatment.
Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171—an oral tyrosine kinase inhibitor of VEGF receptors—has ...rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. Basic FGF, SDF1α, and viable circulating endothelial cells (CECs) increased when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed after drug interruption. Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor.
Advances in immunotherapy have revolutionized the treatment of multiple cancers. Unfortunately, tumors usually have impaired blood perfusion, which limits the delivery of therapeutics and cytotoxic ...immune cells to tumors and also results in hypoxia—a hallmark of the abnormal tumor microenvironment (TME)—that causes immunosuppression. We proposed that normalization of TME using antiangiogenic drugs and/or mechanotherapeutics can overcome these challenges. Recently, immunotherapy with checkpoint blockers was shown to effectively induce vascular normalization in some types of cancer. Although these therapeutic approaches have been used in combination in preclinical and clinical studies, their combined effects on TME are not fully understood. To identify strategies for improved immunotherapy, we have developed a mathematical framework that incorporates complex interactions among various types of cancer cells, immune cells, stroma, angiogenic molecules, and the vasculature. Model predictions were compared with the data from five previously reported experimental studies. We found that low doses of antiangiogenic treatment improve immunotherapy when the two treatments are administered sequentially, but that high doses are less efficacious because of excessive vessel pruning and hypoxia. Stroma normalization can further increase the efficacy of immunotherapy, and the benefit is additive when combined with vascular normalization. We conclude that vessel functionality dictates the efficacy of immunotherapy, and thus increased tumor perfusion should be investigated as a predictive biomarker of response to immunotherapy.
Background and Aims
Activation of the antitumor immune response using programmed death receptor‐1 (PD‐1) blockade showed benefit only in a fraction of patients with hepatocellular carcinoma (HCC). ...Combining PD‐1 blockade with antiangiogenesis has shown promise in substantially increasing the fraction of patients with HCC who respond to treatment, but the mechanism of this interaction is unknown.
Approach and Results
We recapitulated these clinical outcomes using orthotopic—grafted or induced—murine models of HCC. Specific blockade of vascular endothelial receptor 2 (VEGFR‐2) using a murine antibody significantly delayed primary tumor growth but failed to prolong survival, while anti‐PD‐1 antibody treatment alone conferred a minor survival advantage in one model. However, dual anti‐PD‐1/VEGFR‐2 therapy significantly inhibited primary tumor growth and doubled survival in both models. Combination therapy reprogrammed the immune microenvironment by increasing cluster of differentiation 8–positive (CD8+) cytotoxic T cell infiltration and activation, shifting the M1/M2 ratio of tumor‐associated macrophages and reducing T regulatory cell (Treg) and chemokine (C‐C motif) receptor 2–positive monocyte infiltration in HCC tissue. In these models, VEGFR‐2 was selectively expressed in tumor endothelial cells. Using spheroid cultures of HCC tissue, we found that PD‐ligand 1 expression in HCC cells was induced in a paracrine manner upon anti‐VEGFR‐2 blockade in endothelial cells in part through interferon‐gamma expression. Moreover, we found that VEGFR‐2 blockade increased PD‐1 expression in tumor‐infiltrating CD4+ cells. We also found that under anti‐PD‐1 therapy, CD4+ cells promote normalized vessel formation in the face of antiangiogenic therapy with anti‐VEGFR‐2 antibody.
Conclusions
We show that dual anti‐PD‐1/VEGFR‐2 therapy has a durable vessel fortification effect in HCC and can overcome treatment resistance to either treatment alone and increase overall survival in both anti‐PD‐1 therapy–resistant and anti‐PD‐1 therapy–responsive HCC models.
Immunotherapy with immune checkpoint blockade (ICB) has shown limited benefits in hepatocellular carcinoma (HCC) and other cancers, mediated in part by the immunosuppressive tumor microenvironment ...(TME). As p53 loss of function may play a role in immunosuppression, we herein examine the effects of restoring p53 expression on the immune TME and ICB efficacy. We develop and optimize a CXCR4-targeted mRNA nanoparticle platform to effectively induce p53 expression in HCC models. Using p53-null orthotopic and ectopic models of murine HCC, we find that combining CXCR4-targeted p53 mRNA nanoparticles with anti-PD-1 therapy effectively induces global reprogramming of cellular and molecular components of the immune TME. This effect results in improved anti-tumor effects compared to anti-PD-1 therapy or therapeutic p53 expression alone. Thus, our findings demonstrate the reversal of immunosuppression in HCC by a p53 mRNA nanomedicine when combined with ICB and support the implementation of this strategy for cancer treatment.
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