Cardiovascular toxicity of angiogenesis inhibitors and immune checkpoint inhibitors: synergistic anti-tumour effects at the cost of increased cardiovascular risk?

2021 ◽  
Vol 135 (14) ◽  
pp. 1649-1668
Author(s):  
Daan C.H. van Dorst ◽  
Leni van Doorn ◽  
Katrina M. Mirabito Colafella ◽  
Olivier C. Manintveld ◽  
H. Carlijne Hassing ◽  
...  
Keyword(s):  
Cardiovascular Risk ◽  
Combination Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Angiogenesis Inhibitors ◽  
Cardiovascular Toxicity ◽  
Treatment Indications ◽  
Increased Risk ◽  
Wide Range

Abstract In the past two decades, treatment outcomes for a wide range of malignancies have improved remarkably due to the development of novel anti-cancer therapies, including vascular endothelial growth factor inhibitors (VEGFIs) and immune checkpoint inhibitors (ICIs). Despite their unprecedented anti-tumour effects, it is becoming increasingly clear that both types of agents are associated with specific cardiovascular toxicity, including hypertension, congestive heart failure, myocarditis and acceleration of atherosclerosis. Currently, VEGFI and ICI combination therapy is recommended for the treatment of advanced renal cell carcinoma (RCC) and has shown promising treatment efficacy in other tumour types as well. Consequently, VEGFI and ICI combination therapy will most likely become an important therapeutic strategy for various malignancies. However, this combinatory approach is expected to be accompanied by a substantial increase in cardiovascular risk, as both types of agents could act synergistically to induce cardiovascular sequelae. Therefore, a comprehensive baseline assessment and adequate monitoring by specialised cardio-oncology teams is essential in case these agents are used in combination, particularly in high-risk patients. This review summarises the mechanisms of action and treatment indications for currently registered VEGFIs and ICIs, and discusses their main vascular and cardiac toxicity. Subsequently, we provide the biological rationales for the observed promising synergistic anti-tumour effects of combined VEGFI/ICI administration. Lastly, we speculate on the increased risk for cardiovascular toxicity in case these agents are used in combination and its implications and future directions for the clinical situation.

Toxicities of single agent and combination immune checkpoint inhibitors in patients with autoimmune diseases.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14176-e14176
Author(s):  
Samuel Cytryn ◽  
Elizaveta Efuni ◽  
Sabina Sandigursky
Keyword(s):  
Overall Survival ◽  
Combination Therapy ◽  
Autoimmune Diseases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Combination Group ◽  
Safety And Efficacy ◽  
Increased Risk

e14176 Background: Autoimmunity is associated with increased risk of malignancy. However, patients with pre-existing autoimmune diseases (AIDs) have been excluded from trials of immune checkpoint inhibitors (ICIs) known to cause immune activation and lead to immune related adverse events (irAEs). Data is limited on the safety and efficacy of these agents when used in AID patients and physicians are therefore wary to use them in this at-risk population. Methods: We conducted a single institution retrospective study to evaluate the safety and efficacy of ICI therapy in patients with pre-existing AIDs from 2011 to 2018. Primary endpoints were irAEs and AID flares. The secondary endpoint was overall survival (OS). Results: Of 84 total patients, 70 (83%) received ICI monotherapy and 14 (17%) received combination therapy. AIDs included: rheumatic 40 (48%), dermatologic 25 (30%), endocrine 16 (19%) and gastrointestinal 14 (17%) diseases of which 18 (21%) were on immune suppression. Combination therapy was associated with higher rates of severe grade 3-4 irAEs in 5/14 (36%) patients versus 8/70 (11%) with monotherapy (p = 0.022). ICIs were discontinued due to irAEs in 10/84 (12%) of all patients; 4/14 (29%) in the combination group and 6/70 (9%) in the monotherapy group (p = 0.057). While 32 patients (38%) had at least one AID flare, ICI was only permanently discontinued in 2 patients. Flare rates were higher for combination use: 8/14 (57%) compared to 23/70 (33%) for monotherapy (p = 0.086). Combination therapy was associated with higher median OS 27.8 months [95% CI 11.4-44.3] compared to monotherapy 12.3 months [95% CI 9.7-14.8] (p = 0.0007). OS had a positive correlation with flare (p = 0.007) and severe irAEs (p = 0.037). Conclusions: Our data suggest that rates of irAEs in patients with pre-existing AIDs are similar to those reported in the literature with single agent ICIs. While risk of severe irAEs and flares is increased with combination therapy, they are associated with overall survival. In our cohort, irAEs and flares were manageable and in most patients did not require permanent discontinuation for monotherapy or combination therapy suggesting that ICIs should be offered to this population, albeit with caution.

scholarly journals Cardio-Oncology: mechanisms of cardiovascular toxicity

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 113 ◽  
Author(s):  
Timothy M. Markman ◽  
Maurie Markman
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Chemotherapeutic Agents ◽  
Vascular Endothelial ◽  
Cardiovascular Toxicity ◽  
Management Of Complications ◽  
Wide Range ◽  
Endothelial Growth Factor

The therapeutic options available to treat a wide range of malignancies are rapidly increasing. At the same time, the population being treated is aging with more cardiovascular risk factors, comorbid conditions, and associated poor cardiac reserve. Both traditional chemotherapeutic agents (for example, anthracyclines) and newer therapies (for example, targeted tyrosine kinase inhibitors and immune checkpoint inhibitors) have demonstrated profound cardiovascular toxicities. It is important to understand the mechanisms of these toxicities to establish strategies for the prevention and management of complications—arrhythmias, heart failure, and even death. In the first of this two-part review series, we focus on what is known and hypothesized about the mechanisms of cardiovascular toxicity from anthracyclines, HER2/ErbB2 inhibitors, immune checkpoint inhibitors, and vascular endothelial growth factor inhibitors.

scholarly journals From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells: Changing the Landscape of Cancer Immunotherapy

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2278
Author(s):  
Afshin Derakhshani ◽  
Zeinab Rostami ◽  
Hossein Safarpour ◽  
Mahdi Abdoli Shadbad ◽  
Niloufar Sadat Nourbakhsh ◽  
...  
Keyword(s):  
Single Cell ◽  
Signaling Pathways ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cancer Development ◽  
Immune Checkpoints ◽  
Single Cell Sequencing ◽  
Increased Risk

Over the past decade, there have been remarkable advances in understanding the signaling pathways involved in cancer development. It is well-established that cancer is caused by the dysregulation of cellular pathways involved in proliferation, cell cycle, apoptosis, cell metabolism, migration, cell polarity, and differentiation. Besides, growing evidence indicates that extracellular matrix signaling, cell surface proteoglycans, and angiogenesis can contribute to cancer development. Given the genetic instability and vast intra-tumoral heterogeneity revealed by the single-cell sequencing of tumoral cells, the current approaches cannot eliminate the mutating cancer cells. Besides, the polyclonal expansion of tumor-infiltrated lymphocytes in response to tumoral neoantigens cannot elicit anti-tumoral immune responses due to the immunosuppressive tumor microenvironment. Nevertheless, the data from the single-cell sequencing of immune cells can provide valuable insights regarding the expression of inhibitory immune checkpoints/related signaling factors in immune cells, which can be used to select immune checkpoint inhibitors and adjust their dosage. Indeed, the integration of the data obtained from the single-cell sequencing of immune cells with immune checkpoint inhibitors can increase the response rate of immune checkpoint inhibitors, decrease the immune-related adverse events, and facilitate tumoral cell elimination. This study aims to review key pathways involved in tumor development and shed light on single-cell sequencing. It also intends to address the shortcomings of immune checkpoint inhibitors, i.e., their varied response rates among cancer patients and increased risk of autoimmunity development, via applying the data from the single-cell sequencing of immune cells.

scholarly journals Pan-Cancer Analysis Identifies Liver Metastases as Negative Predictive Factor for Immune Checkpoint Inhibitors Treatment Outcome

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiao-Juan Chen ◽  
Aiqun Ren ◽  
Liang Zheng ◽  
En-Dian Zheng ◽  
Tao Jiang
Keyword(s):  
Combination Therapy ◽  
Liver Metastases ◽  
Predictive Factor ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Intrinsic Resistance ◽  
The Impact ◽  
Pan Cancer ◽  
Negative Predictive Factor

This study aimed to investigate the predictive value of liver metastases (LM) in patients with various advanced cancers received immune-checkpoint inhibitors (ICIs). First, clinical and survival data from a published cohort of 1,661 patients who received ICIs therapy were downloaded and analyzed. Second, a retrospective review of 182 patients with advanced non-small-cell lung cancer (NSCLC) who received PD-1/PD-L1 monotherapy was identified. Third, a meta-analysis of published trials was performed to explore the impact of LM on the efficacy of anti-PD-1/PD-L1 based therapy in advanced lung cancers. Pan-cancer analysis revealed that patients with LM had significantly shorter overall survival (OS) than those without LM (10 vs. 20 months; P < 0.0001). Subgroup analysis showed that the presence of LM was associated with markedly shorter OS than those without LM in ICI monotherapy group (P < 0.0001), but it did not reach the statistical significance in ICI-based combination therapy (P = 0.0815). In NSCLC, the presence of LM was associated with significantly inferior treatment outcomes in both pan-cancer and real-world cohort. Interestingly, ICI-based monotherapy and combination therapy could simultaneously prolong progression-free survival (PFS) and OS than chemotherapy in patients without LM. However, ICI-based monotherapy could not prolong PFS than chemotherapy in patients with LM while ICI-based combination therapy could dramatically prolong both PFS and OS. Together, these findings suggested that the presence of LM was the negative predictive factor in cancer patients received ICIs monotherapy, especially in NSCLC. ICI-based combination therapy might overcome the intrinsic resistance of LM to ICIs while the optimal combinatorial strategies remain under further investigation.

Abstract 15395: Immune Checkpoint Inhibitors for Cancer Are Associated With Increased Venous Thromboembolism Events

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Jingyi Gong ◽  
Zsofia Drobni ◽  
Raza Alvi ◽  
Sean Murphy ◽  
Sarah Hartmann ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Immune Activation ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Massachusetts General Hospital ◽  
Control Period ◽  
Fold Increase ◽  
Vein Thrombosis ◽  
Increased Risk

Introduction: Immune checkpoint inhibitors (ICI) lead to immune activation, increased inflammation and cancer cell death. Both immune activation and inflammation are critical pathobiological drivers for venous thromboembolism (VTE). There are no robust data testing the effect of ICIs on the risk of developing VTE. Methods: This is a retrospective study of 2854 patients who received ICIs at Massachusetts General Hospital, Boston, MA. VTE events, defined as a composite of deep vein thrombosis (DVT) or pulmonary embolism (PE), were identified by individual chart review and were blindly adjudicated using standard criteria. A case-crossover design was applied with an “at-risk period” defined as the two-year period after and the “control period” as the two years prior to treatment. Incidence rate ratio (IRR) was calculated using Poisson’s regression. Results: Immune checkpoint inhibitor use increased VTE risk by 1.84-fold from 4.85 per 100-person years to 8.91 per 100 person-years (IRR 1.84, 95% confidence interval: 1.54 - 2.19, p <0.001). Of the individual components, there was a 2.44-fold increase in DVT risk (2.30 to 5.58 per 100 person-years) and 1.68-fold increase in PE risk (2.96 to 5.00 per 100 person-years). Comparing patients with and without a VTE event, those with a VTE event after ICI initiation had a higher rate of prior VTE, lung cancer, urothelial cancer, and a higher platelet count and white blood cell count at baseline. At 6 months post ICI initiation, 165 (8.6%) patients had a VTE event and of these patients 136 (7.1%) had no prior VTE. Conclusions: Patients with cancer treated with ICIs are at increased risk of developing VTE. Whether prophylaxis for VTE among patients starting an ICI reduces this risk is unclear.

Behcet’s-like syndrome following pembrolizumab: An immune-related adverse event associated with programmed death receptor-1 inhibitor therapy

2019 ◽  
Vol 26 (4) ◽  
pp. 995-999 ◽  
Author(s):  
Steffi Thomas ◽  
Chay Bae ◽  
Tabanor Joy-Ann ◽  
William Traverse
Keyword(s):  
Adverse Events ◽  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Death Receptor ◽  
Programmed Death ◽  
Organ Systems ◽  
Wide Range ◽  
The Right

Introduction The landscape for the treatment of metastatic melanoma has been revolutionized with the introduction immune checkpoint inhibitors. Immune checkpoint inhibitors have now become the standard of care for the treatment of cancers. These immune agents including programmed death receptor-1 inhibitors, programmed death-ligand 1 inhibitors and cytotoxic T-lymphocyte antigen-4 inhibitors have shown promising results but have been associated with numerous immune-related complications. Pembrolizumab, a programmed death receptor-1 inhibitor, has been associated with a number of immune-related adverse events affecting multiple organ systems including integument, ocular, endocrine, cardiovascular, pulmonary, renal, gastrointestinal, and musculoskeletal system. Case report We present a case of an 88-year-old Caucasian male with metastatic melanoma of the face with metastasis to the right fifth cranial nerve and into the right cavernous sinus. He underwent resection of the melanoma and was placed on pembrolizumab at 2 mg/kg every three weeks. Interestingly, 24 months on pembrolizumab therapy, he developed corneal erosions, oral and genital ulcerations. Management and outcome Patient completed his 24 months of pembrolizumab and was started on prednisone and colchicine with improvement in his symptoms. At his follow-up eight months, he had recurrence of an oral ulcer. Discussion Here we present a rare case of an elderly male on pembrolizumab who suffered from corneal erosions, oral and genital ulcers, a syndrome similar to Behcet’s disease. Given that pembrolizumab and other immune checkpoint inhibitors are being utilized in the treatment of cancers, physicians should be aware of the wide range immune-related adverse events including the possible Behcet’s-like syndrome presentation.

scholarly journals Successful Treatment of a Patient with anti-PD1 Antibody-Resistant Advanced Mucosal Melanoma with Nivolumab, Ipilimumab plus Denosumab Combination Therapy

2020 ◽  
Vol 13 (1) ◽  
pp. 271-275 ◽  
Author(s):  
Taku Fujimura ◽  
Yumi Kambayashi ◽  
Kentaro Ohuchi ◽  
Ryo Amagai ◽  
Yota Sato ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Combination Therapy ◽  
Nasal Cavity ◽  
Immune Checkpoint ◽  
Cutaneous Melanoma ◽  
Japanese Population ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Mucosal Melanoma ◽  
Mutation Burden

Since the incidence of mucosal melanoma is higher in the Japanese population compared to Caucasians, and since mucosal melanoma possesses a lower mutation burden compared to cutaneous melanoma, the efficacy of anti-PD1 antibody (Ab) monotherapy for mucosal melanoma is limited. Therefore, other targeting molecules that enhance the anti-tumor effects of immune checkpoint inhibitors are needed. In this report, we present a case with anti-PD1 Ab-resistant recurrent malignant melanoma of the nasal cavity successfully treated with nivolu­mab, ipilimumab plus denosumab combination therapy.

Bluish-gray fingernail discoloration due to the use of nivolumab

2020 ◽  
pp. 107815522092997
Author(s):  
Miguel Michel Ocampo ◽  
Jaren Lerner ◽  
Constantin A Dasanu
Keyword(s):  
Case Report ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Skin Toxicity ◽  
Unique Case ◽  
First Case ◽  
Nail Discoloration ◽  
Wide Range ◽  
Causality Relationship

Introduction Immune checkpoint inhibitors have improved clinical outcomes in a wide range of cancers. While skin toxicity is not uncommon with immune checkpoint inhibitors, generalized nail discoloration has not been reported with their use in oncology. Case report Herein, we report a unique case of bluish-gray fingernail discoloration due to nivolumab therapy for relapsed melanoma. Management and outcome: This condition reversed completely 10 weeks after nivolumab discontinuation. Naranjo nomogram assessment renders the causality relationship between nivolumab and nail discoloration probable. Discussion To our knowledge, this is the first case report of an unusual bluish-gray nail discoloration due to therapy with nivolumab. The mechanism by which nivolumab causes this side effect remains to be elucidated.

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