Combination of Ipilimumab and Nivolumab in Cancers: From Clinical Practice to Ongoing Clinical Trials

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are inhibitory checkpoints that are commonly seen on activated T cells and have been offered as promising targets for the treatment of cancers. Immune checkpoint inhibitors (ICIs)targeting PD-1, including pembrolizumab and nivolumab, and those targeting its ligand PD-L1, including avelumab, atezolizumab, and durvalumab, and two drugs targeting CTLA-4, including ipilimumab and tremelimumab have been approved for the treatment of several cancers and many others are under investigating in advanced trial phases. ICIs increased antitumor T cells’ responses and showed a key role in reducing the acquired immune system tolerance which is overexpressed by cancer and tumor microenvironment. However, 50% of patients could not benefit from ICIs monotherapy. To overcome this, a combination of ipilimumab and nivolumab is frequently investigated as an approach to improve oncological outcomes. Despite promising results for the combination of ipilimumab and nivolumab, safety concerns slowed down the development of such strategies. Herein, we review data concerning the clinical activity and the adverse events of ipilimumab and nivolumab combination therapy, assessing ongoing clinical trials to identify clinical outlines that may support combination therapy as an effective treatment. To the best of our knowledge, this paper is one of the first studies to evaluate the efficacy and safety of ipilimumab and nivolumab combination therapy in several cancers.

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Monitoring T Cells Responses Mounted by Therapeutic Cancer Vaccines

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.623475 ◽

2021 ◽

Vol 8 ◽

Author(s):

Kue Peng Lim ◽

Nur Syafinaz Zainal

Keyword(s):

Clinical Trials ◽

T Cells ◽

T Cell ◽

Cancer Vaccine ◽

Cancer Vaccines ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Rapid Development ◽

Activated T Cells ◽

Specific Cytotoxicity

With the regulatory approval of Provenge and Talimogene laherparepvec (T-VEC) for the treatment of metastatic prostate cancer and advanced melanoma respectively, and other promising clinical trials outcomes, cancer vaccine is gaining prominence as a cancer therapeutic agent. Cancer vaccine works to induce T cell priming, expansion, and infiltration resulting in antigen-specific cytotoxicity. Such an approach that can drive cytotoxicity within the tumor could complement the success of checkpoint inhibitors as tumors shown to have high immune cell infiltration are those that would respond well to these antibodies. With the advancements in cancer vaccine, methods to monitor and understand how cancer vaccines modify the immune milieu is under rapid development. This includes using ELISpot and intracellular staining to detect cytokine secretion by activated T cells; tetramer and CyTOF to quantitate the level of antigen specific T cells; proliferation and cell killing assay to detect the expansion of T cell and specific killing activity. More recently, T cell profiling has provided unprecedented detail on immune cell subsets and providing clues to the mechanism involved in immune activation. Here, we reviewed cancer vaccines currently in clinical trials and highlight available techniques in monitoring the clinical response in patients.

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Systemic Therapy for Hepatocellular Carcinoma: Latest Advances

Cancers ◽

10.3390/cancers10110412 ◽

2018 ◽

Vol 10 (11) ◽

pp. 412 ◽

Cited By ~ 56

Author(s):

Masatoshi Kudo

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Trials ◽

Combination Therapy ◽

Systemic Therapy ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Phase Iii ◽

Term Survival ◽

Targeted Agent

Systemic therapy for hepatocellular carcinoma (HCC) has changed drastically since the introduction of the molecular targeted agent sorafenib in 2007. Although sorafenib expanded the treatment options for extrahepatic spread (EHS) and vascular invasion, making long-term survival of patients with advanced disease achievable to a certain extent, new molecular-targeted agents are being developed as alternatives to sorafenib due to shortcomings such as its low response rate and high toxicity. Every single one of the many drugs developed during the 10-year period from 2007 to 2016 was a failure. However, during the two-year period from 2017 through 2018, four drugs—regorafenib, lenvatinib, cabozantinib, and ramucirumab—emerged successfully from clinical trials in quick succession and became available for clinical use. The efficacy of combination therapy with transcatheter arterial chemoembolization (TACE) plus sorafenib was also first demonstrated in 2018. Recently, immune checkpoint inhibitors have been applied to HCC treatment and many phase III clinical trials are ongoing, not only on monotherapy with nivolumab, pembrolizumab, and tislelizumab, but also on combination therapy with checkpoint inhibitors, programmed death-1 (PD-1) or PD-ligand 1 (PD-L1) antibody plus a molecular targeted agent (bevacizumab) or the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody, tremelimumab. These combination therapies have shown higher response rates than PD-1/PD-L1 monotherapy alone, suggesting a synergistic effect by combination therapy in early phases; therefore, further results are eagerly awaited.

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Checkpoint inhibitor induced hepatitis and the relation with liver metastasis and outcome in advanced melanoma patients

Hepatology International ◽

10.1007/s12072-021-10151-4 ◽

2021 ◽

Author(s):

Maaike Biewenga ◽

Monique K. van der Kooij ◽

Michel W. J. M. Wouters ◽

Maureen J. B. Aarts ◽

Franchette W. P. J. van den Berkmortel ◽

...

Keyword(s):

Overall Survival ◽

Liver Metastasis ◽

Combination Therapy ◽

Real World ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Progression Free Survival ◽

Negative Effect ◽

Melanoma Patients

Abstract Background Checkpoint inhibitor-induced hepatitis is an immune-related adverse event of programmed cell death protein 1 (PD-1) inhibition, cytotoxic T-lymphocyte associated 4 (CTLA-4) inhibition or the combination of both. Aim of this study was to assess whether checkpoint inhibitor-induced hepatitis is related to liver metastasis and outcome in a real-world nationwide cohort. Methods Data from the prospective nationwide Dutch Melanoma Treatment Registry (DMTR) was used to analyze incidence, risk factors of checkpoint inhibitor-induced grade 3–4 hepatitis and outcome. Results 2561 advanced cutaneous melanoma patients received 3111 treatments with checkpoint inhibitors between May 2012 and January 2019. Severe hepatitis occurred in 30/1620 (1.8%) patients treated with PD-1 inhibitors, in 29/1105 (2.6%) patients treated with ipilimumab and in 80/386 (20.7%) patients treated with combination therapy. Patients with hepatitis had a similar prevalence of liver metastasis compared to patients without hepatitis (32% vs. 27%; p = 0.58 for PD-1 inhibitors; 42% vs. 29%; p = 0.16 for ipilimumab; 38% vs. 43%; p = 0.50 for combination therapy). There was no difference in median progression free and overall survival between patients with and without hepatitis (6.0 months vs. 5.4 months progression-free survival; p = 0.61; 17.0 vs. 16.2 months overall survival; p = 0.44). Conclusion Incidence of hepatitis in a real-world cohort is 1.8% for PD-1 inhibitor, 2.6% for ipilimumab and 20.7% for combination therapy. Checkpoint inhibitor-induced hepatitis had no relation with liver metastasis and had no negative effect on the outcome.

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Management of Hematologic Adverse Events Associated With Immune Checkpoint Inhibitors

Journal of the Advanced Practitioner in Oncology ◽

10.6004/jadpro.2021.12.4.4 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Barbara Barnes Rogers, CRNP, MN, AOCN, ANP-BC ◽

Carolyn Zawislak, MPAS, PA-C ◽

Victoria Wong, PA-C

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Adverse Events ◽

Immune Checkpoint ◽

Blood Cells ◽

Immune Checkpoint Inhibitors ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

White Blood Cells ◽

Activated T Cells

Immune checkpoint inhibitors target suppressor receptors, including cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1). The activated T cells are not antigen specific; therefore, the blockade of the immune checkpoint may result in the development of autoimmune adverse events. The most common immune-related adverse events (irAEs) are rash, colitis, and endocrinopathies. However, irAEs that affect the hematologic system are rare and can affect red blood cells (e.g., autoimmune hemolytic anemia), white blood cells, and platelets (e.g., immune thrombocytopenia). Usually one cell line is affected; however, in some cases, multiple cell lines can be affected. Other changes in the hematologic system can also be affected (e.g., cryoglobulinemia, cytokine release syndrome). Due to the rarity and lack of recognition of these AEs, the timing, spectrum of events, and clinical presentation are poorly understood. Management of hematologic irAEs usually involves the use of steroids; however, other agents (e.g., IVIG, cyclosporine, rituximab) or procedures (e.g., plasma exchange, transfusions) can also be used.

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Rheumatic immune-related adverse events from checkpoint inhibitor therapy: a case series

Beyond Rheumatology ◽

10.4081/br.2021.65 ◽

2021 ◽

Vol 3 (2) ◽

Cited By ~ 1

Author(s):

Antonella Laria ◽

Alfredomaria Lurati ◽

Laura Castelnovo ◽

Antonio Tamburello ◽

Paola Maria Faggioli ◽

...

Keyword(s):

Adverse Events ◽

T Lymphocyte ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Case Series ◽

Hematologic Malignancies ◽

Checkpoint Inhibitor Therapy ◽

Cancer Immunotherapies ◽

Cell Death Protein

Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), and its ligand PD-L1 are established cancer immunotherapies for solid tumor and hematologic malignancies. These therapies are involved in immune-related adverse events (irAE), both general and rheumatic ones. In general, immune-related adverse events (irAE) management includes drug-holding, tapering doses of corticosteroids, and specific immunosuppression for clinically severe cases, such as infliximab or mycophenolate.

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Immunmoduláló antitestek alkalmazása – az onkológia új fejezete

Orvosi Hetilap ◽

10.1556/oh.2016.30507 ◽

2016 ◽

Vol 157 (Supplement 2) ◽

pp. 9-16 ◽

Cited By ~ 1

Author(s):

Szilvia Szamosi ◽

László Váróczy ◽

Zoltán Szekanecz

Keyword(s):

Metastatic Melanoma ◽

Immune Checkpoint ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Hematologic Malignancies ◽

The United States ◽

Clinical Development ◽

Clinical Activity ◽

The European Union ◽

Tumor Types

In the past decade major advances in tumor immunology, a better understanding of antigen recognition by T-cells likewise discovering the regulatory inhibitory signals resulted in the development of new immunotherapies with promising durable responses in various solid tumor types and in hematologic malignancies. This review focuses on immunomodulatory antibodies, namely immune checkpoint inhibitor therapy. The prototype of this new class of immune stimulating agents was cytotoxic T-lymphocyte antigen-4 (CTLA-4) antagonists. After demonstrating enhanced survival, ipilimumab was approved first in the United States in 2011, further on in the European Union for second-line (2011) and for first-line therapy (2013) of metastatic melanoma. Additional T-cell intrinsic pathways were identified and targeted for clinical development. Antibodies blocking the PD-1 pathway also showed promising clinical activity and objective tumor response in several types of tumors, including metastatic melanoma, non-small- cell lung cancer. On the other hand antitumor activity is frequently accompanied by significant reversible immune-related adverse events. To explore potential new immune checkpoint targets bring forth several challanges. Future clinical development will involve identifying potential biomarkers anticipating responsiveness to pathway blockade and additional tumor types likely to respond to the therapy. Furthermore, combination strategies, immune checkpoint inhibitors combined with cancer vaccines, targeted inhibitors and traditional chemotherapies are being evaluated in pre-clinical studies. Orv. Hetil., 2016, 157(Suppl. 2), 9–16.

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Difficulties in differentiating between checkpoint inhibitor pneumonitis and lung metastasis in a patient with melanoma

Immunotherapy ◽

10.2217/imt-2019-0122 ◽

2020 ◽

Vol 12 (5) ◽

pp. 293-298 ◽

Cited By ~ 1

Author(s):

Houssein Safa ◽

Priya Bhosale ◽

Annika Weissferdt ◽

Isabella C Glitza Oliva

Keyword(s):

Clinical Presentation ◽

Cytotoxic T Lymphocyte ◽

Late Onset ◽

Checkpoint Inhibitors ◽

Lung Nodule ◽

Complete Response ◽

Lung Lesions ◽

Discontinuation Of Treatment ◽

Cell Death Protein ◽

New Onset

The use of immune checkpoint inhibitors is associated with significant toxicities such as pneumonitis; the clinical presentation of the latter can be misleading and may mimic metastasis. We report the case of a melanoma patient who developed late-onset pneumonitis after discontinuation of treatment with anti-programmed cell death protein 1 (PD1) and anti-cytotoxic T lymphocyte antigen 4 (CTLA4) (patient had a complete response). The patient was asymptomatic, however, surveillance computed tomography (CT) scan showed a growing lung nodule and several new-onset, small lung lesions highly suspicious for recurrence. A biopsy of the lesions revealed organizing pneumonia with absence of malignant cells. The lung lesions completely resolved after 6 months without any intervention. The patient is still in complete remission 2 years after the initial diagnosis of melanoma.

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REVIVE study: Prospective observational study of efficacy and safety in chemotherapy (CTx) after progressive disease of nivolumab (NIV) therapy for metastatic gastric cancer (mGC).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.tps178 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. TPS178-TPS178

Author(s):

Yukiya Narita ◽

Hirokazu Shoji ◽

Sadayuki Kawai ◽

Takuro Mizukami ◽

Michio Nakamura ◽

...

Keyword(s):

T Cells ◽

Observational Study ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Group Performance ◽

Checkpoint Inhibitors ◽

Cytotoxic Agents ◽

Efficacy And Safety ◽

Inclusion Criteria ◽

Prior Administration

TPS178 Background: Immune checkpoint inhibitors are drugs that block specific proteins produced by the immune system cells, such as T-cells; these proteins prevent T-cells from killing cancer cells. NIV is a standard care for pretreated mGC patients (pts), with increasing clinical use in Japan. Data from retrospective studies on various tumors have shown that after exposure to immune checkpoint inhibitors, the objective response rate to CTx potentially improves; however, enough data have not been accumulated. Although there are no recommended CTx regimen following NIV therapy, in a clinical setting, an irinotecan or oxaliplatin combination regimen (limited to cisplatin-refractory or cisplatin-intolerant pts) is frequently used as post-NIV CTx. This multicenter observational study aims to evaluate the efficacy and safety of CTx in NIV-refractory or NIV-intolerant mGC pts. Methods: We prospectively collect clinical and imaging data from NIV-pretreated mGC pts; these pts will be treated with cytotoxic agents. Pts who meet inclusion criteria A (histologically proven mGC pretreated with NIV, prior administration of a combination therapy of fluoropyrimidine plus platinum and taxanes, and written informed consent) at primary registration are registered. After primary registration, pts who meet inclusion criteria B [Eastern Cooperative Oncology Group Performance Status (ECOG PS 0-2), refractory or intolerant to NIV; prior administration of irinotecan monotherapy or oxaliplatin combination regimens and prior use of cisplatin; evaluable lesions according to RECIST ver. 1.1] at formal registration are registered. The primary endpoint is overall survival of NIV-pretreated mGC pts after CTx. For this study, we require 146 pts, with bilateral alpha = 0.05 and beta = 0.10, with a median threshold survival of 4.0 months and an expected median survival of 6.0 months. Therefore, we plan to enroll 200 pts, considering exclusions from the analysis; since May 2018, we have enrolled 27 pts. Clinical trial information: UMIN000032182.

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CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion

Blood ◽

10.1182/blood-2007-11-125435 ◽

2008 ◽

Vol 112 (4) ◽

pp. 1175-1183 ◽

Cited By ~ 153

Author(s):

Brian Kavanagh ◽

Shaun O'Brien ◽

David Lee ◽

Yafei Hou ◽

Vivian Weinberg ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Cd4 T Cells ◽

Cytotoxic T Lymphocyte ◽

Effector T Cells ◽

Activated T Cells ◽

Ctla4 Blockade ◽

Dose Dependent Fashion ◽

Dose Dependent

AbstractCytotoxic T lymphocyte–associated antigen 4 (CTLA4) delivers inhibitory signals to activated T cells. CTLA4 is constitutively expressed on regulatory CD4+ T cells (Tregs), but its role in these cells remains unclear. CTLA4 blockade has been shown to induce antitumor immunity. In this study, we examined the effects of anti-CTLA4 antibody on the endogenous CD4+ T cells in cancer patients. We show that CTLA4 blockade induces an increase not only in the number of activated effector CD4+ T cells, but also in the number of CD4+ FoxP3+ Tregs. Although the effects were dose-dependent, CD4+ FoxP3+ regulatory T cells could be expanded at lower antibody doses. In contrast, expansion of effector T cells was seen only at the highest dose level studied. Moreover, these expanded CD4+ FoxP3+ regulatory T cells are induced to proliferate with treatment and possess suppressor function. Our results demonstrate that treatment with anti-CTLA4 antibody does not deplete human CD4+ FoxP3+ Tregs in vivo, but rather may mediate its effects through the activation of effector T cells. Our results also suggest that CTLA4 may inhibit Treg proliferation similar to its role on effector T cells. This study is registered at http://www.clinicaltrials.gov/ct2/show/NCT00064129, registry number NCT00064129.

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Immune checkpoint blockade in the treatment of malignant tumor: current statue and future strategies

Cancer Cell International ◽

10.1186/s12935-021-02299-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Wenwen Yang ◽

Caining Lei ◽

Shaoming Song ◽

Wutang Jing ◽

Chuanwei Jin ◽

...

Keyword(s):

T Cells ◽

Malignant Tumor ◽

Immune Checkpoint ◽

Cytotoxic T Lymphocyte ◽

Malignant Tumors ◽

Checkpoint Inhibitors ◽

Immune Surveillance ◽

Immune Checkpoint Blockade ◽

Checkpoint Response ◽

Inhibitory Molecule

AbstractAfter being stagnant for decades, there has finally been a paradigm shift in the treatment of cancer with the emergence and application of immune checkpoint inhibitors (ICIs). The most extensively utilized ICIs are targeting the pathways involving programmed death-1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4). PD-1, as an crucial immune inhibitory molecule, by and large reasons the immune checkpoint response of T cells, making tumor cells get away from immune surveillance. Programmed cell death ligand-1 (PD-L1) is exceptionally expressed in most cancers cells and approves non-stop activation of the PD-1 pathway in the tumor microenvironment. PD-1/PD-L1 inhibitors can block the combination of PD-1 and PD-L1, inhibit hostile to regulatory signals, and restore the activity of T cells, thereby bettering immune response. The current researchers assume that the efficacy of these drugs is related to PD-L1 expression in tumor tissue, tumor mutation burden (TMB), and other emerging biomarkers. Although malignant tumors can benefit from the immunotherapy of PD-1/PD-L1 inhibitors, formulating a customized medication model and discovering biomarkers that can predict efficacy are the new trend in the new era of malignant tumor immunotherapy. This review summarizes the mechanism of action of PD-1/PD-L1 inhibitors, their clinical outcomes on various malignant tumors, their efficacy biomarkers, as well as predictive markers of irAEs.

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