Pharmacokinetics and Systems Pharmacology of Anti-CD47 Macrophage Immune Checkpoint Inhibitor Hu5F9-G4

2020 ◽  
Vol 17 (1) ◽  
pp. 14-24 ◽  
Author(s):  
Adarsh Mishra ◽  
Ishant Kataria ◽  
Sujit Nair
Keyword(s):  
Annual Meeting ◽  
Immune Checkpoint ◽  
Cancer Care ◽  
Checkpoint Inhibitors ◽  
B Cell Lymphoma ◽  
Great Promise ◽  
Systems Pharmacology ◽  
Immunoglobulin G4 ◽  
American Society ◽  
Anti Cd20

Background: Hu5F9-G4, a human immunoglobulin G4 (IgG4) monoclonal antibody (mAb) has recently been granted fast-track designation by the FDA for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. Hu5F9-G4 has the ability to block CD47-SIRPα signaling along with anti- EGFR and anti-PD-L1 immune checkpoint activity that is involved in a variety of cancers like solid tumors, Non-Hodgkin’s Lymphoma (NHL), colorectal cancer (CRC), breast, ovarian and bladder cancers, and hematological malignancies. Thus, Hu5F9-G4 is an important biologic that has increasing clinical relevance in cancer care. Methods: We queried PubMed, Web of Science, Google Scholar, Science Direct and Scopus databases with keywords pertaining to Hu5F9-G4. In addition, we have included the Hu5F9-G4 data presented at the 60th American Society of Hematology (ASH) Annual Meeting, the American Society of Clinical Oncology (ASCO) Annual Meeting and 23rd Congress of the European Hematology Association (EHA). Results: We discuss the mechanistic basis and preclinical evidence for the anticancer activity of Hu5F9-G4. Further, we delineate clinical studies, alone and in combination with anti-CD20 mAb rituximab, anti-EGFR mAb cetuximab, PD-L1 checkpoint inhibitors avelumab and atezolizumab, and anti-HER2 mAb trastuzumab. Moreover, the potential adverse effects, pharmacokinetics, and pharmacodynamics of Hu5F9-G4 with emphasis on the role of CD47-SIRPα signaling in phagocytosis are presented. Conclusions: Taken together, we review the pharmacokinetics and systems pharmacology of Hu5F9-G4 which appears to hold great promise for the future of cancer care.

scholarly journals Destaques da ASCO 2016 - Imunoterapia no Tratamento do Cancro do Pulmão | Rastreio do Cancro do Pulmão: Considerações Lógicas e Práticas

2018 ◽  
Author(s):  
Maria Bárbara Parente
Keyword(s):  
Annual Meeting ◽  
Clinical Oncology ◽  
Immune Checkpoint ◽  
National Lung Screening Trial ◽  
American Society ◽  
Lung Screening ◽  
Screening Trial

Inibidores de immune checkpoint são uma promessa na luta contra o cancro do pulmão e outros tumores malignos, alterando o microambiente do tumor e bloqueando a evasão ao sistema imunitário. Dois anticorpos anti-PD-1, nivolumab e pembrolizumab, estão aprovados para uso clínico, no cancro do pulmão, doença avançada em segunda linha. Anticorpos PD-L1 tal como atezolizumab e MEDI-4736 estão em desenvolvimento clínico e são alvo atual de vários estudos de fase II/III inclusivamente a decorrer em Portugal; tratamento de segunda linha em doentes com cancro do pulmão de não pequenas células doença avançada tem tido até agora como opção padrão o docetaxel. Desde a publicação dos resultados do National Lung Screening Trial (NLST) em 2011, o rastreio do cancro do pulmão com tomografia computorizada de dose baixa tem sido o centro da investigação, guidelines e discussão geral deste tema. O racional para o screening tem evoluído nos últimos anos, dado que hospitais e outros sistemas de saúde ganharam experiência na implementação de programas de rastreio. O screening também mostra a importância do tabagismo, não apenas como um fator de risco para o cancro, mas também como uma variável que pode afetar drasticamente os resultados do cancro. Estas foram, entre outras, questões discutidas por Especialistas no 2016 ASCO Annual Meeting - American Society of Clinical Oncology, que decorreu em Chicago de 3 a 7 de junho de 2016. Recebido: 20/08/2016 – Aceite: 25/08/2016

scholarly journals Therapeutic Ultrasound-Enhanced Immune Checkpoint Inhibitor Therapy

2021 ◽  
Vol 9 ◽  
Author(s):  
Jinyun Yuan ◽  
Dezhuang Ye ◽  
Si Chen ◽  
Hong Chen
Keyword(s):  
Immune Responses ◽  
Cancer Treatment ◽  
Immune Checkpoint ◽  
Focused Ultrasound ◽  
Checkpoint Inhibitors ◽  
Complete Response ◽  
High Intensity Focused Ultrasound ◽  
Great Promise ◽  
Combination Strategy ◽  
Antitumor Effects

Immune checkpoint inhibitors (ICIs) are designed to reinvigorate antitumor immune responses by interrupting inhibitory signaling pathways and promote the immune-mediated elimination of malignant cells. Although ICI therapy has transformed the landscape of cancer treatment, only a subset of patients achieve a complete response. Focused ultrasound (FUS) is a noninvasive, nonionizing, deep penetrating focal therapy that has great potential to improve the efficacy of ICIs in solid tumors. Five FUS modalities have been incorporated with ICIs to explore their antitumor effects in preclinical studies, namely, high-intensity focused ultrasound (HIFU) thermal ablation, HIFU hyperthermia, HIFU mechanical ablation, ultrasound-targeted microbubble destruction (UTMD), and sonodynamic therapy (SDT). The enhancement of the antitumor immune responses by these FUS modalities demonstrates the great promise of FUS as a transformative cancer treatment modality to improve ICI therapy. Here, this review summarizes these emerging applications of FUS modalities in combination with ICIs. It discusses each FUS modality, the experimental protocol for each combination strategy, the induced immune effects, and therapeutic outcomes.

scholarly journals Updates from the American Society of Hematology 2019 annual meeting: practice-changing studies in treatment-naïve chronic lymphocytic leukemia

2020 ◽  
Vol 27 (2) ◽  
Author(s):  
Versha Banerji ◽  
Peter Anglin ◽  
Anna Christofides ◽  
Sarah Doucette ◽  
Pierre Laneuville
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Annual Meeting ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Meeting Report ◽  
Efficacy And Safety ◽  
Treatment Naïve ◽  
American Society

The 2019 annual meeting of the American Society of Hematology took place 7–10 December in Orlando, Florida. At the meeting, results from key studies in treatment-naïve chronic lymphocytic leukemia were presented. Of those studies, phase III oral presentations focused on the efficacy and safety of therapy with Bruton tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) inhibitors. One presentation reported updated results of the ECOG 1912 trial comparing the efficacy and safety of ibrutinib plus rituximab to fludarabine, cyclophosphamide, rituximab in patients with CLL younger than 70 years of age. A second presentation reported interim results of the ELEVATE-TN trial, which is investigating the efficacy and safety of acalabrutinib plus obinutuzumab or acalabrutinib monotherapy versus chlorambucil plus obinutuzumab. A third presentation reported on the single-agent zanubrutinib arm of the SEQUOIA trial in patients with del(17p). The final presentation reported a data update from the CLL14 trial, which is evaluating fixed-duration venetoclax and obinutuzumab versus chlorambucil and obinutuzumab, including the association of minimal residual disease status on progression-free survival. Our meeting report describes the foregoing studies and presents interviews with investigators and commentaries by Canadian hematologists about potential effects on Canadian practice.

scholarly journals The Evolving Role of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma Treatment

Vaccines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 532
Author(s):  
Patrizia Leone ◽  
Antonio Giovanni Solimando ◽  
Rossella Fasano ◽  
Antonella Argentiero ◽  
Eleonora Malerba ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Kinase Inhibitors ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Chemotherapeutic Agents ◽  
Protein Kinase Inhibitors ◽  
Great Promise ◽  
Chronic Injury

Hepatocellular carcinoma (HCC) is one of most common cancers and the fourth leading cause of death worldwide. Commonly, HCC development occurs in a liver that is severely compromised by chronic injury or inflammation. Liver transplantation, hepatic resection, radiofrequency ablation (RFA), transcatheter arterial chemoembolization (TACE), and targeted therapies based on tyrosine protein kinase inhibitors are the most common treatments. The latter group have been used as the primary choice for a decade. However, tumor microenvironment in HCC is strongly immunosuppressive; thus, new treatment approaches for HCC remain necessary. The great expression of immune checkpoint molecules, such as programmed death-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), lymphocyte activating gene 3 protein (LAG-3), and mucin domain molecule 3 (TIM-3), on tumor and immune cells and the high levels of immunosuppressive cytokines induce T cell inhibition and represent one of the major mechanisms of HCC immune escape. Recently, immunotherapy based on the use of immune checkpoint inhibitors (ICIs), as single agents or in combination with kinase inhibitors, anti-angiogenic drugs, chemotherapeutic agents, and locoregional therapies, offers great promise in the treatment of HCC. This review summarizes the recent clinical studies, as well as ongoing and upcoming trials.

scholarly journals The Synergistic Effect of PARP Inhibitors and Immune Checkpoint Inhibitors

2021 ◽  
Vol 15 ◽  
pp. 117955492199628
Author(s):  
Zhaozhen Wu ◽  
Pengfei Cui ◽  
Haitao Tao ◽  
Sujie Zhang ◽  
Junxun Ma ◽  
...  
Keyword(s):  
Immune Response ◽  
Dna Damage ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Parp Inhibitors ◽  
Resistance Mechanisms ◽  
Great Promise ◽  
Immunogenic Cell Death

Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated great promise for treating cancers with homologous recombination (HR) defects, such as germline BRCA1/2 mutation. Further studies suggest that PARP inhibitors (PARPi) can also exhibit efficacy in HR-competent cancers, by amplifying the DNA damage and inducing immunogenic cell death, and PARPi lead to increasing tumor neoantigen, upregulation of interferons and PD-L1, and modulation of the tumor microenvironment, which may facilitate a more profound antitumor immune response. Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 or CTLA-4 have achieved impressive success in the treatment of different malignancies. However, only a subset of populations derive clinical benefit, and the biomarkers and resistance mechanisms are not fully understood. Therefore, given that PARPi could potentiate the therapeutic effect of ICIs, PARPi combined with ICIs are becoming an alternative for patients who cannot benefit from ICI monotherapy. In this review, we focus on the mechanisms and immune role of PARPi and discuss the rationale and clinical studies of this combined regimen.

scholarly journals Checkpoint blockade in Hodgkin and non-Hodgkin lymphoma

2017 ◽  
Vol 1 (26) ◽  
pp. 2643-2654 ◽  
Author(s):  
Reid W. Merryman ◽  
Philippe Armand ◽  
Kyle T. Wright ◽  
Scott J. Rodig
Keyword(s):  
Hodgkin Lymphoma ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Constitutive Expression ◽  
Clinical Trial Design ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

AbstractClassical Hodgkin lymphoma (cHL) is characterized by nearly universal genetic alterations in 9p24.1, resulting in constitutive expression of PD-1 ligands. This likely underlies the unique sensitivity of cHL to PD-1 blockade, with response rates of ∼70% in relapsed/refractory disease. There are now numerous clinical trials testing PD-1 inhibitors in earlier stages of treatment and in combination with many other therapies. In general, non-Hodgkin lymphomas (NHLs) do not display a high frequency of 9p24.1 alterations and do not share cHL’s vulnerability to PD-1 blockade. However, a few entities have genetic or immunologic features that may predict sensitivity to immune checkpoint blockade. These include primary mediastinal B cell lymphoma, primary central nervous system lymphoma, and primary testicular lymphoma, which harbor frequent alterations in 9p24.1, as well as Epstein Barr virus (EBV)–infected lymphomas, where EBV infection leads to increased PD-L1 expression. Although these subtypes may be specifically vulnerable to PD-1 blockade, the majority of NHLs appear to be minimally sensitive to PD-1 blockade monotherapy. Current investigations in NHL are therefore focusing on targeting other checkpoints or studying PD-1–based combination therapy. Looking forward, additional insight into the most common mechanisms of resistance to immune checkpoint inhibitors will be important to guide rational clinical trial design. In this review, we describe the biological basis for checkpoint blockade in cHL and NHL and summarize the clinical data generated to date. Guided by our rapidly evolving understanding of the pathobiology of various lymphoma subtypes, we are hopeful that the role of checkpoint inhibitors in lymphoma treatment will continue to grow.

scholarly journals Activating the Antitumor Immune Response in Non-Hodgkin Lymphoma Using Immune Checkpoint Inhibitors

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Maansi Joshi ◽  
Stephen M. Ansell
Keyword(s):  
Immune System ◽  
Combination Therapy ◽  
Hodgkin Lymphoma ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Tumor Biology ◽  
B Cell Lymphoma ◽  
Response Rates ◽  
Innate Immune ◽  
Success Rates

Non-Hodgkin lymphomas comprise a heterogenous group of disorders which differ in biology. Although response rates are high in some groups, relapsed disease can be difficult to treat, and newer approaches are needed for this patient population. It is increasingly apparent that the immune system plays a significant role in the propagation and survival of malignant cells. Immune checkpoint blocking agents augment cytotoxic activity of the adaptive and innate immune systems and enhance tumor cell killing. Anti-PD-1 and anti-CTLA-4 antibodies have been tested as both single agents and combination therapy. Although success rates with anti-PD-1 antibodies are high in patients with Hodgkin lymphoma, the results are yet to be replicated in those with non-Hodgkin lymphomas. Some lymphoma histologies, such as primary mediastinal B cell lymphoma (PMBL), central nervous system, and testicular lymphomas and gray zone lymphoma, respond favorably to PD-1 blockade, but the response rates in most lymphoma subtypes are low. Other agents including those targeting the adaptive immune system such as TIM-3, TIGIT, and BTLA and innate immune system such as CD47 and KIR are therefore in trials to test alternative ways to activate the immune system. Patient selection based on tumor biology is likely to be a determining factor in treatment response in patients, and further research exploring optimal patient populations, newer targets, and combination therapy as well as identifying biomarkers is needed.

Nivolumab-induced hepatitis: A rare side effect of an immune check point inhibitor

2019 ◽  
Vol 26 (2) ◽  
pp. 459-461 ◽  
Author(s):  
Vinay Mathew Thomas ◽  
Poorva Bindal ◽  
Swetha Ann Alexander ◽  
Kymberly McDonald
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Hepatitis A ◽  
Checkpoint Inhibitors ◽  
Early Recognition ◽  
Cell Activity ◽  
Host Cells ◽  
Immunoglobulin G4 ◽  
Mortality And Morbidity ◽  
Cancer Management

Immune checkpoint inhibitors have ushered in a new era in cancer management. Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor. This inhibits suppression of the T-cell activity, which can in turn cause increased killing of cancer cells. This alteration in the activity of the T cells can cause them to lose their ability to identify host cells and leads to immune-related adverse effects (irAE). Nivolumab-induced hepatotoxicity is rare and accounts for 3–6% of all irAE. We present a case of nivolumab-induced hepatitis. A woman who was treated for recurrent renal cell carcinoma presented with hepatitis. Workup for other causes was negative and the hepatitis was attributed to the administration of nivolumab. She was started on oral steroids followed which she initially improved. However, she later presented with massive upper gastrointestinal bleeding secondary to gastroduodenal ulcers and subsequently developed acute tubular necrosis and passed from the complications. Immune checkpoint inhibitors have proven to be a promising approach in the management of a wide array of neoplasms by immunomodulation. As these agents are becoming standard of therapy in the management of cancers, a heightened vigilance in the diagnosis of irAE is warranted. With heightened vigilance, early recognition can lead to decreased mortality and morbidity.

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