|
1
|
Mirbahari SN, Da Silva M, Zúñiga AIM, Kooshki Zamani N, St-Laurent G, Totonchi M, Azad T. Recent progress in combination therapy of oncolytic vaccinia virus. Front Immunol 2024; 15:1272351. [PMID: 38558795 PMCID: PMC10979700 DOI: 10.3389/fimmu.2024.1272351] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 02/29/2024] [Indexed: 04/04/2024] Open
Abstract
In recent years, oncolytic viruses have emerged as promising agents for treating various cancers. An oncolytic virus is a non-pathogenic virus that, due to genetic manipulation, tends to replicate in and cause lysis of cancerous cells while leaving healthy cells unaffected. Among these viruses, vaccinia virus is an attractive platform for use as an oncolytic platform due to its 190 Kb genome with a high capacity for encoding therapeutic payloads. Combining oncolytic VV therapy with other conventional cancer treatments has been shown to be synergistic and more effective than monotherapies. Additionally, OVV can be used as a vector to deliver therapeutic payloads, alone or in combination with other treatments, to increase overall efficacy. Here, we present a comprehensive analysis of preclinical and clinical studies that have evaluated the efficacy of oncolytic vaccinia viruses in cancer immunotherapy. We discuss the outcomes of these studies, including tumor regression rates, overall survival benefits, and long-term responses. Moreover, we provide insights into the challenges and limitations associated with oncolytic vaccinia virus- based therapies, including immune evasion mechanisms, potential toxicities, and the development of resistance.
Collapse
Affiliation(s)
- Seyedeh Nasim Mirbahari
- Faculty of Sciences and Advanced Technologies in Biology, University of Science and Culture, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Miles Da Silva
- Department of Microbiology and Immunology, University of British Colombia, Vancouver, BC, Canada
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
| | - Abril Ixchel Muñoz Zúñiga
- Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, QC, Canada
- Centre de Recherche du CHUS, Sherbrooke, QC, Canada
| | - Nika Kooshki Zamani
- Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, QC, Canada
- Centre de Recherche du CHUS, Sherbrooke, QC, Canada
| | - Gabriel St-Laurent
- Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, QC, Canada
- Centre de Recherche du CHUS, Sherbrooke, QC, Canada
| | - Mehdi Totonchi
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Taha Azad
- Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, QC, Canada
- Centre de Recherche du CHUS, Sherbrooke, QC, Canada
| |
Collapse
|
|
2
|
Shyr CR, Liu LC, Chien HS, Huang CP. Immunotherapeutic Agents for Intratumoral Immunotherapy. Vaccines (Basel) 2023; 11:1717. [PMID: 38006049 PMCID: PMC10674963 DOI: 10.3390/vaccines11111717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 10/22/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
Immunotherapy using systemic immune checkpoint inhibitors (ICI) and chimeric antigen receptor (CAR) T cells has revolutionized cancer treatment, but it only benefits a subset of patients. Systemic immunotherapies cause severe autoimmune toxicities and cytokine storms. Immune-related adverse events (irAEs) plus the immunosuppressive tumor microenvironment (TME) have been linked to the inefficacy of systemic immunotherapy. Intratumoral immunotherapy that increases immunotherapeutic agent bioavailability inside tumors could enhance the efficacy of immunotherapies and reduce systemic toxicities. In preclinical and clinical studies, intratumoral administration of immunostimulatory agents from small molecules to xenogeneic cells has demonstrated antitumor effects not only on the injected tumors but also against noninjected lesions. Herein, we review and discuss the results of these approaches in preclinical models and clinical trials to build the landscape of intratumoral immunotherapeutic agents and we describe how they stimulate the body's immune system to trigger antitumor immunity as well as the challenges in clinical practice. Systemic and intratumoral combination immunotherapy would make the best use of the body's immune system to treat cancers. Combining precision medicine and immunotherapy in cancer treatment would treat both the mutated targets in tumors and the weakened body's immune system simultaneously, exerting maximum effects of the medical intervention.
Collapse
Affiliation(s)
- Chih-Rong Shyr
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404328, Taiwan; (C.-R.S.); (H.-S.C.)
- eXCELL Biotherapeutics Inc., Taichung 404328, Taiwan
| | - Lang-Chi Liu
- Department of Medicine, Department of Surgery, College of Medicine, China Medical University and Hospital, Taichung 404328, Taiwan;
| | - Hui-Shan Chien
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404328, Taiwan; (C.-R.S.); (H.-S.C.)
| | - Chi-Ping Huang
- Department of Medicine, Urology Division, China Medical University and Hospital, Taichung 404328, Taiwan
| |
Collapse
|
|
3
|
Onnockx S, Baldo A, Pauwels K. Oncolytic Viruses: An Inventory of Shedding Data from Clinical Trials and Elements for the Environmental Risk Assessment. Vaccines (Basel) 2023; 11:1448. [PMID: 37766125 PMCID: PMC10535390 DOI: 10.3390/vaccines11091448] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/18/2023] [Accepted: 08/31/2023] [Indexed: 09/29/2023] Open
Abstract
Attenuated and/or genetically modified oncolytic viruses (OV) gain increasing interest as a promising approach for cancer therapy. Beside the assessment of subject safety, quality and efficacy aspects of medicinal products for human use, genetically modified viruses are also governed by EU regulatory frameworks requiring an environmental risk assessment (ERA). An important element to be assessed as part of the ERA is the incidence of exposure to OV of individuals, other than the trial subjects, and the environment. The evidence-based evaluation of shedding data is considered to be decisive in that context, as it may impact the OV capacity to be transmitted. This is particularly true for OV still able to (conditionally) replicate as opposed to replication-defective viral vectors commonly used in gene therapy or vaccination. To our knowledge, this article presents the most extensive and up-to-date review of shedding data reported with OV employed in clinics. Besides the identification of a topical need for improving the collection of shedding data, this article aims at providing an aid to the design of an appropriate shedding study, thereby relying on and further complementing principles described in existing guidelines issued by European and international institutions.
Collapse
Affiliation(s)
- Sheela Onnockx
- Sciensano, Service Biosafety and Biotechnology, Rue Juliette Wytsmanstraat 14, B-1050 Brussels, Belgium; (A.B.); (K.P.)
| | | | | |
Collapse
|
|
4
|
Ghosn M, Tselikas L, Champiat S, Deschamps F, Bonnet B, Carre É, Testan M, Danlos FX, Farhane S, Susini S, Suzzoni S, Ammari S, Marabelle A, De Baere T. Intratumoral Immunotherapy: Is It Ready for Prime Time? Curr Oncol Rep 2023; 25:857-867. [PMID: 37129706 DOI: 10.1007/s11912-023-01422-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/02/2023] [Indexed: 05/03/2023]
Abstract
PURPOSE OF REVIEW This review presents the rationale for intratumoral immunotherapy, technical considerations and safety. Clinical results from the latest trials are provided and discussed. RECENT FINDINGS Intratumoral immunotherapy is feasible and safe in a wide range of cancer histologies and locations, including lung and liver. Studies mainly focused on multi-metastatic patients, with some positive trials such as T-VEC in melanoma, but evidence of clinical benefit is still lacking. Recent results showed improved outcomes in patients with a low tumor burden. Intratumoral immunotherapy can lower systemic toxicities and boost local and systemic immune responses. Several studies have proven the feasibility, repeatability, and safety of this approach, with some promising results in clinical trials. The clinical benefit might be improved in patients with a low tumor burden. Future clinical trials should focus on adequate timing of treatment delivery during the course of the disease, particularly in the neoadjuvant setting.
Collapse
Affiliation(s)
- Mario Ghosn
- Radiologie Interventionnelle, Département d'Anesthésie Chirurgie Et Imagerie Interventionnelle (DACI), Gustave Roussy, Villejuif, 94800, France
- Centre D'Investigation Clinique BIOTHERIS, INSERM CIC1428, Villejuif, France
| | - Lambros Tselikas
- Radiologie Interventionnelle, Département d'Anesthésie Chirurgie Et Imagerie Interventionnelle (DACI), Gustave Roussy, Villejuif, 94800, France.
- Centre D'Investigation Clinique BIOTHERIS, INSERM CIC1428, Villejuif, France.
- Laboratoire de Recherche Translationnelle en Immunothérapie (LRTI), INSERM U1015, Villejuif, France.
- Faculté de Médecine, Université Paris Saclay, Le Kremlin-Bicêtre, France.
| | - Stéphane Champiat
- Centre D'Investigation Clinique BIOTHERIS, INSERM CIC1428, Villejuif, France
- Laboratoire de Recherche Translationnelle en Immunothérapie (LRTI), INSERM U1015, Villejuif, France
- Département D'Innovation Thérapeutique Et D'Essais Précoces (DITEP), Gustave Roussy, Villejuif, France
| | - Frederic Deschamps
- Radiologie Interventionnelle, Département d'Anesthésie Chirurgie Et Imagerie Interventionnelle (DACI), Gustave Roussy, Villejuif, 94800, France
| | - Baptiste Bonnet
- Radiologie Interventionnelle, Département d'Anesthésie Chirurgie Et Imagerie Interventionnelle (DACI), Gustave Roussy, Villejuif, 94800, France
| | - Émilie Carre
- Centre D'Investigation Clinique BIOTHERIS, INSERM CIC1428, Villejuif, France
| | - Marine Testan
- Centre D'Investigation Clinique BIOTHERIS, INSERM CIC1428, Villejuif, France
| | - François-Xavier Danlos
- Centre D'Investigation Clinique BIOTHERIS, INSERM CIC1428, Villejuif, France
- Laboratoire de Recherche Translationnelle en Immunothérapie (LRTI), INSERM U1015, Villejuif, France
- Département D'Innovation Thérapeutique Et D'Essais Précoces (DITEP), Gustave Roussy, Villejuif, France
| | - Siham Farhane
- Centre D'Investigation Clinique BIOTHERIS, INSERM CIC1428, Villejuif, France
| | - Sandrine Susini
- Centre D'Investigation Clinique BIOTHERIS, INSERM CIC1428, Villejuif, France
- Laboratoire de Recherche Translationnelle en Immunothérapie (LRTI), INSERM U1015, Villejuif, France
| | - Steve Suzzoni
- Département Pharmacie, Gustave Roussy, Villejuif, France
| | - Samy Ammari
- Department of Imaging, Gustave Roussy, Université Paris Saclay, 94805, Villejuif, France
- Biomaps, UMR1281 INSERM, CEA, CNRS, Université Paris-Saclay, 94805, Villejuif, France
| | - Aurélien Marabelle
- Centre D'Investigation Clinique BIOTHERIS, INSERM CIC1428, Villejuif, France
- Laboratoire de Recherche Translationnelle en Immunothérapie (LRTI), INSERM U1015, Villejuif, France
- Faculté de Médecine, Université Paris Saclay, Le Kremlin-Bicêtre, France
- Département D'Innovation Thérapeutique Et D'Essais Précoces (DITEP), Gustave Roussy, Villejuif, France
| | - Thierry De Baere
- Radiologie Interventionnelle, Département d'Anesthésie Chirurgie Et Imagerie Interventionnelle (DACI), Gustave Roussy, Villejuif, 94800, France
- Centre D'Investigation Clinique BIOTHERIS, INSERM CIC1428, Villejuif, France
- Faculté de Médecine, Université Paris Saclay, Le Kremlin-Bicêtre, France
| |
Collapse
|
|
5
|
Mandlik DS, Mandlik SK, Choudhary HB. Immunotherapy for hepatocellular carcinoma: Current status and future perspectives. World J Gastroenterol 2023; 29:1054-1075. [PMID: 36844141 PMCID: PMC9950866 DOI: 10.3748/wjg.v29.i6.1054] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 12/23/2022] [Accepted: 01/20/2023] [Indexed: 02/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the world’s deadliest and fastest-growing tumors, with a poor prognosis. HCC develops in the context of chronic liver disease. Curative resection, surgery (liver transplantation), trans-arterial chemoembolization, radioembolization, radiofrequency ablation and chemotherapy are common treatment options for HCC, however, they will only assist a limited percentage of patients. Current treatments for advanced HCC are ineffective and aggravate the underlying liver condition. Despite promising preclinical and early-phase clinical trials for some drugs, existing systemic therapeutic methods for advanced tumor stages remain limited, underlining an unmet clinical need. In current years, cancer immunotherapy has made significant progress, opening up new treatment options for HCC. HCC, on the other hand, has a variety of causes and can affects the body’s immune system via a variety of mechanisms. With the speedy advancement of synthetic biology and genetic engineering, a range of innovative immunotherapies, such as immune checkpoint inhibitors [anti-programmed cell death-1 (PD-1), anti-cytotoxic T lymphocyte antigen-4, and anti-PD ligand 1 cell death antibodies], therapeutic cancer vaccines, engineered cytokines, and adoptive cell therapy have all been used for the treatment of advanced HCC. In this review, we summarize the present clinical and preclinical landscape of immunotherapies in HCC, critically discuss recent clinical trial outcomes, and address future perspectives in the field of liver cancer.
Collapse
Affiliation(s)
- Deepa S Mandlik
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Satish K Mandlik
- Department of Pharmaceutics, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Heena B Choudhary
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| |
Collapse
|
|
6
|
Laface C, Ranieri G, Maselli FM, Ambrogio F, Foti C, Ammendola M, Laterza M, Cazzato G, Memeo R, Mastrandrea G, Lioce M, Fedele P. Immunotherapy and the Combination with Targeted Therapies for Advanced Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:654. [PMID: 36765612 PMCID: PMC9913568 DOI: 10.3390/cancers15030654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/11/2023] [Accepted: 01/17/2023] [Indexed: 01/24/2023] Open
Abstract
One of the most important abilities of a tumor is to establish a state of immunosuppression inside the tumor microenvironment. This is made possible through numerous mechanisms of tumor immune escape that have been identified in experimental studies during the last decades. In addition, the hepatic microenvironment is commonly oriented towards a state of immune tolerance because the liver receives blood from the hepatic arteries and portal veins containing a variety of endogenous antigens. Therefore, the hepatic microenvironment establishes an autoimmune tolerance, preventing an autoimmune reaction in the liver. On this basis, hepatic tumor cells may escape the immune system, avoiding being recognized and destroyed by immune cells. Moreover, since the etiology of Hepatocellular Carcinoma (HCC) is often related to cirrhosis, and hepatitis B or C, this tumor develops in the context of chronic inflammation. Thus, the HCC microenvironment is characterized by important immune cell infiltration. Given these data and the poor prognosis of advanced HCC, different immunotherapeutic strategies have been developed and evaluated for these patients. In this review, we describe all the clinical applications of immunotherapy for advanced HCC, from the drugs that have already been approved to the ongoing clinical trials.
Collapse
Affiliation(s)
- Carmelo Laface
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | | | | | - Francesca Ambrogio
- Section of Dermatology, Department of Biomedical Science and Human Oncology, University of Bari, 70124 Bari, Italy
| | - Caterina Foti
- Section of Dermatology, Department of Biomedical Science and Human Oncology, University of Bari, 70124 Bari, Italy
| | - Michele Ammendola
- Department of Health Science, General Surgery, Medicine School of Germaneto, Magna Graecia University, 88100 Catanzaro, Italy
| | - Marigia Laterza
- Division of Cardiac Surgery, University of Bari, 70124 Bari, Italy
| | - Gerardo Cazzato
- Department of Emergency and Organ Transplantation, Pathology Section, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy
| | - Riccardo Memeo
- Unit of Hepato-Pancreatic-Biliary Surgery, “F. Miulli” General Regional Hospital, 70021 Acquaviva Delle Fonti, Italy
| | | | - Marco Lioce
- IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy
| | - Palma Fedele
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| |
Collapse
|
|
7
|
Zhu Y, Qin LX. Strategies for improving the efficacy of immunotherapy in hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2022; 21:420-429. [PMID: 35977874 DOI: 10.1016/j.hbpd.2022.08.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 08/02/2022] [Indexed: 02/05/2023]
Abstract
Primary liver cancer, mainly hepatocellular carcinoma (HCC), is the sixth most diagnosed cancer and third leading cause of cancer-related death globally. Recently, immunotherapies such as immune checkpoint inhibitors (ICIs) have made great progress in the systemic treatment of HCC. However, anti-PD-1 therapy with pembrolizumab or nivolumab as a single agent did not meet their predefined end points of overall survival in the KEYNOTE-240 and CheckMate 459 trials. It is urgent to understand the immunological rationale and explore novel ways to improve the efficacy of immunotherapy. The combination of ICIs with other therapies, such as tyrosine kinase inhibitors (TKIs), monoclonal antibodies, or local therapy, has been demonstrated to improve overall response rate and survival. In addition, modulating tumor microenvironment is a potential way to overcome the primary and secondary resistance to immunotherapies. In this review, we summarized the latest findings in the immune microenvironment, the mechanisms of their synergistic effects when combined with anti-VEGF agents or TKIs, as well as other kinds of immune treatment.
Collapse
Affiliation(s)
- Ying Zhu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai 200040, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Lun-Xiu Qin
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai 200040, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
| |
Collapse
|
|
8
|
Valery M, Cervantes B, Samaha R, Gelli M, Smolenschi C, Fuerea A, Tselikas L, Klotz-Prieux C, Hollebecque A, Boige V, Ducreux M. Immunotherapy and Hepatocellular Cancer: Where Are We Now? Cancers (Basel) 2022; 14:cancers14184523. [PMID: 36139683 PMCID: PMC9497386 DOI: 10.3390/cancers14184523] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 09/09/2022] [Accepted: 09/14/2022] [Indexed: 02/05/2023] Open
Abstract
Immunotherapy has demonstrated its effectiveness in many cancers. In hepatocellular carcinoma (HCC), promising results shown in the first phase II studies evaluating anti-PD-1 or anti-PD-L1 monotherapies resulted in their approval in the United States. Approval was not obtained in Europe; subsequent randomized studies in first- or second-line treatment did not confirm these initial results. However, first data with immunotherapy plus antiangiogenic treatments or dual immunotherapy combinations were positive. In this context, the combination of bevacizumab and atezolizumab took the lead. The IMbrave150 trial revealed an improved objective response rate (ORR), progression-free survival, and overall survival with this combination versus the previous standard, sorafenib. Subsequent results of dual immunotherapy with the anti-CTLA-4 and anti-PD-1 monotherapies tremelimumab and durvalumab (also superior to sorafenib monotherapy) confirmed the value of using a combination in first-line treatment. These significant therapeutic advances, and the increase in ORR, raise two main questions. Whereas response was very limited with previous treatments, the ORR reported with these new combinations are between 20% and 30%. This raises the question of whether immunotherapy (ICI single agent, combination of ICI with antiangiogenic agent or other antitumoral treatment) can be used in patients beyond those in BCLC group C, the traditional candidate group for systemic therapy. We have thus seen an increasing number of patients previously treated with trans-arterial chemoembolization (BCLC group B) receiving these new treatments, and we develop the results of several studies combining loco-regional therapies and immunotherapy-based systemic treatments. The other major question is that of how and when to use these medical treatments as "adjuvants" to interventional radiology or surgery; the results of several works are discussed for this purpose. In this review, we cover all of these points in a fairly comprehensive manner.
Collapse
Affiliation(s)
- Marine Valery
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France
- Correspondence:
| | - Baptiste Cervantes
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France
| | - Ramy Samaha
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France
| | - Maximiliano Gelli
- Département d’Anesthésie, Chirurgie et Interventionnel, Gustave Roussy, F-94805 Villejuif, France
| | - Cristina Smolenschi
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France
- Département d’Innovation Thérapeutique, Gustave Roussy, F-94805 Villejuif, France
| | - Alina Fuerea
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France
| | - Lambros Tselikas
- Département d’Anesthésie, Chirurgie et Interventionnel, Gustave Roussy, F-94805 Villejuif, France
| | | | - Antoine Hollebecque
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France
- Département d’Innovation Thérapeutique, Gustave Roussy, F-94805 Villejuif, France
| | - Valérie Boige
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France
| | - Michel Ducreux
- Département de Médecine Oncologique, Gustave Roussy, F-94805 Villejuif, France
- Inserm Unité Dynamique des Cellules Tumorales, Gustave Roussy, Université Paris-Saclay, F-94805 Villejuif, France
| |
Collapse
|
|
9
|
Rallis KS, Makrakis D, Ziogas IA, Tsoulfas G. Immunotherapy for advanced hepatocellular carcinoma: From clinical trials to real-world data and future advances. World J Clin Oncol 2022; 13:448-472. [PMID: 35949435 PMCID: PMC9244967 DOI: 10.5306/wjco.v13.i6.448] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 04/27/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated mortality worldwide. HCC is an inflammation-associated immunogenic cancer that frequently arises in chronically inflamed livers. Advanced HCC is managed with systemic therapies; the tyrosine kinase inhibitor (TKI) sorafenib has been used in 1st-line setting since 2007. Immunotherapies have emerged as promising treatments across solid tumors including HCC for which immune checkpoint inhibitors (ICIs) are licensed in 1st- and 2nd-line treatment setting. The treatment field of advanced HCC is continuously evolving. Several clinical trials are investigating novel ICI candidates as well as new ICI regimens in combination with other therapeutic modalities including systemic agents, such as other ICIs, TKIs, and anti-angiogenics. Novel immunotherapies including adoptive cell transfer, vaccine-based approaches, and virotherapy are also being brought to the fore. Yet, despite advances, several challenges persist. Lack of real-world data on the use of immunotherapy for advanced HCC in patients outside of clinical trials constitutes a main limitation hindering the breadth of application and generalizability of data to this larger and more diverse patient cohort. Consequently, issues encountered in real-world practice include patient ineligibly for immunotherapy because of contraindications, comorbidities, or poor performance status; lack of response, efficacy, and safety data; and cost-effectiveness. Further real-world data from high-quality large prospective cohort studies of immunotherapy in patients with advanced HCC is mandated to aid evidence-based clinical decision-making. This review provides a critical and comprehensive overview of clinical trials and real-world data of immunotherapy for HCC, with a focus on ICIs, as well as novel immunotherapy strategies underway.
Collapse
Affiliation(s)
- Kathrine S Rallis
- Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AD, United Kingdom
- Surgery Working Group, Society of Junior Doctors, Athens 15123, Greece
| | - Dimitrios Makrakis
- Surgery Working Group, Society of Junior Doctors, Athens 15123, Greece
- Division of Oncology, University of Washington School of Medicine, Seattle, WA 98195, United States
| | - Ioannis A Ziogas
- Surgery Working Group, Society of Junior Doctors, Athens 15123, Greece
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States
| | - Georgios Tsoulfas
- Department of Transplantation Surgery, Aristotle University School of Medicine, Thessaloniki 54622, Greece
| |
Collapse
|
|
10
|
Ziogas DC, Martinos A, Petsiou DP, Anastasopoulou A, Gogas H. Beyond Immunotherapy: Seizing the Momentum of Oncolytic Viruses in the Ideal Platform of Skin Cancers. Cancers (Basel) 2022; 14:2873. [PMID: 35740539 PMCID: PMC9221332 DOI: 10.3390/cancers14122873] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/30/2022] [Accepted: 06/03/2022] [Indexed: 11/24/2022] Open
Abstract
Despite the durable remissions induced by ICIs and targeted therapies in advanced melanoma and non-melanoma skin cancers, both subtypes usually relapse. Many systematic therapies have been tested to increase efficacy and delay relapse in ICIs, but their success has been limited. Due the feasibility of this approach, skin cancers have become the ideal platform for intralesional infusions of many novel agents, including oncolytic viruses (OVs). Talimogene laherparepvec (T-VEC) was the first FDA-approved OV for the treatment of unresectable melanoma and this virus opened up further potential for the use of this class of agents, especially in combination with ICIs, in order to achieve deeper and longer immune-mediated responses. However, the recently announced phase III MASTERKEY-265 trial was not able to confirm that the addition of T-VEC to pembrolizumab treatment improves progression-free or overall survival over the use of pembrolizumab alone. Despite these results, numerous studies are currently active, evaluating T-VEC and several other OVs as monotherapies or in regimens with ICIs in different subtypes of skin cancer. This overview provides a comprehensive update on the evolution status of all available OVs in melanoma and non-melanoma skin cancers and summarizes the more interesting preclinical findings, the latest clinical evidence, and the future insights in relation to the expected selective incorporation of some of these OVs into oncological practice.
Collapse
Affiliation(s)
| | | | | | | | - Helen Gogas
- First Department of Medicine, School of Medicine, National and Kapodistrian University of Athens, 115 27 Athens, Greece; (D.C.Z.); (A.M.); (D.-P.P.); (A.A.)
| |
Collapse
|
|
11
|
Foerster F, Gairing SJ, Ilyas SI, Galle PR. Emerging immunotherapy for HCC: A guide for hepatologists. Hepatology 2022; 75:1604-1626. [PMID: 35253934 PMCID: PMC9117522 DOI: 10.1002/hep.32447] [Citation(s) in RCA: 157] [Impact Index Per Article: 52.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 01/31/2022] [Accepted: 01/31/2022] [Indexed: 12/12/2022]
Abstract
HCC is one of the most common cancers worldwide, and the third leading cause of cancer-related death globally. HCC comprises nearly 90% of all cases of primary liver cancer. Approximately half of all patients with HCC receive systemic therapy during their disease course, particularly in the advanced stages of disease. Immuno-oncology has been paradigm shifting for the treatment of human cancers, with strong and durable antitumor activity in a subset of patients across a variety of malignancies including HCC. Immune checkpoint inhibition with atezolizumab and bevacizumab, an antivascular endothelial growth factor neutralizing antibody, has become first-line therapy for patients with advanced HCC. Beyond immune checkpoint inhibition, immunotherapeutic strategies such as oncolytic viroimmunotherapy and adoptive T-cell transfer are currently under investigation. The tumor immune microenvironment of HCC has significant immunosuppressive elements that may affect response to immunotherapy. Major unmet challenges include defining the role of immunotherapy in earlier stages of HCC, evaluating combinatorial strategies that use targeting of the immune microenvironment plus immune checkpoint inhibition, and identifying treatment strategies for patients who do not respond to the currently available immunotherapies. Herein, we review the rationale, mechanistic basis and supporting preclinical evidence, and available clinical evidence for immunotherapies in HCC as well as ongoing clinical trials of immunotherapy.
Collapse
Affiliation(s)
- Friedrich Foerster
- Department of Medicine I, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany
| | - Simon Johannes Gairing
- Department of Medicine I, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany
| | - Sumera Irie Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Peter Robert Galle
- Department of Medicine I, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany
| |
Collapse
|
|
12
|
Kang SM, Khalil L, El-Rayes BF, Akce M. Rapidly Evolving Landscape and Future Horizons in Hepatocellular Carcinoma in the Era of Immuno-Oncology. Front Oncol 2022; 12:821903. [PMID: 35433430 PMCID: PMC9008732 DOI: 10.3389/fonc.2022.821903] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 03/08/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a serious global health problem as one of the leading causes of cancer-related death worldwide. Systemic therapy for advanced HCC has progressed with the development of molecular targeted agents, however survival benefits remain modest. More recently, immune checkpoint inhibitors (ICI) have emerged and exhibited promising therapeutic benefits in a subset of patients. Physiologically, the intrinsic microenvironment in the liver is immunosuppressive, which represents a major obstacle for effective immune therapies in primary and secondary liver malignancies. For this reason, combination therapies that can overcome immune inhibitory mechanisms and enhance the immune response are a rationale approach for drug development in HCC. A recent example is the combination of the anti-PD-L1 antibody (atezolizumab) and anti-VEGF-A antibody (bevacizumab), which has shown significant improvement in survival as compared to standard of care in the first-line treatment for HCC. Other immunotherapy approaches including cancer vaccines and adoptive cell therapy are also under investigation. This review summarizes the key trials leading to our current HCC treatment options and provides an overview of future immune-based strategies in development.
Collapse
Affiliation(s)
| | | | | | - Mehmet Akce
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, United States
| |
Collapse
|
|
13
|
Liu JKH, Irvine AF, Jones RL, Samson A. Immunotherapies for hepatocellular carcinoma. Cancer Med 2022; 11:571-591. [PMID: 34953051 PMCID: PMC8817091 DOI: 10.1002/cam4.4468] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 10/29/2021] [Accepted: 11/02/2021] [Indexed: 12/21/2022] Open
Abstract
Cases of hepatocellular carcinoma (HCC) are rapidly rising. This is particularly the case in the Western world, as a result of increasing rates of chronic liver disease, secondary to lifestyle-associated risk factors and the lack of an established screening programme for the general population. Traditionally, radical/curative treatment options for HCC, including liver transplantation and surgical resection are reserved for the minority of patients, presenting with an early stage cancer. For patients with advanced disease, Sorafenib and Lenvatinib were, until recently, the only licensed systemic treatments, and provided only limited survival benefits at the cost of a multitude of potential side effects. Recent scientific advances in the field of cancer immunotherapy have renewed significant interest in advanced HCC, in order to fulfil this apparent area of unmet clinical need. This has led to the success and recent regulatory approval of an Atezolizumab/Bevacizumab combination for the first-line treatment of advanced HCC following results from the IMbrave150 clinical trial in 2019, with further immune checkpoint inhibitors currently undergoing testing in advanced clinical trials. Furthermore, other cancer immunotherapies, including chimeric antigen receptor T-cells, dendritic cell vaccines and oncolytic viruses are also in early stage clinical trials, for the treatment of advanced HCC. This review will summarise the major approaches that have been and are currently in development for the systemic treatment of advanced HCC, their advantages, drawbacks, and predictions of where this revolutionary treatment field will continue to travel for the foreseeable future.
Collapse
Affiliation(s)
- Justin K. H. Liu
- Leeds Institute of Medical Research at St James's (LIMR)School of MedicineFaculty of Medicine and HealthUniversity of LeedsSt James's University HospitalLeedsUK
| | - Andrew F. Irvine
- Leeds Institute of Medical Research at St James's (LIMR)School of MedicineFaculty of Medicine and HealthUniversity of LeedsSt James's University HospitalLeedsUK
| | - Rebecca L. Jones
- Leeds Liver UnitSt James's University HospitalLeeds Teaching Hospitals NHS TrustLeedsUK
| | - Adel Samson
- Leeds Institute of Medical Research at St James's (LIMR)School of MedicineFaculty of Medicine and HealthUniversity of LeedsSt James's University HospitalLeedsUK
| |
Collapse
|
|
14
|
Park JS, Lee ME, Jang WS, Kim J, Park SM, Oh K, Lee N, Ham WS. Systemic Injection of Oncolytic Vaccinia Virus Suppresses Primary Tumor Growth and Lung Metastasis in Metastatic Renal Cell Carcinoma by Remodeling Tumor Microenvironment. Biomedicines 2022; 10:173. [PMID: 35052851 PMCID: PMC8773601 DOI: 10.3390/biomedicines10010173] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 12/20/2021] [Accepted: 01/11/2022] [Indexed: 02/04/2023] Open
Abstract
Immune checkpoint inhibitors and tyrosine kinase inhibitors are the first-line treatment for metastatic renal cell carcinoma (mRCC), but their benefits are limited to specific patient subsets. Here, we aimed to evaluate the therapeutic efficacy of JX-594 (pexastimogene devacirepvec, Pexa-vec) monotherapy by systemic injection in comparison with sunitinib monotherapy in metastatic orthotopic RCC murine models. Two highly metastatic orthotopic RCC models were developed to compare the treatment efficacy in the International Metastatic RCC Database Consortium favorable-risk and intermediate- or poor-risk groups. JX-594 was systemically injected through the peritoneum, whereas sunitinib was orally administered. Post-treatment, tumor microenvironment (TME) remodeling was determined using immunofluorescence analysis. Systemic JX-594 monotherapy injection demonstrated therapeutic benefit in both early- and advanced-stage mRCC models. Sunitinib monotherapy significantly reduced the primary tumor burden and number of lung metastases in the early-stage, but not in the advanced-stage mRCC model. Systemic JX-594 delivery remodeled the primary TME and lung metastatic sites by increasing tumor-infiltrating CD4/8+ T cells and dendritic cells. Systemic JX-594 monotherapy demonstrated significantly better therapeutic outcomes compared with sunitinib monotherapy in both early- and advanced-stage mRCCs by converting cold tumors into hot tumors. Sunitinib monotherapy effectively suppressed primary tumor growth and lung metastasis in early-stage mRCC.
Collapse
Affiliation(s)
- Jee Soo Park
- Department of Urology, Urological Science Institute, College of Medicine, Yonsei University, Seoul 03722, Korea; (J.S.P.); (M.E.L.); (W.S.J.); (J.K.); (S.M.P.)
- Department of Urology, Sorokdo National Hospital, Goheung 59562, Korea
| | - Myung Eun Lee
- Department of Urology, Urological Science Institute, College of Medicine, Yonsei University, Seoul 03722, Korea; (J.S.P.); (M.E.L.); (W.S.J.); (J.K.); (S.M.P.)
| | - Won Sik Jang
- Department of Urology, Urological Science Institute, College of Medicine, Yonsei University, Seoul 03722, Korea; (J.S.P.); (M.E.L.); (W.S.J.); (J.K.); (S.M.P.)
| | - Jongchan Kim
- Department of Urology, Urological Science Institute, College of Medicine, Yonsei University, Seoul 03722, Korea; (J.S.P.); (M.E.L.); (W.S.J.); (J.K.); (S.M.P.)
- Department of Urology, Yongin Severance Hospital, Yonsei University Health System, Seoul 03722, Korea
| | - Se Mi Park
- Department of Urology, Urological Science Institute, College of Medicine, Yonsei University, Seoul 03722, Korea; (J.S.P.); (M.E.L.); (W.S.J.); (J.K.); (S.M.P.)
| | - Keunhee Oh
- Research Center, SillaJen, Inc., Seoul 07325, Korea; (K.O.); (N.L.)
| | - Namhee Lee
- Research Center, SillaJen, Inc., Seoul 07325, Korea; (K.O.); (N.L.)
| | - Won Sik Ham
- Department of Urology, Urological Science Institute, College of Medicine, Yonsei University, Seoul 03722, Korea; (J.S.P.); (M.E.L.); (W.S.J.); (J.K.); (S.M.P.)
| |
Collapse
|
|
15
|
Devan AR, Kumar AR, Nair B, Anto NP, Muraleedharan A, Mathew B, Kim H, Nath LR. Insights into an Immunotherapeutic Approach to Combat Multidrug Resistance in Hepatocellular Carcinoma. Pharmaceuticals (Basel) 2021; 14:656. [PMID: 34358082 PMCID: PMC8308499 DOI: 10.3390/ph14070656] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/01/2021] [Accepted: 07/07/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) has emerged as one of the most lethal cancers worldwide because of its high refractoriness and multi-drug resistance to existing chemotherapies, which leads to poor patient survival. Novel pharmacological strategies to tackle HCC are based on oral multi-kinase inhibitors like sorafenib; however, the clinical use of the drug is restricted due to the limited survival rate and significant side effects, suggesting the existence of a primary or/and acquired drug-resistance mechanism. Because of this hurdle, HCC patients are forced through incomplete therapy. Although multiple approaches have been employed in parallel to overcome multidrug resistance (MDR), the results are varying with insignificant outcomes. In the past decade, cancer immunotherapy has emerged as a breakthrough approach and has played a critical role in HCC treatment. The liver is the main immune organ of the lymphatic system. Researchers utilize immunotherapy because immune evasion is considered a major reason for rapid HCC progression. Moreover, the immune response can be augmented and sustained, thus preventing cancer relapse over the post-treatment period. In this review, we provide detailed insights into the immunotherapeutic approaches to combat MDR by focusing on HCC, together with challenges in clinical translation.
Collapse
Affiliation(s)
- Aswathy R. Devan
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi 682041, Kerala, India; (A.R.D.); (A.R.K.); (B.N.)
| | - Ayana R. Kumar
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi 682041, Kerala, India; (A.R.D.); (A.R.K.); (B.N.)
| | - Bhagyalakshmi Nair
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi 682041, Kerala, India; (A.R.D.); (A.R.K.); (B.N.)
| | - Nikhil Ponnoor Anto
- The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B. 653, Beer Sheva 84105, Israel; (N.P.A.); (A.M.)
| | - Amitha Muraleedharan
- The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B. 653, Beer Sheva 84105, Israel; (N.P.A.); (A.M.)
| | - Bijo Mathew
- Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi 682041, Kerala, India;
| | - Hoon Kim
- Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Korea
| | - Lekshmi R. Nath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi 682041, Kerala, India; (A.R.D.); (A.R.K.); (B.N.)
| |
Collapse
|
|
16
|
Bhatt S, Kanoujia J, Dhar AK, Singh RK, Rajangam J. Current and Future Scenario of Immunotherapy for the Treatment of Hepatocellular Carcinoma. CURRENT CANCER THERAPY REVIEWS 2021. [DOI: 10.2174/1573394716999200818103724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The discovery of the immune checkpoint inhibitors such as programed cell death-1 protein/
Programmed death ligand-1 or 2 and (PD-1/PD-L1 or PD-L2) and Cytotoxic T-lymphocyte associated
protein 4 (CTLA-4) paved the way for developing novel cancer treatment. The check
point inhibitors are found to be very efficient in treating many hot tumors (with immune environment)
such as bladder cancer, melanoma, renal cell carcinoma (RCC), non-small cell lung cancer
(NSCLC), etc. Numerous clinical trials have been initiated to evaluate the safety and effectiveness
of immune checkpoint inhibitors for patients with different cancer types, including hepatocellular
carcinoma (HCC), pancreatic and prostate cancer. The results and findings of these trials are highly
appreciated. However, the search for check point inhibitors with better efficacy for the treatment of
HCC is still going on. The present review focuses on advancement in HCC treatments with respect
to various standard therapies and immunotherapy.
Collapse
Affiliation(s)
- Shvetank Bhatt
- Amity Institute of Pharmacy, Amity University Madhya Pradesh (AUMP), Gwalior-474005, India
| | - Jovita Kanoujia
- Amity Institute of Pharmacy, Amity University Madhya Pradesh (AUMP), Gwalior-474005, India
| | - Arghya K. Dhar
- Gurunanak Institute of Pharmaceutical Science and Technology, Kolkata-700110, India
| | - Rakesh K. Singh
- Amity Institute of Pharmacy, Amity University Haryana, Manesar, Panchgaon, Haryana 122412, India
| | - Jayaraman Rajangam
- Sree Vidya Niketan College of Pharmacy, Tirupati, Andhra Pradesh 517102, India
| |
Collapse
|
|
17
|
The Current Landscape of Clinical Trials for Systemic Treatment of HCC. Cancers (Basel) 2021; 13:cancers13081962. [PMID: 33921731 PMCID: PMC8073471 DOI: 10.3390/cancers13081962] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 04/10/2021] [Accepted: 04/12/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Liver cancer is a life-threatening disease. Apart from surgery and catheter-guided therapies, drugs are a central pillar for its treatment. Clinical trials are research studies that are designed to evaluate the treatment effect of a given drug. Therefore, they are the driving force behind innovation and medical progress. One such innovation in the past years has been immunotherapy, which has become increasingly important for treating cancer. Recently, the first such therapy has been approved for the treatment of liver cancer. Current clinical trials are exploring the benefit of immunotherapy and other therapies for this disease. This article gives an overview of such trials paying attention to the different underlying treatment strategies and the varying clinical settings, depending on the stage of the disease. Abstract The clinical development of systemic treatments for hepatocellular carcinoma (HCC) has gained significant momentum in recent years. After the unexpected failure of the phase 3 trials testing the PD1-inhibitors nivolumab and pembrolizumab as monotherapy in advanced HCC, a multitude of trials employing different agents in various combinations and at different disease stages have been initiated. The first positive results reported for the combination of atezolizumab and bevacizumab, as the first line treatment of advanced HCC, will bring lasting change to the management of HCC and has increased the odds of success for alternative combination therapies. This review article seeks to provide clarity on the complex and evolving landscape of clinical trials on systemic treatments of HCC. It covers current trials which test various systemic treatments (i) in the first and second line in advanced HCC, (ii) in intermediate HCC, (iii) as adjuvant as well as (iv) neoadjuvant strategies, and (v) including immune interventions other than immune checkpoint inhibition.
Collapse
|
|
18
|
Lurje I, Hammerich L, Tacke F. Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer. Int J Mol Sci 2020; 21:ijms21197378. [PMID: 33036244 PMCID: PMC7583774 DOI: 10.3390/ijms21197378] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/01/2020] [Accepted: 10/04/2020] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a chronic, highly prevalent disease that may progress to cirrhosis and substantially increases the risk for development of hepatocellular carcinoma (HCC). Fibrotic livers are characterized by an inflammatory microenvironment that is composed of various immunologically active cells, including liver-resident populations (e.g., Kupffer cells, hepatic stellate cells and sinusoidal endothelium) and infiltrating leukocytes (e.g., monocytes, monocyte-derived macrophages, neutrophils and lymphocytes). While inflammatory injury drives both fibrogenesis and carcinogenesis, the tolerogenic microenvironment of the liver conveys immunosuppressive effects that encourage tumor growth. An insufficient crosstalk between dendritic cells (DCs), the professional antigen presenting cells, and T cells, the efficient anti-tumor effector cells, is one of the main mechanisms of HCC tumor tolerance. The meticulous analysis of patient samples and mouse models of fibrosis-HCC provided in-depth insights into molecular mechanisms of immune interactions in liver cancer. The therapeutic modulation of this multifaceted immunological response, e.g., by inhibiting immune checkpoint molecules, in situ vaccination, oncolytic viruses or combinations thereof, is a rapidly evolving field that holds the potential to improve the outcome of patients with HCC. This review aims to highlight the current understanding of DC–T cell interactions in fibrogenesis and hepatocarcinogenesis and to illustrate the potentials and pitfalls of therapeutic clinical translation.
Collapse
|
|
19
|
Raybould AL, Sanoff H. Combination Antiangiogenic and Immunotherapy for Advanced Hepatocellular Carcinoma: Evidence to Date. J Hepatocell Carcinoma 2020; 7:133-142. [PMID: 32984090 PMCID: PMC7501959 DOI: 10.2147/jhc.s224938] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 07/30/2020] [Indexed: 12/18/2022] Open
Abstract
For over a decade, sorafenib remained the only systemic agent with proven clinical efficacy for patients with advanced hepatocellular carcinoma (HCC). Recent years have seen a proliferation of agents. In the first line, lenvatinib was found to be non-inferior to sorafenib in terms of overall survival (OS), with significantly better progression-free survival and objective response rate. Meanwhile, encouraging efficacy signals were observed in phase I/II studies of immune checkpoint inhibitors as monotherapy in HCC. Although subsequent phase III trials failed to demonstrate statistically significant benefit in OS, other clinically meaningful outcomes were observed, including long-term disease control with a favorable toxicity profile. In addition, a synergistic response has been postulated based on the interplay between antiangiogenic molecular targeted agents and immunotherapy. On this basis, interest has turned toward combination strategies of immunotherapy with these standard-of-care medications in the hope of improving treatment efficacy for advanced HCC, while maintaining tolerable safety profiles. Indeed, preliminary results from phase I studies of lenvatinib plus pembrolizumab and atezolizumab plus bevacizumab have proved favorable, prompting phase III investigations in the frontline setting, and for atezolizumab plus bevacizumab, these positive findings have been substantiated by recent reporting of phase III data from IMbrave150. In this review, we will present the currently available data on combination therapy atezolizumab plus bevacizumab in advanced HCC, and compare these findings to other promising combination treatments, most notably that of lenvatinib plus pembrolizumab.
Collapse
Affiliation(s)
- Alison L Raybould
- Department of Medicine, Division of Hematology-Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC27599, USA
| | - Hanna Sanoff
- Department of Medicine, Division of Hematology-Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC27599, USA
| |
Collapse
|
|
20
|
Hager S, Fittler FJ, Wagner E, Bros M. Nucleic Acid-Based Approaches for Tumor Therapy. Cells 2020; 9:E2061. [PMID: 32917034 PMCID: PMC7564019 DOI: 10.3390/cells9092061] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 09/06/2020] [Accepted: 09/07/2020] [Indexed: 12/24/2022] Open
Abstract
Within the last decade, the introduction of checkpoint inhibitors proposed to boost the patients' anti-tumor immune response has proven the efficacy of immunotherapeutic approaches for tumor therapy. Furthermore, especially in the context of the development of biocompatible, cell type targeting nano-carriers, nucleic acid-based drugs aimed to initiate and to enhance anti-tumor responses have come of age. This review intends to provide a comprehensive overview of the current state of the therapeutic use of nucleic acids for cancer treatment on various levels, comprising (i) mRNA and DNA-based vaccines to be expressed by antigen presenting cells evoking sustained anti-tumor T cell responses, (ii) molecular adjuvants, (iii) strategies to inhibit/reprogram tumor-induced regulatory immune cells e.g., by RNA interference (RNAi), (iv) genetically tailored T cells and natural killer cells to directly recognize tumor antigens, and (v) killing of tumor cells, and reprograming of constituents of the tumor microenvironment by gene transfer and RNAi. Aside from further improvements of individual nucleic acid-based drugs, the major perspective for successful cancer therapy will be combination treatments employing conventional regimens as well as immunotherapeutics like checkpoint inhibitors and nucleic acid-based drugs, each acting on several levels to adequately counter-act tumor immune evasion.
Collapse
Affiliation(s)
- Simone Hager
- Department of Chemistry and Pharmacy, Ludwig-Maximilians-University (LMU), 81377 Munich, Germany;
| | | | - Ernst Wagner
- Department of Chemistry and Pharmacy, Ludwig-Maximilians-University (LMU), 81377 Munich, Germany;
| | - Matthias Bros
- Department of Dermatology, University Medical Center, 55131 Mainz, Germany;
| |
Collapse
|
|
21
|
Abou-Alfa GK, Jarnagin W, El Dika I, D'Angelica M, Lowery M, Brown K, Ludwig E, Kemeny N, Covey A, Crane CH, Harding J, Shia J, O'Reilly EM. Liver and Bile Duct Cancer. ABELOFF'S CLINICAL ONCOLOGY 2020:1314-1341.e11. [DOI: 10.1016/b978-0-323-47674-4.00077-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
22
|
Zhu XD, Sun HC. Emerging agents and regimens for hepatocellular carcinoma. J Hematol Oncol 2019; 12:110. [PMID: 31655607 PMCID: PMC6815423 DOI: 10.1186/s13045-019-0794-6] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 09/25/2019] [Indexed: 12/24/2022] Open
Abstract
Liver cancer, mostly hepatocellular carcinoma (HCC), is the second leading cause of cancer mortality globally. Most patients need at least one systemic therapy at different phases of their treatment for HCC. Sorafenib was the first agent shown to improve the survival of patients with advanced HCC. A decade after the approval of sorafenib, most agents failed to improve patient survival more than sorafenib. In recent years, treatment practices have changed, with lenvatinib as another first-line treatment choice and regorafenib, ramucirumab, and cabozantinib as second-line treatment options. Anti-PD-1 antibodies, including nivolumab, pembrolizumab, and camrelizumab, have demonstrated promising anti-tumor effects as monotherapy for advanced HCC in phase II clinical trials. The combination of an anti-PD-1 antibody and an anti-angiogenesis agent has shown more potent anti-tumor effects in early phase clinical trials and is now the hotspot in clinical studies. Furthermore, these agents are investigated in combination treatment with surgery or other loco-regional therapies in patients with early or intermediate-stage HCC.
Collapse
Affiliation(s)
- Xiao-Dong Zhu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Hui-Chuan Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| |
Collapse
|
|
23
|
Fu LQ, Wang SB, Cai MH, Wang XJ, Chen JY, Tong XM, Chen XY, Mou XZ. Recent advances in oncolytic virus-based cancer therapy. Virus Res 2019; 270:197675. [PMID: 31351879 DOI: 10.1016/j.virusres.2019.197675] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 07/24/2019] [Accepted: 07/24/2019] [Indexed: 12/14/2022]
Abstract
Administration of oncolytic viruses (OVs) is an emerging anticancer strategy that exploits the lytic nature of viral replication to enhance the killing of malignant cells. OVs can be used as tools to directly induce cancer cell death and to trigger local and/or systemic immune responses to metastatic cancer in vivo. The effectiveness of OV therapy was initially highlighted by the clinical use of the genetically modified herpes virus, talimogene laherparepvec, for melanoma therapy. A number of OVs are now being evaluated as potential treatments for cancer in clinical trials. In spite of being engineered to specifically target tumor cells, the safety and off-target effects of OV therapy are a concern. The potential safety concerns of OVs are highlighted by current clinical trial criteria, which exclude individuals harbouring other viral infections and people who are immunocompromised. Despite the potential for adverse effects, clinical trials to date revealed relatively minimal adverse immune-related effects, such as fever. With advances in our understanding of virus replication cycles, several novel OVs have emerged. Reverse genetic systems have facilitated the insertion of anticancer genes into a range of OVs to further enhance their tumor-killing capacity. In this review, we highlight the recent advances in OV therapy for a range of human cancers in in vitro and in in vivo animal studies. We further discuss the future of OVs as a therapeutic strategy for a range of life-threatening cancers.
Collapse
Affiliation(s)
- Luo-Qin Fu
- Department of General Surgery, Chun'an First People's Hospital (Zhejiang Provincial People's Hospital Chun'an Branch), Hangzhou 311700, Zhejiang Province, China; State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 21513, Jiangsu Province, China
| | - Shi-Bing Wang
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou 310014, China
| | - Mao-Hua Cai
- Department of General Surgery, Chun'an First People's Hospital (Zhejiang Provincial People's Hospital Chun'an Branch), Hangzhou 311700, Zhejiang Province, China
| | - Xue-Jun Wang
- Department of General Surgery, Chun'an First People's Hospital (Zhejiang Provincial People's Hospital Chun'an Branch), Hangzhou 311700, Zhejiang Province, China
| | - Jin-Yang Chen
- Research and Development Department, Zhejiang Healthfuture Institute For Cell-Based Applied Technology, Hangzhou 310052, Zhejiang Province, China
| | - Xiang-Min Tong
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou 310014, China; Clinical Research Institute, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou 310014, China
| | - Xiao-Yi Chen
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou 310014, China; Clinical Research Institute, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou 310014, China.
| | - Xiao-Zhou Mou
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou 310014, China; Clinical Research Institute, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou 310014, China.
| |
Collapse
|
|
24
|
Johnston MP, Khakoo SI. Immunotherapy for hepatocellular carcinoma: Current and future. World J Gastroenterol 2019; 25:2977-2989. [PMID: 31293335 PMCID: PMC6603808 DOI: 10.3748/wjg.v25.i24.2977] [Citation(s) in RCA: 139] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 04/24/2019] [Accepted: 05/18/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) arises on the background of chronic liver disease. Despite the development of effective anti-viral therapeutics HCC is continuing to rise, in part driven by the epidemic of non-alcoholic fatty liver disease. Many patients present with advanced disease out with the criteria for transplant, resection or even locoregional therapy. Currently available therapeutics for HCC are effective in a small minority of individuals. However, there has been a major global interest in immunotherapies for cancer and although HCC has lagged behind other cancers, great opportunities now exist for treating HCC with newer and more sophisticated agents. Whilst checkpoint inhibitors are at the forefront of this revolution, other therapeutics such as inhibitory cytokine blockade, oncolytic viruses, adoptive cellular therapies and vaccines are emerging. Broadly these may be categorized as either boosting existing immune response or stimulating de novo immune response. Although some of these agents have shown promising results as monotherapy in early phase trials it may well be that their future role will be as combination therapy, either in combination with one another or in combination with treatment modalities such as locoregional therapy. Together these agents are likely to generate new and exciting opportunities for treating HCC, which are summarized in this review.
Collapse
Affiliation(s)
- Michael P Johnston
- Department of Hepatology, Southampton General Hospital, University Hospital Southampton, Southampton SO16 6YD, United Kingdom
| | - Salim I Khakoo
- Department of Clinical and Experimental Sciences, Faculty of Medicine, Southampton General Hospital, University of Southampton, Southampton SO16 6YD, United Kingdom
| |
Collapse
|
|
25
|
McCarthy C, Jayawardena N, Burga LN, Bostina M. Developing Picornaviruses for Cancer Therapy. Cancers (Basel) 2019; 11:E685. [PMID: 31100962 PMCID: PMC6562951 DOI: 10.3390/cancers11050685] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 05/02/2019] [Accepted: 05/08/2019] [Indexed: 12/24/2022] Open
Abstract
Oncolytic viruses (OVs) form a group of novel anticancer therapeutic agents which selectively infect and lyse cancer cells. Members of several viral families, including Picornaviridae, have been shown to have anticancer activity. Picornaviruses are small icosahedral non-enveloped, positive-sense, single-stranded RNA viruses infecting a wide range of hosts. They possess several advantages for development for cancer therapy: Their genomes do not integrate into host chromosomes, do not encode oncogenes, and are easily manipulated as cDNA. This review focuses on the picornaviruses investigated for anticancer potential and the mechanisms that underpin this specificity.
Collapse
Affiliation(s)
- Cormac McCarthy
- Department of Microbiology and Immunology, University of Otago, Dunedin 9016, New Zealand.
| | - Nadishka Jayawardena
- Department of Microbiology and Immunology, University of Otago, Dunedin 9016, New Zealand.
| | - Laura N Burga
- Department of Microbiology and Immunology, University of Otago, Dunedin 9016, New Zealand.
| | - Mihnea Bostina
- Department of Microbiology and Immunology, University of Otago, Dunedin 9016, New Zealand.
- Otago Micro and Nano Imaging, University of Otago, Dunedin 9016, New Zealand.
| |
Collapse
|
|
26
|
Warner SG, Kim SI, Chaurasiya S, O'Leary MP, Lu J, Sivanandam V, Woo Y, Chen NG, Fong Y. A Novel Chimeric Poxvirus Encoding hNIS Is Tumor-Tropic, Imageable, and Synergistic with Radioiodine to Sustain Colon Cancer Regression. MOLECULAR THERAPY-ONCOLYTICS 2019; 13:82-92. [PMID: 31061881 PMCID: PMC6495072 DOI: 10.1016/j.omto.2019.04.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 04/04/2019] [Indexed: 12/11/2022]
Abstract
Colon cancer has a high rate of recurrence even with good response to modern therapies. Novel curative adjuncts are needed. Oncolytic viral therapy has shown preclinical promise against colon cancer but lacks robust efficacy in clinical trials and raises regulatory concerns without real-time tracking of viral replication. Novel potent vectors are needed with adjunctive features to enhance clinical efficacy. We have thus used homologous recombination and high-throughput screening to create a novel chimeric poxvirus encoding a human sodium iodide symporter (hNIS) at a redundant tk locus. The resulting virus (CF33-hNIS) consistently expresses hNIS and demonstrates replication efficiency and immunogenic cell death in colon cancer cells in vitro. Tumor-specific CF33-hNIS efficacy against colon cancer results in tumor regression in vivo in colon cancer xenograft models. Early expression of hNIS by infected cells makes viral replication reliably imageable via positron emission tomography (PET) of I-124 uptake. The intensity of I-124 uptake mirrors viral replication and tumor regression. Finally, systemic delivery of radiotherapeutic I-131 isotope following CF33-hNIS infection of colon cancer xenografts enhances and sustains tumor regression compared with virus treatment alone in HCT116 xenografts, demonstrating synergy of oncolytic viral therapy with radioablation in vivo.
Collapse
Affiliation(s)
- Susanne G Warner
- Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA.,Center for Gene Therapy, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Sang-In Kim
- Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Shyambabu Chaurasiya
- Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Michael P O'Leary
- Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Jianming Lu
- Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Venkatesh Sivanandam
- Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Yanghee Woo
- Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Nanhai G Chen
- Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA.,Center for Gene Therapy, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Yuman Fong
- Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA.,Center for Gene Therapy, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| |
Collapse
|
|
27
|
Chang Lee R, Tebbutt N. Systemic treatment of advanced hepatocellular cancer: new hope on the horizon. Expert Rev Anticancer Ther 2019; 19:343-353. [PMID: 30793991 DOI: 10.1080/14737140.2019.1585245] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality in the world. The majority of the patients present at an advanced or incurable stage where neither locoregional treatment nor combination treatment of locoregional treatment and systemic therapies is feasible. For decades sorafenib was the only treatment option available for advanced HCC. However, with the advent of new and more effective therapies recently, the overall prognosis of advanced HCC has improved significantly. Areas covered: This review summarises the current systemic treatment options available and future prospects in the management of advanced HCC where patients are not suitable for locoregional treatment. Expert opinion: New effective targeted therapeutics have dramatically changed the treatment landscape for advanced HCC. The incorporation of sequential therapy including sorafenib or lenvatinib as first-line treatment and immunotherapy, regorafenib or cabozantinib as second-line treatment have significantly improved outcomes for patients with advanced HCC. Further development of novel combinations of these new agents and predictive/prognostic biomarkers are being explored. Efforts should also be made to tailor treatment to individual patients based on etiology, clinical and molecular factors.
Collapse
Affiliation(s)
- Rachael Chang Lee
- a Department of Medical Oncology , Olivia Newton-John Cancer Wellness and Research Centre , Heidelberg , Australia
| | - Niall Tebbutt
- a Department of Medical Oncology , Olivia Newton-John Cancer Wellness and Research Centre , Heidelberg , Australia
| |
Collapse
|
|
28
|
Greten TF, Lai CW, Li G, Staveley-O'Carroll KF. Targeted and Immune-Based Therapies for Hepatocellular Carcinoma. Gastroenterology 2019; 156:510-524. [PMID: 30287171 PMCID: PMC6340758 DOI: 10.1053/j.gastro.2018.09.051] [Citation(s) in RCA: 196] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 09/21/2018] [Accepted: 09/24/2018] [Indexed: 02/06/2023]
Abstract
Treatment options for patients with hepatocellular carcinoma are rapidly changing based on positive results from phase 3 trials of targeted and immune-based therapies. More agents designed to target specific pathways and immune checkpoints are in clinical development. Some agents have already been shown to improve outcomes of patients with hepatocellular carcinoma, as first- and second-line therapies, and are awaiting approval by the Food and Drug Administration or have been recently approved. We summarize the targeted and immune-based agents in trials of patients with advanced hepatocellular carcinoma and discuss the future of these strategies for liver cancer.
Collapse
Affiliation(s)
- Tim F Greten
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; National Cancer Institute CCR Liver Cancer Program, Bethesda, Maryland.
| | - Chunwei Walter Lai
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; Liver Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, Maryland
| | - Guangfu Li
- Department of Surgery, University of Missouri-Columbia, Columbia, Missouri; Department of Molecular Microbiology & Immunology, University of Missouri-Columbia, Columbia, Missouri
| | | |
Collapse
|
|
29
|
Chon HJ, Lee WS, Yang H, Kong SJ, Lee NK, Moon ES, Choi J, Han EC, Kim JH, Ahn JB, Kim JH, Kim C. Tumor Microenvironment Remodeling by Intratumoral Oncolytic Vaccinia Virus Enhances the Efficacy of Immune-Checkpoint Blockade. Clin Cancer Res 2018; 25:1612-1623. [PMID: 30538109 DOI: 10.1158/1078-0432.ccr-18-1932] [Citation(s) in RCA: 111] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 10/22/2018] [Accepted: 12/06/2018] [Indexed: 02/04/2023]
Abstract
PURPOSE Cancer immunotherapy is a potent treatment modality, but its clinical benefit depends on the tumor's immune profile. Here, we used mJX-594 (JX), a targeted and GM-CSF-armed oncolytic vaccinia virus, as a strategy to remodel the tumor microenvironment (TME) and subsequently increase sensitivity to αPD-1 and/or αCTLA-4 immunotherapy. EXPERIMENTAL DESIGN The remodeling of the TME was determined using histologic, flow-cytometric, and NanoString immune profiling analyses. JX was intratumorally injected into implanted Renca kidney tumors or MMTV-PyMT transgenic mouse breast cancers with or without αPD-1 and/or αCTLA-4. Various combination regimens were used to evaluate immunotherapeutic anticancer responses. RESULTS Intratumoral injection of JX remodeled the TME through dynamic changes in the immune system, as shown by increased tumor-infiltrating T cells and upregulation of immune-related gene signatures. This remodeling induced conversion of a noninflamed tumor into an inflamed tumor. JX virotherapy led to enhanced abscopal effects in distant tumors, with increased intratumoral infiltration of CD8+ T cells. A depletion study revealed that GM-CSF is an indispensable regulator of anticancer efficacy of JX. Dual-combination therapy with intratumoral JX and systemic αPD-1 or αCTLA-4 further enhanced the anticancer immune response, regardless of various treatment schedules. Of note, triple combination immunotherapy with JX, αPD-1, and αCTLA-4 elicited the most potent anticancer immunity and induced complete tumor regression and long-term overall survival. CONCLUSIONS Our results show that intratumoral JX treatment induces dramatic remodeling of the TME and more potently suppresses cancer progression with immune-checkpoint blockades by overcoming resistance to immunotherapy.
Collapse
Affiliation(s)
- Hong Jae Chon
- Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea.,Laboratory of Translational Immuno-Oncology, Seongnam, Republic of Korea.,Yonsei Graduate School, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Won Suk Lee
- Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea.,Laboratory of Translational Immuno-Oncology, Seongnam, Republic of Korea
| | - Hannah Yang
- Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea.,Laboratory of Translational Immuno-Oncology, Seongnam, Republic of Korea
| | - So Jung Kong
- Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea.,Laboratory of Translational Immuno-Oncology, Seongnam, Republic of Korea
| | - Na Keum Lee
- Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea.,Laboratory of Translational Immuno-Oncology, Seongnam, Republic of Korea
| | | | - Jiwon Choi
- SillaJen, Inc., Seoul, Republic of Korea
| | - Eun Chun Han
- Laboratory of Translational Immuno-Oncology, Seongnam, Republic of Korea
| | - Joo Hoon Kim
- Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea.,Laboratory of Translational Immuno-Oncology, Seongnam, Republic of Korea
| | - Joong Bae Ahn
- Yonsei Graduate School, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Joo Hang Kim
- Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Chan Kim
- Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea. .,Laboratory of Translational Immuno-Oncology, Seongnam, Republic of Korea
| |
Collapse
|
|
30
|
Eatrides J, Wang E, Kothari N, Kim R. Role of Systemic Therapy and Future Directions for Hepatocellular Carcinoma. Cancer Control 2018; 24:1073274817729243. [PMID: 28975834 PMCID: PMC5937243 DOI: 10.1177/1073274817729243] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive tumor that often arises in the setting of liver cirrhosis. Although early-stage disease is often amenable for surgical resection, transplant, or locoregional therapies, many patients are diagnosed at an advanced stage or have poor liver reserve. Systemic therapy is the mainstay of treatment for these patients. At present, the only approved therapy for the treatment of advanced disease is the tyrosine multikinase inhibitor sorafenib. Candidacy for treatment is based on liver reserve. Novel agents for the treatment of this disease are urgently needed. In this article, we review systemic therapy trials and upcoming data for the treatment of HCC.
Collapse
Affiliation(s)
- Jennifer Eatrides
- 1 Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Emilie Wang
- 1 Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Nishi Kothari
- 1 Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Richard Kim
- 1 Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| |
Collapse
|
|
31
|
Hamid O, Hoffner B, Gasal E, Hong J, Carvajal RD. Oncolytic immunotherapy: unlocking the potential of viruses to help target cancer. Cancer Immunol Immunother 2017; 66:1249-1264. [PMID: 28712033 PMCID: PMC5626801 DOI: 10.1007/s00262-017-2025-8] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 05/23/2017] [Indexed: 12/22/2022]
Abstract
Oncolytic immunotherapy is a research area of cancer immunotherapy investigating the use of modified viruses to target cancer cells. A variety of different viral backbones (e.g., adenovirus, reovirus) with a diverse range of genetic modifications are currently being investigated for the treatment of a variety of cancers. The oncolytic virus that has advanced the furthest in clinical development is talimogene laherparepvec, a recombinant HSV-1 virus expressing granulocyte-macrophage colony-stimulating factor (GM-CSF). In a phase 3 study in patients with unresectable metastatic melanoma, intralesional talimogene laherparepvec treatment resulted in a higher durable response rate compared with subcutaneous GM-CSF treatment (16.3 versus 2.1%; P < 0.001). Notably, responses were observed at uninjected lesions including visceral lesions, indicating a systemic antitumor response had occurred. Studies evaluating combination treatments involving oncolytic viruses and immunologic agents are ongoing. This review focuses on the mechanisms of action for oncolytic viruses and highlights select agents and combinations currently in development.
Collapse
Affiliation(s)
- Omid Hamid
- The Angeles Clinic and Research Institute, 11818 Wilshire Blvd #200, Los Angeles, CA, 90025, USA.
| | | | | | - Jenny Hong
- Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | | |
Collapse
|