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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 61320

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Prof. Dr. Nicola Silvestris

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Department of Human Pathology of the Adult and the Developmental Age “G. Barresi”, University of Messina, Messina, Italy
Interests: gastrointestinal tumors; translational research; clinical trials
Special Issues, Collections and Topics in MDPI journals

Dr. Afshin Derakhshani

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Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

Dr. Oronzo Brunetti

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IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Various research studies have focused on many of the immunological approaches for cancer treatment. Current therapies for cancer are ineffective, with unacceptably high toxicity, and most of them have severe side effects on the patients. Among some of the most common treatments for cancer, immunotherapy is a potential and promising treatment strategy for various forms of cancer. Nevertheless, there are challenges that researchers and doctors should consider. Immune checkpoint inhibitors (ICIs), bi-specific T-cell engagers (BiTEs), and chimeric antigen receptor T cell (CAR-T cells) are the most effective methods for cancer therapy. Recently, researchers have been considering the potential of a combination therapy based on the aforementioned methods, which in some cases has been shown to have a much greater effect on cancer therapy. Novel research strategies are therefore required for a better description of the mechanisms of these approaches for cancer therapy.

The focus of this Special Issue is to consider the following research aspects summarized below: a) Novel immune checkpoint targets; b) clinical experience with bi-specific T Cell engagers; c) chimeric antigen receptor (CAR) T-Cell therapy; and d) immuno-oncology combination therapy.

Dr. Nicola Silvestris
Dr. Afshin Derakhshani
Dr. Oronzo Brunetti
Guest Editors

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Published Papers (13 papers)

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Research

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14 pages, 2417 KiB

Open AccessArticle

Clinically Applicable Assessment of Tisagenlecleucel CAR T Cell Treatment by Digital Droplet PCR for Copy Number Variant Assessment

by Soragia Athina Gkazi, Emma Gravett, Carla Bautista, Jack Bartram, Sara Ghorashian and Stuart Paul Adams

Int. J. Mol. Sci. 2022, 23(14), 7573; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147573 - 08 Jul 2022

Cited by 2 | Viewed by 2006

Abstract

Chimeric antigen receptor (CAR) T cell therapy is an innovative immunotherapy for treating cancers in both children and adults with proven utility in numerous clinical trials. Significantly, some CAR T cell therapies have now been approved by relevant national regulatory bodies across numerous countries for clinical therapeutic use outside of clinical trials. One such recently licensed product is tisagenlecleucel, a CAR T therapy approved for the treatment of B-cell acute lymphoblastic leukemia (B-ALL) using autologous T cells from the patient. The genetically engineered T cells target a protein called CD19, common to B cells, through a CAR incorporating a 4-1BB costimulatory domain to improve response. Since tisagenlecleucel is now a standard of care treatment for B-ALL, it is clinically essential to be able to accurately monitor these CAR T cells in patients. Assessment of the copy number variant (CNV) of the CAR T cell products allows this within a clinically acceptable timeframe for optimal patient benefit. However, no standardized method with high reproducibility and efficiency has been described within a routine clinical laboratory setting. Here, we demonstrated a novel digital droplet PCR (ddPCR)-based methodology for the study of CNV (ddPCR-CNV) in 4-1BB CD19-specific CAR T cells with universal applicability across clinical diagnostic laboratories. Full article

(This article belongs to the Special Issue Immunotherapy for Cancer)

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12 pages, 1979 KiB

Open AccessArticle

Identification of Potent CD19 scFv for CAR T Cells through scFv Screening with NK/T-Cell Line

by Chung Hyo Kang, Yeongrin Kim, Heung Kyoung Lee, So Myoung Lee, Hye Gwang Jeong, Sang Un Choi and Chi Hoon Park

Int. J. Mol. Sci. 2020, 21(23), 9163; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239163 - 01 Dec 2020

Cited by 11 | Viewed by 6433

Abstract

CD19 is the most promising target for developing chimeric-antigen receptor (CAR) T cells against B-cell leukemic cancer. Currently, two CAR-T-cell products, Kymriah and Yescarta, are approved for leukemia patients, and various anti-CD19 CAR T cells are undergoing clinical trial. Most of these anti-CD19 CAR T cells use FMC63 single-chain variable fragments (scFvs) for binding CD19 expressed on the cancer cell surface. In this study, we screened several known CD19 scFvs for developing anti-CD19 CAR T cells. We used the KHYG-1 NK/T-cell line for screening of CD19 scFvs because it has advantages in terms of cell culture and gene transduction compared to primary T cells. Using our CAR construct backbone, we made anti-CD19 CAR constructs which each had CD19 scFvs including FMC63, B43, 25C1, BLY3, 4G7, HD37, HB12a, and HB12b, then made each anti-CD19 CAR KHYG-1 cells. Interestingly, only FMC63 CAR KHYG-1 and 4G7 CAR KHYG-1 efficiently lysed CD19-positive cell lines. In addition, in Jurkat cell line, only these two CAR Jurkat cell lines secreted IL-2 when co-cultured with CD19-positive cell line, NALM-6. Based on these results, we made FMC63 CAR T cells and 4G7 CAR T cells from PBMC. In in vitro lysis assay, 4G7 CAR T cells lysed CD19-positive cell line as well as FMC63 CAR T cells. In in vivo assay with NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice, 4G7 CAR T cells eradicated NALM-6 as potently as FMC63 CAR T cells. Therefore, we anticipate that 4G7 CAR T cells will show as good a result as FMC63 CAR T cells for B-cell leukemia patients. Full article

(This article belongs to the Special Issue Immunotherapy for Cancer)

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19 pages, 5410 KiB

Open AccessArticle

Combination of NKT14m and Low Dose IL-12 Promotes Invariant Natural Killer T Cell IFN-γ Production and Tumor Control

by Peng Guan, Robert Schaub, Kim E. Nichols and Rupali Das

Int. J. Mol. Sci. 2020, 21(14), 5085; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145085 - 18 Jul 2020

Cited by 2 | Viewed by 3049

Abstract

Invariant natural killer T (iNKT) cells are innate-like T lymphocytes characterized by the expression of an invariant T cell receptor (iTCR) that recognizes glycolipid antigens presented by the MHC I-like CD1d molecule. Following antigenic stimulation, iNKT cells rapidly produce large amounts of cytokines that can trans-activate dendritic cells (DC) and promote the anti-tumor functions of cytotoxic lymphocytes, such as natural killer (NK) and CD8 T cells. Additionally, iNKT cells can mediate robust and direct cytotoxicity against CD1d⁺ tumor targets. However, many tumors down-regulate CD1d and evade iNKT cell attack. To circumvent this critical barrier to iNKT cell anti-tumor activity, a novel monoclonal antibody (mAb), NKT14 has been recently developed. This agonistic antibody binds directly and specifically to the iTCR of murine iNKT cells. In the current study, we demonstrate that NKT14m mediates robust activation, cytokine production and degranulation of murine iNKT cells, in vitro. Consistently, NKT14m also promoted iNKT cell activation and immunomodulatory functions, in vivo. Finally, administration of NKT14m with low dose interleukin (IL)-12 further augmented iNKT cell IFN-γ production in vivo, and this combination conferred superior suppression of tumor cell growth compared to NKT14m or IL-12 alone. Together, these data demonstrate that a combination treatment consisting of low dose IL-12 and iTCR-specific mAb may be an attractive alternative to activate iNKT cell anti-tumor functions. Full article

(This article belongs to the Special Issue Immunotherapy for Cancer)

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17 pages, 2632 KiB

Open AccessArticle

Cancer Immunotherapeutic Potential of NKTT320, a Novel, Invariant, Natural Killer T Cell-Activating, Humanized Monoclonal Antibody

by Nishant P. Patel, Peng Guan, Devika Bahal, Tanwir Hashem, Felix Scheuplein, Robert Schaub, Kim E. Nichols and Rupali Das

Int. J. Mol. Sci. 2020, 21(12), 4317; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124317 - 17 Jun 2020

Cited by 6 | Viewed by 2993

Abstract

Invariant natural killer T cells (iNKTs) directly kill tumor cells and trans-activate the anti-tumor functions of dendritic cells (DC), natural killer (NK) cells, and T and B cells. As such, iNKTs serve as a powerful tool for use in cell-based cancer immunotherapy. iNKT cell activation commonly requires engagement of the invariant T cell receptor (iTCR) by CD1d presenting glycolipid antigens. However, transformed cells often down-regulate CD1d expression, which results in a reduction of iNKT cell anti-tumor functions. One approach to circumvent this critical barrier to iNKT cell activation is to develop an agonistic antibody that binds directly to the iTCR without the requirement for CD1d-mediated antigen presentation. To this end, we have characterized the iNKT cell stimulatory properties of NKTT320, a novel, recombinant, humanized, monoclonal antibody that binds selectively and with high affinity to human iTCRs. Strikingly, immobilized NKTT320 mediated robust iNKT cell activation (upregulation of CD25 and CD69) and proliferation (carboxyfluorescein succinimidyl ester (CFSE) dilution), as well as Th1 and Th2 cytokine production. Additionally, iNKTs stimulated by plate-bound NKTT320 exhibited increased intracellular levels of granzyme B and degranulation (exposure of CD107 on the cell surface). Furthermore, both soluble and immobilized NKTT320 induced iNKT cell-mediated activation of bystander immune cells, suggesting that this novel anti-iTCR antibody facilitates both direct and indirect iNKT cell cytotoxicity. These studies are significant, as they provide a framework by which iNKT cell anti-cancer functions could be enhanced for therapeutic purposes. Full article

(This article belongs to the Special Issue Immunotherapy for Cancer)

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Review

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13 pages, 1267 KiB

Open AccessReview

The Immunotherapy for Colorectal Cancer, Lung Cancer and Pancreatic Cancer

by Shiu-Jau Chen, Shao-Cheng Wang and Yuan-Chuan Chen

Int. J. Mol. Sci. 2021, 22(23), 12836; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312836 - 27 Nov 2021

Cited by 20 | Viewed by 4026

Abstract

Immunotherapy is a novel anti-cancer method which employs a different mechanism to conventional treatment. It has become a significant strategy because it provides a better or an alternative option for cancer patients. Recently, immunotherapy has been increasingly approved for the treatment of cancer; however, it has various limitations; for instance, it is only suitable for specific patients, the response rate is still low in most cases, etc. Colorectal cancer, lung cancer and pancreatic cancer are known as three major death-causing cancers in most countries. In this review, we discuss immunotherapeutic treatment for these three cancers, and consider the option, prospects and limitations of immunotherapy. The development of immunotherapy should focus on the discovery of biomarkers to screen suitable patients, new targets on tumors, neoadjuvant immunotherapy and the combination of immunotherapy with conventional therapeutic methods. We can expect that immunotherapy potentially will develop as one of the best therapies for patients with advanced cancer or poor responses to traditional methods. Full article

(This article belongs to the Special Issue Immunotherapy for Cancer)

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20 pages, 1815 KiB

Open AccessReview

Reconstituting Immune Surveillance in Breast Cancer: Molecular Pathophysiology and Current Immunotherapy Strategies

by Chiara Cilibrasi, Panagiotis Papanastasopoulos, Mark Samuels and Georgios Giamas

Int. J. Mol. Sci. 2021, 22(21), 12015; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222112015 - 06 Nov 2021

Cited by 11 | Viewed by 6652

Abstract

Over the past 50 years, breast cancer immunotherapy has emerged as an active field of research, generating novel, targeted treatments for the disease. Immunotherapies carry enormous potential to improve survival in breast cancer, particularly for the subtypes carrying the poorest prognoses. Here, we review the mechanisms by which cancer evades immune destruction as well as the history of breast cancer immunotherapies and recent developments, including clinical trials that have shaped the treatment of the disease with a focus on cell therapies, vaccines, checkpoint inhibitors, and oncolytic viruses. Full article

(This article belongs to the Special Issue Immunotherapy for Cancer)

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25 pages, 1706 KiB

Open AccessReview

The Positive and Negative Immunoregulatory Role of B7 Family: Promising Novel Targets in Gastric Cancer Treatment

by Nadia Bolandi, Afshin Derakhshani, Nima Hemmat, Amir Baghbanzadeh, Zahra Asadzadeh, Mina Afrashteh Nour, Oronzo Brunetti, Renato Bernardini, Nicola Silvestris and Behzad Baradaran

Int. J. Mol. Sci. 2021, 22(19), 10719; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910719 - 03 Oct 2021

Cited by 37 | Viewed by 5647

Abstract

Gastric cancer (GC), with a heterogeneous nature, is the third leading cause of death worldwide. Over the past few decades, stable reductions in the incidence of GC have been observed. However, due to the poor response to common treatments and late diagnosis, this cancer is still considered one of the lethal cancers. Emerging methods such as immunotherapy with immune checkpoint inhibitors (ICIs) have transformed the landscape of treatment for GC patients. There are presently eleven known members of the B7 family as immune checkpoint molecules: B7-1 (CD80), B7-2 (CD86), B7-H1 (PD-L1, CD274), B7-DC (PDCD1LG2, PD-L2, CD273), B7-H2 (B7RP1, ICOS-L, CD275), B7-H3 (CD276), B7-H4 (B7x, B7S1, Vtcn1), B7-H5 (VISTA, Gi24, DD1α, Dies1 SISP1), B7-H6 (NCR3LG1), B7-H7 (HHLA2), and Ig-like domain-containing receptor 2 (ILDR2). Interaction of the B7 family of immune-regulatory ligands with the corresponding receptors resulted in the induction and inhibition of T cell responses by sending co-stimulatory and co-inhibitory signals, respectively. Manipulation of the signals provided by the B7 family has significant potential in the management of GC. Full article

(This article belongs to the Special Issue Immunotherapy for Cancer)

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15 pages, 2287 KiB

Open AccessReview

A Systematic Review and Meta-Analysis on the Significance of TIGIT in Solid Cancers: Dual TIGIT/PD-1 Blockade to Overcome Immune-Resistance in Solid Cancers

by Negar Hosseinkhani, Mahdi Abdoli Shadbad, Mohammad Asghari Jafarabadi, Noora Karim Ahangar, Zahra Asadzadeh, Seyede Momeneh Mohammadi, Parisa Lotfinejad, Nazila Alizadeh, Oronzo Brunetti, Rossella Fasano, Nicola Silvestris and Behzad Baradaran

Int. J. Mol. Sci. 2021, 22(19), 10389; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910389 - 27 Sep 2021

Cited by 14 | Viewed by 2563

Abstract

Preclinical studies have indicated that T-cell immunoglobulin and ITIM domain (TIGIT) can substantially attenuate anti-tumoral immune responses. Although multiple clinical studies have evaluated the significance of TIGIT in patients with solid cancers, their results remain inconclusive. Thus, we conducted the current systematic review and meta-analysis based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) to determine its significance in patients with solid cancers. We systematically searched the Web of Science, Embase, PubMed, and Scopus databases to obtain peer-reviewed studies published before September 20, 2020. Our results have shown that increased TIGIT expression has been significantly associated with inferior overall survival (OS) (HR = 1.42, 95% CI: 1.11–1.82, and p-value = 0.01). Besides, the level of tumor-infiltrating TIGIT⁺CD8⁺ T-cells have been remarkably associated inferior OS and relapse-free survival (RFS) of affected patients (HR = 2.17, 95% CI: 1.43–3.29, and p-value < 0.001, and HR = 1.89, 95% CI: 1.36–2.63, and p-value < 0.001, respectively). Also, there is a strong positive association between TIGIT expression with programmed cell death-1 (PD-1) expression in these patients (OR = 1.71, 95% CI: 1.10–2.68, and p-value = 0.02). In summary, increased TIGIT expression and increased infiltration of TIGIT⁺CD8⁺ T-cells can substantially worsen the prognosis of patients with solid cancers. Besides, concerning the observed strong association between TIGIT and PD-1, ongoing clinical trials, and promising preclinical results, PD-1/TIGIT dual blockade can potentially help overcome the immune-resistance state seen following monotherapy with a single immune checkpoint inhibitor in patients with solid cancers. Full article

(This article belongs to the Special Issue Immunotherapy for Cancer)

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15 pages, 520 KiB

Open AccessReview

Cancer-Associated Glycosphingolipids as Tumor Markers and Targets for Cancer Immunotherapy

by Sophie Groux-Degroote and Philippe Delannoy

Int. J. Mol. Sci. 2021, 22(11), 6145; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116145 - 07 Jun 2021

Cited by 30 | Viewed by 4212

Abstract

Aberrant expression of glycosphingolipids is a hallmark of cancer cells and is associated with their malignant properties. Disialylated gangliosides GD2 and GD3 are considered as markers of neuroectoderm origin in tumors, whereas fucosyl-GM1 is expressed in very few normal tissues but overexpressed in a variety of cancers, especially in small cell lung carcinoma. These gangliosides are absent in most normal adult tissues, making them targets of interest in immuno-oncology. Passive and active immunotherapy strategies have been developed, and have shown promising results in clinical trials. In this review, we summarized the current knowledge on GD2, GD3, and fucosyl-GM1 expression in health and cancer, their biosynthesis pathways in the Golgi apparatus, and their biological roles. We described how their overexpression can affect intracellular signaling pathways, increasing the malignant phenotypes of cancer cells, including their metastatic potential and invasiveness. Finally, the different strategies used to target these tumor-associated gangliosides for immunotherapy were discussed, including the use and development of monoclonal antibodies, vaccines, immune system modulators, and immune effector-cell therapy, with a special focus on adoptive cellular therapy with T cells engineered to express chimeric antigen receptors. Full article

(This article belongs to the Special Issue Immunotherapy for Cancer)

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23 pages, 6454 KiB

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The Regulatory Cross-Talk between microRNAs and Novel Members of the B7 Family in Human Diseases: A Scoping Review

by Noora Karim Ahangar, Nima Hemmat, Mohammad Khalaj-Kondori, Mahdi Abdoli Shadbad, Hani Sabaie, Ahad Mokhtarzadeh, Nazila Alizadeh, Afshin Derakhshani, Amir Baghbanzadeh, Katayoun Dolatkhah, Nicola Silvestris and Behzad Baradaran

Int. J. Mol. Sci. 2021, 22(5), 2652; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052652 - 06 Mar 2021

Cited by 13 | Viewed by 2571

Abstract

The members of the B7 family, as immune checkpoint molecules, can substantially regulate immune responses. Since microRNAs (miRs) can regulate gene expression post-transcriptionally, we conducted a scoping review to summarize and discuss the regulatory cross-talk between miRs and new B7 family immune checkpoint molecules, i.e., B7-H3, B7-H4, B7-H5, butyrophilin like 2 (BTNL2), B7-H6, B7-H7, and immunoglobulin like domain containing receptor 2 (ILDR2). The current study was performed using a six-stage methodology structure and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. PubMed, Embase, Scopus, Cochrane, ProQuest, and Google Scholar were systematically searched to obtain the relevant records to 5 November 2020. Two authors independently reviewed the obtained records and extracted the desired data. After quantitative and qualitative analyses, we used bioinformatics approaches to extend our knowledge about the regulatory cross-talk between miRs and the abovementioned B7 family members. Twenty-seven articles were identified that fulfilled the inclusion criteria. Studies with different designs reported gene–miR regulatory axes in various cancer and non-cancer diseases. The regulatory cross-talk between the aforementioned B7 family molecules and miRs might provide valuable insights into the pathogenesis of various human diseases. Full article

(This article belongs to the Special Issue Immunotherapy for Cancer)

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25 pages, 3794 KiB

Open AccessReview

Engineering Next-Generation CAR-T Cells for Better Toxicity Management

by Alain E. Andrea, Andrada Chiron, Stéphanie Bessoles and Salima Hacein-Bey-Abina

Int. J. Mol. Sci. 2020, 21(22), 8620; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228620 - 16 Nov 2020

Cited by 38 | Viewed by 7026

Abstract

Immunoadoptive therapy with genetically modified T lymphocytes expressing chimeric antigen receptors (CARs) has revolutionized the treatment of patients with hematologic cancers. Although clinical outcomes in B-cell malignancies are impressive, researchers are seeking to enhance the activity, persistence, and also safety of CAR-T cell therapy—notably with a view to mitigating potentially serious or even life-threatening adverse events like on-target/off-tumor toxicity and (in particular) cytokine release syndrome. A variety of safety strategies have been developed by replacing or adding various components (such as OFF- and ON-switch CARs) or by combining multi-antigen-targeting OR-, AND- and NOT-gate CAR-T cells. This research has laid the foundations for a whole new generation of therapeutic CAR-T cells. Here, we review the most promising CAR-T cell safety strategies and the corresponding preclinical and clinical studies. Full article

(This article belongs to the Special Issue Immunotherapy for Cancer)

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26 pages, 5050 KiB

Open AccessReview

Immune Checkpoints and CAR-T Cells: The Pioneers in Future Cancer Therapies?

by Negar Hosseinkhani, Afshin Derakhshani, Omid Kooshkaki, Mahdi Abdoli Shadbad, Khalil Hajiasgharzadeh, Amir Baghbanzadeh, Hossein Safarpour, Ahad Mokhtarzadeh, Oronzo Brunetti, Simon C. Yue, Nicola Silvestris and Behzad Baradaran

Int. J. Mol. Sci. 2020, 21(21), 8305; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218305 - 05 Nov 2020

Cited by 58 | Viewed by 4937

Abstract

Although the ever-increasing number of cancer patients pose substantial challenges worldwide, finding a treatment with the highest response rate and the lowest number of side effects is still undergoing research. Compared to chemotherapy, the relatively low side effects of cancer immunotherapy have provided ample opportunity for immunotherapy to become a promising approach for patients with malignancy. However, the clinical translation of immune-based therapies requires robust anti-tumoral immune responses. Immune checkpoints have substantial roles in the induction of an immunosuppressive tumor microenvironment and tolerance against tumor antigens. Identifying and targeting these inhibitory axes, which can be established between tumor cells and tumor-infiltrating lymphocytes, can facilitate the development of anti-tumoral immune responses. Bispecific T-cell engagers, which can attract lymphocytes to the tumor microenvironment, have also paved the road for immunological-based tumor elimination. The development of CAR-T cells and their gene editing have brought ample opportunity to recognize tumor antigens, independent from immune checkpoints and the major histocompatibility complex (MHC). Indeed, there have been remarkable advances in developing various CAR-T cells to target tumoral cells. Knockout of immune checkpoints via gene editing in CAR-T cells might be designated for a breakthrough for patients with malignancy. In the midst of this fast progress in cancer immunotherapies, there is a need to provide up-to-date information regarding immune checkpoints, bispecific T-cell engagers, and CAR-T cells. Therefore, this review aims to provide recent findings of immune checkpoints, bispecific T-cell engagers, and CAR-T cells in cancer immunotherapy and discuss the pertained clinical trials. Full article

(This article belongs to the Special Issue Immunotherapy for Cancer)

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27 pages, 1098 KiB

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

by Omid Kooshkaki, Afshin Derakhshani, Negar Hosseinkhani, Mitra Torabi, Sahar Safaei, Oronzo Brunetti, Vito Racanelli, Nicola Silvestris and Behzad Baradaran

Int. J. Mol. Sci. 2020, 21(12), 4427; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124427 - 22 Jun 2020

Cited by 67 | Viewed by 6870

Abstract

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

(This article belongs to the Special Issue Immunotherapy for Cancer)

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