Immune checkpoint inhibitors and Chimeric Antigen Receptor (CAR)-T cell therapy: Potential treatment options against Testicular Germ Cell Tumors

Abstract

Germ cell tumors (GCTs) represent a heterogeneous neoplasm family affecting gonads and rarely occurring in extragonadal areas. Most of patients have a good prognosis, often even in the presence of metastatic disease; however, in almost 15% of cases, tumor relapse and platinum resistance are the main challenges. Thus, novel treatment strategies with both improved antineoplastic activity and minor treatment-related adverse events compared with platinum are really expected. In this context, the development and the high activity demonstrated by immune checkpoint inhibitors in solid tumors and, subsequently, the interesting results obtained from the use of chimeric antigen receptor (CAR-) T cell therapy in hematological tumors, have stimulated research in this direction also in GCTs. In this article, we will analyze the molecular mechanisms underlying the immune action in the development of GCTs, and we will report the data from the studies that tested the new immunotherapeutic approaches in these neoplasms.

Recent Advancements in Research on DNA Methylation and Testicular Germ Cell Tumors: Unveiling the Intricate Relationship

“…While some of the mentioned genes have been associated with response to immunotherapy, the current understanding of immune system activation in TGCT is limited. The most common type of immunotherapy involves the use of immune checkpoint inhibitors, which so far has led to disappointing results in this cancer type [83][84][85][86][87]. CAR-T cell therapy, however, has shown more promising results recently in a small cohort of patients and could provide a new avenue of treatment in patients whose only option so far is chemotherapy [88].…”

“…CAR-T cell therapy, however, has shown more promising results recently in a small cohort of patients and could provide a new avenue of treatment in patients whose only option so far is chemotherapy [88]. Future insights into immunological mechanisms and the involvement of methylation in their regulation may lead to general use of immunotherapy as well as targeted biomarkers [87].…”

Biomarkers for Salvage Therapy in Testicular Germ Cell Tumors

“…CAR-T cell therapy consists of genetically engineered T cells expressing antigen-specific receptors on their cell membranes. This structure is composed of four regions: an antigen-binding domain; a hinge region, which connects scFV with the transmembrane region; and an intracellular extremity, which comprises the signal transduction part of the TCR linked with one or two costimulatory domains [85]. The advantages of CAR-T cell therapy are as follows: (1) the immune mechanism of action is not MHC restricted [86], and (2) its low antigen affinity in TCRs can induce off-target toxicities [87].…”

Breaking the Mold: Epigenetics and Genomics Approaches Addressing Novel Treatments and Chemoresponse in TGCT Patients

“…Recently, CAR T-cell therapy was studied as a unique approach for neoplasms that do not react to immune checkpoint inhibitors and for those that are less immunogenic, with promising results in 13 TGCT patients. However, more research and a deeper understanding of the immune system's activation processes is needed to validate its function as an immune checkpoint inhibitor therapy for TGCTs [41,43,160]. Epidrugs, combined with im-munotherapies and cisplatin, could enhance tumor death, even for cisplatin resistant TGCTs.…”

“…Further genetic, histological, and immunohistochemical research is required to demonstrate predictive variables controlling immunotherapy response. New trial designs should combine these novel drugs with the conventional standard of care in order to target benefits in early lines of treatment and assess their value in tackling this neoplasia [43,[160][161][162].…”