ABSTRACT
The interaction of immune checkpoint molecules in the tumor microenvironment reduces the anti-tumor immune response by suppressing the recognition of T cells to tumor cells. Immune checkpoint inhibitor (ICI) therapy is emerging as a promising therapeutic option for cancer treatment. However, modulating the immune system with ICIs still faces obstacles with severe immunogenic side effects and a lack of response against many cancer types. Plant-derived natural compounds offer regulation on various signaling cascades and have been applied for the treatment of multiple diseases, including cancer. Accumulated evidence provides the possibility of efficacy of phytochemicals in combinational with other therapeutic agents of ICIs, effectively modulating immune checkpoint-related signaling molecules. Recently, several phytochemicals have been reported to show the modulatory effects of immune checkpoints in various cancers in in vivo or in vitro models. This review summarizes druggable immune checkpoints and their regulatory factors. In addition, phytochemicals that are capable of suppressing PD-1/PD-L1 binding, the best-studied target of ICI therapy, were comprehensively summarized and classified according to chemical structure subgroups. It may help extend further research on phytochemicals as candidates of combinational adjuvants. Future clinical trials may validate the synergetic effects of preclinically investigated phytochemicals with ICI therapy.
Subject(s)
Immune Checkpoint Inhibitors/metabolism , Neoplasms/drug therapy , Neoplasms/immunology , Phytochemicals/chemistry , Programmed Cell Death 1 Receptor/metabolism , Animals , Antigens, CD/metabolism , Antineoplastic Agents/pharmacology , B7 Antigens/metabolism , B7-H1 Antigen/metabolism , CTLA-4 Antigen/metabolism , Camptothecin/chemistry , Diterpenes/chemistry , Epoxy Compounds/chemistry , Flavonoids/chemistry , Hepatitis A Virus Cellular Receptor 2/metabolism , Humans , Immunotherapy , Isothiocyanates/chemistry , Mice , Phenanthrenes/chemistry , Phytochemicals/pharmacology , Plant Extracts/pharmacology , Receptors, Immunologic/metabolism , Saponins/chemistry , Sulfoxides/chemistry , Terpenes/chemistry , Tumor Microenvironment/drug effects , Lymphocyte Activation Gene 3 ProteinABSTRACT
B7-H3, also referred to as CD276, is a member of the B7 family of immune regulatory proteins. B7-H3 is overexpressed on many solid cancers, including prostate cancer, renal cell carcinoma, melanoma, squamous cell carcinoma of the head and neck, non-small cell lung cancer, and breast cancer. Overexpression of B7-H3 is associated with disease severity, risk of recurrence and reduced survival. In this article, we report the preclinical development of MGC018, an antibody-drug conjugate targeted against B7-H3. MGC018 is comprised of the cleavable linker-duocarmycin payload, valine-citrulline-seco duocarmycin hydroxybenzamide azaindole (vc-seco-DUBA), conjugated to an anti-B7-H3 humanized IgG1/kappa mAb through reduced interchain disulfides, with an average drug-to-antibody ratio of approximately 2.7. MGC018 exhibited cytotoxicity toward B7-H3-positive human tumor cell lines, and exhibited bystander killing of target-negative tumor cells when cocultured with B7-H3-positive tumor cells. MGC018 displayed potent antitumor activity in preclinical tumor models of breast, ovarian, and lung cancer, as well as melanoma. In addition, antitumor activity was observed toward patient-derived xenograft models of breast, prostate, and head and neck cancer displaying heterogeneous expression of B7-H3. Importantly, MGC018 exhibited a favorable pharmacokinetic and safety profile in cynomolgus monkeys following repeat-dose administration. The antitumor activity observed preclinically with MGC018, together with the positive safety profile, provides evidence of a potentially favorable therapeutic index and supports the continued development of MGC018 for the treatment of solid cancers. GRAPHICAL ABSTRACT: http://mct.aacrjournals.org/content/molcanther/19/11/2235/F1.large.jpg.
Subject(s)
B7 Antigens/antagonists & inhibitors , Drug Evaluation, Preclinical , Immune Checkpoint Inhibitors/pharmacology , Immunoconjugates/pharmacology , Neoplasms/drug therapy , Animals , B7 Antigens/genetics , B7 Antigens/metabolism , Bystander Effect , Cell Line, Tumor , Cell Survival/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Monitoring , Gene Knockdown Techniques , Humans , Immune Checkpoint Inhibitors/chemistry , Immune Checkpoint Inhibitors/isolation & purification , Immunoconjugates/chemistry , Immunoconjugates/isolation & purification , Mice , Neoplasms/metabolism , Neoplasms/pathology , Treatment Outcome , Xenograft Model Antitumor AssaysABSTRACT
Rationale: Current traditional treatment options are frequently ineffective to fight against ovarian cancer due to late diagnosis and high recurrence. Therefore, there is a vital need for the development of novel therapeutic agents. B7H3, an immune checkpoint protein, is highly expressed in various cancers, representing it a promising target for cancer immunotherapy. Although targeting B7H3 by bispecific T cell-engaging antibodies (BiTE) has achieved successes in hematological malignancies during recent years, attempts to use them for the treatment of solid cancers are less favorable, in part due to the heterogeneity of tumors. Sorafenib is an unselective inhibitor of multiple kinases currently being tested in clinical trials for several tumors, including ovarian cancer which showed limited activity and inevitable side effect for ovarian cancer treatment. However, it is able to enhance antitumor immune response, which indicates sorafenib may improve the efficiency of immunotherapy. Methods: We evaluated the expression of B7H3 in ovarian cancer using online database and validated its expression of tumor tissues by immunohistochemistry staining. Then, B7H3 expression and the effects of sorafenib on ovarian cancer cell lines were determined by flow cytometry. In addition, 2D and 3D ovarian cancer models were established to test the combined therapeutic effect in vitro. Finally, the efficiency of B7H3×CD3 BiTE alone and its combination with sorafenib were evaluated both in vitro and in vivo. Results: Our data showed that B7H3 was highly expressed in ovarian cancer compared with normal samples. Treatment with sorafenib inhibited ovarian cancer cell proliferation and induced a noticeable upregulation of B7H3 expression level. Further study suggested that B7H3×CD3 BiTE was effective in mediating T cell killing to cancer cells. Combined treatment of sorafenib and B7H3×CD3 BiTE had synergistic anti-tumor effects in ovarian cancer models. Conclusions: Overall, our study indicates that combination therapy with sorafenib and B7H3×CD3 BiTE may be a new therapeutic option for the further study of preclinical treatment of OC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , B7 Antigens/antagonists & inhibitors , Carcinoma, Ovarian Epithelial/therapy , Ovarian Neoplasms/therapy , Sorafenib/pharmacology , Animals , Antibodies, Bispecific/pharmacology , Antibodies, Bispecific/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , B7 Antigens/analysis , B7 Antigens/metabolism , CD3 Complex/antagonists & inhibitors , Carcinoma, Ovarian Epithelial/immunology , Carcinoma, Ovarian Epithelial/mortality , Carcinoma, Ovarian Epithelial/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Datasets as Topic , Drug Synergism , Female , HEK293 Cells , Humans , Kaplan-Meier Estimate , Lymphocytes, Tumor-Infiltrating/drug effects , Lymphocytes, Tumor-Infiltrating/immunology , Mice , Neoplasm Recurrence, Local , Ovarian Neoplasms/immunology , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , Ovary/pathology , Sorafenib/therapeutic use , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Xenograft Model Antitumor AssaysABSTRACT
INTRODUCTION: The B7/CD28/CTLA4 signaling cascade is the most thoroughly studied costimulatory pathway and blockade with CTLA4Ig (abatacept) or its derivative belatacept has emerged as a valuable option for pharmacologic immune modulation. Several clinical studies have ultimately led to the approval of belatacept for immunosuppression in kidney transplant recipients. Areas covered: This review will discuss the immunological background of costimulation blockade and recent preclinical data and clinical results of CTLA4Ig/belatacept. Expert commentary: The development of belatacept is a major advance in clinical transplantation. However, in spite of promising results in preclinical and clinical trials, clinical use remains limited at present, in part due to increased rates of acute rejection. Recent efforts showing encouraging progress in refining such protocols might be a step toward harnessing the full potential of costimulation blockade-based immunosuppression.
Subject(s)
Abatacept/therapeutic use , Graft Rejection/drug therapy , Kidney Transplantation , Animals , B7 Antigens/metabolism , CD28 Antigens/metabolism , CTLA-4 Antigen/metabolism , Clinical Trials as Topic , Drug Evaluation, Preclinical , Humans , Immunosuppression Therapy , Signal TransductionABSTRACT
AIMS: This study was aimed to explore the interaction between environment and CD28/B7 pathway to provide the potential epidemiology for prevention and treatment of recurrent spontaneous abortion (RSA). METHODS: The retrospective study included 630 RSA cases and 1320 healthy women during their middle and late prenatal care. Their living environment was investigated, and the influence of environmental factors on pregnancy abortion was analyzed. The genomic DNAs were extracted from the study subjects, and the polymorphisms of CD28 and B7 were analyzed. Finally, the interaction of gene and environment on RSA was analyzed with the logistic regression analyses. RESULTS: The multi-variate regression analysis indicated that vitamin supplement, intake of fresh fruits or vegetables, night shift, staying up late, history miscarriage, as well as history induced abortion were, independently, risk factors for RSA (all P< 0.05). Moreover, rs3116496 (T>C), rs3181098 (G>A) and rs3181100 (G>C) of CD28, rs1915087 (C>T) of B7-2, as well as rs6804441 (A>G) and rs41271391 (G>T) of B7-1 were correlated with modified RSA risk (all P< 0.05). The haplotypes TGT and TAG could also regulate the risk of RSA (both P< 0.05). The synthetic influences of the aforementioned SNPs and environmental factors could also significantly affect the susceptibility to RSA (all P< 0.05). CONCLUSION: The interaction of environment and SNPs of CD28/B7 pathway on RSA risk was distinct from CD28/B7 pathway or environment alone.