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Immunotherapy
Published in Prakash Srinivasan Timiri Shanmugam, Understanding Cancer Therapies, 2018
Sowmiya Renjith, Sathya Chandran
It is now evident that tumors co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumor antigens. Because many of the immune checkpoints are triggered by ligand-receptor interactions, they can be actively blocked by antibodies or manipulated by recombinant forms of ligands or receptors. Ipilimumab, a mAb against CTLA-4 that has acquired FDA approval for metastatic melanoma, is presently being evaluated in clinical trials along with cetuximab and intensity-modulated radiation therapy (IMRT) in individuals with advanced HNSCC (NCT01860430 and NCT01935921). A phase 1, open-label, dose escalation study of MGA271 (enoblituzumab, a humanized mAb against CD276 [B7-H3] in combination with ipilimumab in patients with B7-H3–expressing HNSCC and other solid tumors) is also proceeding (NCT02381314). Tremelimumab is another anti-CTLA4 antibody presently being assessed in clinical trials.
B7-H3-targeted CAR-T cell therapy for solid tumors
Published in International Reviews of Immunology, 2022
Guangfei Li, Haopeng Wang, Haitao Wu, Jian Chen
As another Fc-optimized and humanized antibody targeting B7-H3, MGA271 could mediate potent antibody-dependent cell-mediated cytotoxicity (ADCC) against various solid tumor cell lines, and significantly inhibit B7-H3-expressing renal and bladder cancer cell growth in xenograft models [32]. Furthermore, MGA271 (Enoblituzumab) has been extensively studied in a number of clinical trials for melanoma, non-small-cell lung cancer (NCT02381314), neuroblastoma, rhabdomyosarcoma, osteosarcoma (NCT02982941), prostate cancer (NCT02923180), and head and neck cancer (NCT02475213, NCT04129320, NCT04634825). Moreover, the B7-H3 antibody could also serve as a tool for targeted drug delivery which has been proved to be effective against a panel of pediatric solid malignancies in both cell line-derived xenograft (CDX) and patient-derived (PDX) models [33]. Blocking monoantibodies targeting B7-H3 exert effector functions by neutralizing the inhibitory ligand B7-H3 to receptor interactions partially or completely [21]. However, patients have to accept frequent administrations of drugs due to the short half-life of antibodies [34]. The efficacy of Enoblituzumab and Pembrolizumab in treating advanced solid tumors was unsatisfactory, whereas treatment-related adverse events were observed in most patients [35]. Therefore, B7-H3 antibody-based therapies are prone to noticeable side effects and frequent recurrence due to the lack of immunological memory. Novel immunotherapy with durable efficacy needs urgently developed.
B7-H3 targeted antibody-based immunotherapy of malignant diseases
Published in Expert Opinion on Biological Therapy, 2021
Theodoros Michelakos, Filippos Kontos, Omar Barakat, Luke Maggs, Joseph H. Schwab, Cristina R. Ferrone, Soldano Ferrone
Another B7-H3-targeting immunotherapeutic strategy is represented by Fc-enhanced mAbs. In that therapeutic category, enoblituzumab (MGA271, MacroGenics), a fully humanized mAb bearing an Fc domain engineered to enhance its anti-tumor function by increasing its binding to the activating receptor CD16A and reducing that to the inhibitory receptor CD32B [141], was found in two Phase I trials (NCT01391143, NCT02475213) to be well-tolerated and safe [72, 142]. Results from a Phase I trial evaluating enoblituzumab combined with ipilimumab in non-small cell lung cancer and melanoma (NCT02381314), as well as from a Phase II trial assessing neoadjuvant enoblituzumab in prostate cancer (NCT02923180) are pending.
Checkpoint inhibitors in NSCLC for the elderly: current challenges and perspectives
Published in Expert Review of Anticancer Therapy, 2021
Teodora Alexa, Sabina A Antoniu, Ioana Alexa, Adina Ilie, Mihai Marinca, Bogdan Gafton, Ramona Stefaniu
The research in the area of checkpoint inhibitors did not stop despite the discovery and authorization on the market of valuable compounds such as those discussed in this review. New checkpoint molecules were identified over the last decade and these are represented lymphocyte activation gene 3 (LAG3), T-cell immunoglobulin 3 (TIM3) or B7-H3, the latter being found to be particularly relevant in NSCLC [29,30] . Enoblituzumab is a monoclonal anti B7-H3 antibody which recently demonstrated clinical efficacy in combination with Pembrolizumab in a phase I study in patients with NSCLC [31] .