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Immunomodulatory Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
It is worth noting that some investigators have pursued a combination approach in an attempt to increase the ORR associated with metastatic melanoma. Multiple clinical trials have studied the efficacy of a combination of TIL therapies with checkpoint inhibiting antibodies such as PD-1 and CTLA-4 inhibitors, on the grounds that PD-1 has been shown to be highly expressed on TAA-reactive TILs. At the time of writing, an early clinical trial sponsored by Bristol-Myers Squibb and Iovance Biotherapeutics is underway using nivolumab (an anti-PD-1 antibody) and urelumab (an anti-4-1BB/CD137 antibody) in combination with TIL therapy in melanoma patients.
Immunotherapy
Published in Prakash Srinivasan Timiri Shanmugam, Understanding Cancer Therapies, 2018
Sowmiya Renjith, Sathya Chandran
Another group of receptors with a manipulating effect on immune cells includes other checkpoint receptors such as LAG-3 or the killer-cell immunoglobulin-like receptors (KIRs) (Campbell and Purdy 2011). They regulate immune response by interaction with MHC I molecules. Most of the receptors inhibit cytotoxicity, mostly by turning off NK cells when HLA is exhibited on tumor cells. Current ongoing trials are testing an anti-KIR moAb in conjugation with ipilimumab (NCT01750580) or nivolumab (NCT01714739). Anti-PD1 monoclonal antibodies were also being examined in various novel combinations in a phase I setting, such as nivolumab plus agonistic anti-CD137 moAbs (urelumab, NCT02253992), nivolumab plus anti-LAG-3 (NCT01968109), and cetuximab plus urelumab.
Current and emerging systemic therapies for cutaneous metastatic melanoma
Published in Expert Opinion on Pharmacotherapy, 2019
Robert Mason, Lewis Au, Alvaro Ingles Garces, James Larkin
4-1BB (CD 137) is a stimulatory coreceptor not only expressed on T, NK, and dendritic cells but in a wide variety of other cell types. Similar to OX40 and GITR, binding of the 4-1BB receptor and its corresponding ligand causes proliferation and survival of effector phenotype T cells and cytokine release [75]. Phase 1 trials of Urelumab (a fully humanized anti-4-1BB monoclonal antibody) highlighted a safety signal with transaminitis developing at higher doses [76]. A phase 1/2 study of urelumab with nivolumab which included patients with melanoma has demonstrated efficacy for the combination. The RR was 50% (irrespective of PDL-1 expression) for melanoma patients. There was a 17% rate of > grade 3 AEs. Further trials are underway in melanoma.
Daratumumab in combination with urelumab to potentiate anti-myeloma activity in lymphocyte-deficient mice reconstituted with human NK cells
Published in OncoImmunology, 2019
Maria C. Ochoa, Elisabeth Perez-Ruiz, Luna Minute, Carmen Oñate, Guiomar Perez, Inmaculada Rodriguez, Aintzane Zabaleta, Diego Alignani, Myriam Fernandez-Sendin, Ascension Lopez, Aura Muntasell, Miguel F. Sanmamed, Bruno Paiva, Miguel Lopez-Botet, Pedro Berraondo, Ignacio Melero
CD38 is a transmembrane protein expressed on all malignant plasma cells in multiple myeloma.1 The anti-CD38 IgG1 human monoclonal antibody daratumumab is used in combination with other drugs in relapsed or refractory multiple myeloma patients2 and has been recently approved in combination with bortezomib, melphalan, and prednisone for newly diagnosed multiple myeloma.3 Its clinical activity is contingent on antibody dependent-cellular cytotoxicity (ADCC) as mediated by NK cells and macrophages4,5 and probably the additional poorly understood effects of CD38 ligation on immune system cells and on myeloma cells themselves.6 Complement-mediated cytotoxicity and reductions of myeloid-derived suppressor cells in the myeloma microenvironment have also been observed.4,7 CD137 (4-1BB) is a TNFR family surface glycoprotein expressed on activated T and NK cells.8 Agonist monoclonal antibodies directed to CD137, such as urelumab, enhance T-cell mediated antitumor immunity9 and have been shown to enhance anti-tumor ADCC as mediated by rituximab,10 cetuximab,11 and trastuzumab.12 The mechanism proposed is that CD16 (FcRɣIIIa) ligation by a cell surface-bound IgG1 Fc leads to the induction of CD137 on the surface of NK cells. Once on the NK surface, if CD137 is stimulated by a CD137 agonist antibody, it enhances the survival and cytotoxic performance of NK cells in terms of more efficient ADCC.10–12 These preclinical studies support the combined use of daratumumab with urelumab in multiple myeloma including evidence in NK-humanized mice.
Emerging PD-1/PD-L1 antagonists for the treatment of malignant melanoma
Published in Expert Opinion on Emerging Drugs, 2021
Vito Vanella, Lucia Festino, Maria Grazia Vitale, Benedetta Alfano, Paolo Antonio Ascierto
CD137 is a costimulatory membrane receptor, expressed by cytotoxic T-cells, and a member of the tumor necrosis factor (TNF) receptor family [80]. Urelumab is a fully human immunoglobulin G4 monoclonal antibody determining its activation. Urelumab and nivolumab enhance immune-cell activity through two different mechanisms, so their activity may be synergistic. A combination study evaluated urelumab plus nivolumab in 128 patients with different kinds of tumors, including melanoma. Fatigue was the most frequent adverse event reported. Adverse events led to treatment discontinuation in 10% of patients. Among 46 patients with melanoma who were anti PD-1/PD-L1 naïve, ORR was 50% and DCR was 70%. PD-L1 status had no impact on ORR.