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Non-Hodgkin Lymphoma
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
The enhanced understanding of the genetic events and immune microenvironment has facilitated a greater application of targeted and immunological therapies for patients with relapsed and rituximab refractory FL. In such patients, earlier studies with the BTK inhibitor, ibrutinib, resulted in a modest efficacy, possibly due to the presence of coexisting mutations, such as CARD11, which are now considered to confer resistance to ibrutinib. Several novel anti-CD20 monoclonal antibodies, such as veltuzumab, as monotherapy and in combination with the anti-CD74, milatuzumab and ocrartuzumab (AME-133) are ongoing. There appears to be greater promise for epigentically targeted therapies (such as tazemetostat, an EZH2 inhibitor) and vorinostat (a histone deactylase inhibitor). Studies are also testing the inclusion of immune checkpoint inhibitors and CAR T-cell specific for CD19, a differentiation antigen expressed in B-cells and B lineage malignancies. The next generation of novel antibody-based therapies, such as bispecific antibodies, which combine the specificity of two antibodies, so they can bind to different antigens. Bispecific T-cell engager (BiTE) binds CD3 on T-cells and an antigen on tumour cells to activate T-cells to kill the cancer cells. The first-in-class BiTE antibody, blinatumomab, which specifically targets CD19 on B-cells, was approved in 2014 for clinical use in patients with relapsed or refractory ALL and is now being tested in FL, and preliminary results when the drug is administered at very low doses are encouraging.
MIF inhibition as a strategy for overcoming resistance to immune checkpoint blockade therapy in melanoma
Published in OncoImmunology, 2020
Ricardo A. de Azevedo, Einav Shoshan, Shanzhi Whang, Gal Markel, Ashvin R. Jaiswal, Arthur Liu, Michael A. Curran, Luiz R. Travassos, Menashe Bar-Eli
Pharmacologic blockade of MIF/CD74 interaction restores the TME immunogenic profile, as well as the effective anti-tumor immune response against metastatic melanoma and glioblastoma.5,51 The CD74 monoclonal blocking antibody milatuzumab is currently approved by the Food and Drug Administration (FDA) in the United States for the treatment of multiple myeloma, non-Hodgkin lymphomas, and other CD74 positive cancers.52,53 Also imalumab (Bax69), a novel recombinant monoclonal antibody that targets oxMIF, has been evaluated in a phase 1 clinical study in patients with advanced solid tumors.54 Our current study combining immune-checkpoint blockade with MIF/CD74 axis inhibition to restore the immunogenic phenotype and to overcome immune resistance is, however, the first to be reported.
Macrophage migration inhibitory factor (MIF) as a therapeutic target for rheumatoid arthritis and systemic lupus erythematosus
Published in Expert Opinion on Therapeutic Targets, 2019
Joshua B. Bilsborrow, Edward Doherty, Pathricia V. Tilstam, Richard Bucala
The anti-CD74 monoclonal antibody milatuzumab is a humanized form of the mouse anti-CD74 LL1 [122]. Milatuzumab was evaluated in a 24-week phase 1b clinical trial for the treatment of SLE (NCT01845740), with patients demonstrating improvement per the British Isles Lupus Assessment Group (BILAG) index and SLE Disease Activity Index (SLEDAI) scoring systems, and only mild-moderate adverse effects [123]. Further safety and efficacy trials have been pursued in patients with graft-versus-host disease (NCT01663766), multiple myeloma (NCT01101594 and NCT00421525), chronic lymphocytic leukemia (NCT00603668 and NCT00868478), and B-cell non-Hodgkin lymphoma (NCT00989586). With these early phase clinical trials having been completed and milatuzumab reportedly having been well-tolerated by patients, further development has nonetheless not been continued [124]. Early outcomes of the combination therapy of milatuzumab with the anti-CD20 monoclonal antibody rituximab were also promising for the treatment of mantle cell lymphoma [125]. Milatuzumab has been granted orphan designation by the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) for multiple myeloma and chronic lymphocytic leukemia [126–128].
Antibody-drug conjugates for multiple myeloma
Published in Expert Opinion on Biological Therapy, 2021
Annabel McMillan, Dana Warcel, Rakesh Popat
Hll1-Dox is a humanized CD74 monoclonal antibody conjugated to doxorubicin which demonstrated cytotoxicity in MM cell lines [74]. Milatuzumab doxorubin was investigated in a phase 1 trial as monotherapy (NCT01101594) and terminated due to lack of efficacy.