New targeted treatments for cutaneous T-cell Lymphomas

Abstract

Cutaneous T-cell lymphomas (CTCLs) represent a group of rare and heterogeneous diseases that are very difficult to treat at advanced stages. The development of monoclonal antibodies is a new hope for the treatment of these diseases. Alemtuzumab (Campath) is a humanized IgG1 kappa monoclonal antibody specific for CD52, an antigen expressed by most T and B lymphocytes. Alemtuzumab may frequently induce long-term remissions in patients with Sezary syndrome but high-dose treatments lead to severe cytopenia, immune depletion, and opportunistic infections. This treatment is less efficient in mycosis fungoides (MF). Brentuximab vedotin is a chimeric anti-CD30 monoclonal antibody conjugated to monomethyl auristatin E, a cytotoxic antitubulin agent. Brentuximab vedotin is a very interesting new treatment for advanced tumor MF, Sezary syndrome, and primary cutaneous CD30+ lymphoproliferative disorders. The main limiting adverse event is neurosensitive peripheral neuropathy. Mogamulizumab is a humanized anti-C-C chemokine receptor Type 4 monoclonal antibody with a defucosylated Fc region leading to increased antibody-dependent cellular cytotoxicity. Mogamulizumab is very efficient on aggressive peripheral T-cell lymphomas, particularly adult T-cell leukemia/lymphoma and CTCLs, especially on the blood component of tumor cells. The main limiting events are related to the concomitant depletion of regulatory T-cells. IPH4102 is a humanized monoclonal antibody that targets the immune receptor KIR3DL2/CD158k. Preclinical results with this antibody offer proofs of concept for the clinical development of IPH4102 to treat patients with advanced CTCL.

An Update on Molecular Biology of Cutaneous T Cell Lymphoma

“…CD158k/KIR3DL2 has emerged as a therapeutic target with phase 1 clinical trials currently underway (52). CD158k/KIR3DL2 is highly expressed in SS and advanced MF confers resistance to activation induced cell death in SS and has been found efficacious in reducing tumor size and improved survival in vivo and in vitro (59,60).…”

New Therapies and Immunological Findings in Cutaneous T-Cell Lymphoma

“…Mogamulizumab, a defucosylated humanized anti-CCR4 antibody that was first approved for relapsed ATL, as described in further detail in Section “ Adult T-cell leukemia/lymphoma ,” is also effective for CTCL including MF/SS ( 132 , 133 ), and approved for relapsed or refractory CCR4-positive CTCL. In addition, an anti-CD158k monoclonal antibody, IPH4102, has also recently been developed ( 134 ), for which clinical studies in CTCL are ongoing ( 135 ). Lenalidomide ( 136 ), bortezomib ( 137 ), and immune checkpoint blockade are also under investigation.…”

Synchronous Occurrence of Mycosis Fungoides, Diffuse Large B Cell Lymphoma and Acute Myeloid Leukemia

“…These therapies have the potential to generate an intense immune response, resulting in a chronic inflammatory systemic response. In addition, they induce direct or indirect DNA damage, which also contributes to the increased risk of malignant transformation ( 14 , 15 ). Furthermore, reduced levels of vitamin D or possessing a risk allele of the vitamin D receptor gene have been reported to contribute to the pathogenesis of MF and to increase the risk of secondary malignancies ( 16 ).…”