Adverse Reactions of Antibody-Therapy for Primary Cutaneous Lymphomas: Rituximab, Brentuximab Vedotin, Alemtuzumab, and Mogamulizumab

Abstract

Treatment of advanced PCLs is limited and rarely reaches complete remission despite aggressive treatment modalities, such as polychemotherapy with various adverse effects. However, several monoclonal antibodies drug agents in patients with advanced primary cutaneous lymphomas demonstrate promising efficacy and manageable safety profiles. The monoclonal antibodies drug agents have favourable tolerability compared with multi-agent cytotoxic chemotherapy. However, adverse effects manifest with a broad clinical spectrum, hence the markers of targeted therapies are not limited to tumour cells but found on tumour cells and also on benign T and/or B cells. Moreover, the safety profile and direct causal association of drug and adverse effects should be interpreted with caution because many of the patients in clinical studies have received multiple treatments. Here, we focus on the safety profile of mAbs therapies that have recently been approved or are currently under preclinical or clinical investigation for CBCLs (rituximab) and CTCLs (brentuximab, mogamulizumab, and alemtuzumab). Further studies to define clinical safety profile in the patient cohort with cutaneous lymphomas are needed.

Blockade of programmed cell death protein 1 (PD-1) in Sézary syndrome reduces Th2 phenotype of non-tumoral T lymphocytes but may enhance tumor proliferation

“…55 It is not yet sufficiently elucidated if in the setting of a tumor arising in T cells themselves, PD-1 blockade strengthens more antitumor T cell immunity or rather facilitates tumor progression. 50,[56][57][58][59][60] We evaluated the impact of PD-1 blockade (nivolumab 10 µg/mL) on T cell proliferation by measuring non-radioactive 5-bromo-2ʹ-deoxyuridine (BrdU) incorporation. PD-1 blockade resulted in enhanced proliferation of T cells upon stimulation; however, we observed the strongest enhancement of proliferation within the fraction of the clonal tumor T cell as compared to their benign non-clonal counterparts ( Figure 6).…”

Novel Piperidinyl-Azetidines as Potent and Selective CCR4 Antagonists Elicit Antitumor Response as a Single Agent and in Combination with Checkpoint Inhibitors

“…In August of 2018, the FDA approved mogamulizumab to treat two types of CTCL, Sézary disease and mycosis fungoides . However, systemic depletion of CCR4 containing cells in healthy tissues appears to lead to serious skin-related side effects, , including cases of Stevens–Johnson Syndrome (SJS). This is presumably due to depletion of T reg in the skin, leading to drastic changes in the ratio of T effector cells to T reg and thus triggering an autoimmune response.…”

Discovery of a Potent and Selective CCR4 Antagonist That Inhibits Treg Trafficking into the Tumor Microenvironment

“…While targeting CCR4 via an antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism has shown clinical efficacy, the mechanism of action is much different compared to targeting CCR4 with a small molecule antagonist. Depletion of T reg that serve other essential functions could cause a severe autoimmune reaction leading to further complications. , However, simply inhibiting T reg trafficking into the TME via a small molecule antagonist may lead to tumor killing without affecting other vital immune cell functions.…”

“…Depletion of T reg that serve other essential functions could cause a severe autoimmune reaction leading to further complications. 32,33 However, simply inhibiting T reg trafficking into the TME via a small molecule antagonist may lead to tumor killing without affecting other vital immune cell functions.…”