Immune Checkpoint Inhibitors in Peripheral T-Cell Lymphoma

Abstract

Peripheral T-cell lymphomas (PTCLs) are highly heterogeneous and present significant treatment challenges. Immune checkpoint therapies, such as PD-1 and CTLA-4 inhibitors, have significantly changed the clinical management paradigm of tumors. The roles of immune checkpoints in PTCL and related agents have been actively explored over recent years. PD-1 and PD-L1 expression is detectable in both PTCL and immune cells within the tumor microenvironment and forms the basis for the exploration of antibodies targeting these proteins. Such antibodies are currently being investigated in clinical trials to guide individualized therapy. PD-1/PD-L1 inhibitors alone and in combination with chemotherapy, radiotherapy, or targeted therapy have shown broad clinical efficacy and improved the survival of cancer patients. Studies of other immune checkpoint proteins, such as CTLA-4, TIM-3, LAG-3, and TIGIT, are likely to provide potential novel targets for immunotherapy. Here, we review the role of and recent advances in immune checkpoint blockade in common subtypes of PTCL, focusing on the anti-tumor immune responses to PD-1/PD-L1 blockers.

Education and Empowering Special Forces to Eradicate Secret Defectors: Immune System-Based Treatment Approaches for Mature T- and NK-Cell Malignancies

“…Two prerequisites for this strategy are (i) the sufficient availability of residual healthy T cells and (ii) the independence of lymphoma cell growth from checkpoint-mediated signaling, a particular pitfall when targeting T cell lymphomas using T cell reactivators. Two important immune-checkpoint signals that regulate T cell activity, and that can be targeted for anti-cancer therapies, are PD-1-PDL-1 and CTLA-4-CD80/CD86 interactions [21,92].…”

“…Notably, only three immune system-based therapies have ever achieved approval by drug administration agencies for the treatment of only a small subgroup of MTCL/L, with only two remaining FDA approved medications to date: the anti-CD30 antibodydrug conjugate Brentuximab vedotin (ALCL and CD30 + CTCL; first-line in 2018) [17]; the anti-CD52 antibody Alemtuzumab (originally for B-cell CLL in 2007, withdrawal from market for oncologic applications in 2012) [13,18], and the anti-CCR4-receptor antibody Mogamulizumab for SS and MF (second-line in 2018), as well as CCR4 + ATLL (in Japan 2018) [19,20]. In the case of relapsed/refractory (r/r) disease, only a few targeted substances are approved (e.g., the histone deacetylase (HDAC) inhibitor Belinostat), showing unsatisfactory responses [21].…”

Emerging predictive biomarkers for novel therapeutics in peripheral T-cell and natural killer/T-cell lymphoma

“…CTLA-4 inhibitors thus function by inhibiting CTLA-4, allowing CD28-B7 crosslinking and activation of T cells for its activity against tumor cells. A study of PTCL via Sanger sequencing identified that CTLA-4/CD28 fusion genes occurred in approximately 30% of PTCL samples, and up to 58% in AITL ( 128 ). Despite the similarities that it shares with the PD-1/PD-L1 pathways, CTLA-4 inhibitors have not yet been adequately studied in the population of PTCL within clinical trials despite there being pharmacological agents such as ipilimumab available in the market for the treatment of other malignancies ( 128 ).…”

“…A study of PTCL via Sanger sequencing identified that CTLA-4/CD28 fusion genes occurred in approximately 30% of PTCL samples, and up to 58% in AITL ( 128 ). Despite the similarities that it shares with the PD-1/PD-L1 pathways, CTLA-4 inhibitors have not yet been adequately studied in the population of PTCL within clinical trials despite there being pharmacological agents such as ipilimumab available in the market for the treatment of other malignancies ( 128 ). However, a case series performed on PTCL tumors had found substantial CTLA-4 mutations in various subtypes of PTCL, notably in that of AITL and PTCL-NOS, suggesting possible room for therapeutics against the CTLA-4 surface marker in future studies ( 129 ).…”

Immune checkpoint blockade for locally advanced or recurrent/metastatic cervical cancer: An update on clinical data

“…Current ICB activates tumor-reactive T cells by downregulating the inhibitory signaling pathway or overcoming regulatory mechanisms that prevent T cell activation (26). Promising immune targets of ICB that focus on PD-1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), are summarized in Figure 1 (26)(27)(28)(29). These immune checkpoints are primarily located on the surface of T cells, natural killer (NK) cells, dendritic cells (DCs), B cells, monocytes, macrophages, and neutrophils (30).…”