by Michele Tameris, Hennie Geldenhuys, Angelique KanyKany Luabeya, Erica Smit, Jane E. Hughes, Samantha Vermaak, Willem A. Hanekom, Mark Hatherill, Hassan Mahomed, Helen McShane, Thomas J.
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|Suggested by Brian Shilling|
Cancer immunotherapy can induce long lasting responses in patients with metastatic
cancers of a wide range of histologies. Broadening the clinical applicability of these
treatments requires an improved understanding of the mechanisms limiting cancer immunotherapy.
The interactions between the immune system and cancer cells are continuous, dynamic,
and evolving from the initial establishment of a cancer cell to the development of
metastatic disease, which is dependent on immune evasion. As the molecular mechanisms
of resistance to immunotherapy are elucidated, actionable strategies to prevent or
treat them may be derived to improve clinical outcomes for patients.
CD4+ and CD8+ effector T cell subpopulations can display regulatory potential characterized by expression of the prototypically anti-inflammatory cytokine IL-10. However, the underlying cellular mechanisms that regulate expression of IL-10 in different T cell subpopulations are not yet fully elucidated. We recently showed that TNF inhibitors (TNFi) promote IL-10 expression in human CD4+ T cells, including IL-17+ CD4+ T cells. Here we further characterized the regulation of IL-10 expression via blockade of TNF signaling, or other cytokine/co-stimulatory pathways, in human T cell subpopulations. Addition of the TNFi drug adalimumab to anti-CD3-stimulated human CD4+ T cell/monocyte co-cultures led to increased percentages of IL-10+ cells in pro-inflammatory IL-17+, IFNγ+, TNFα+, GM-CSF+ and IL-4+ CD4+ T cell subpopulations. Conversely, exogenous TNFα strongly decreased IL-10+ cell frequencies. TNF blockade also regulated IL-10 expression in CD4+ T cells upon antigenic stimulation. Using time-course experiments in whole PBMC cultures, we show that TNF blockade maintained, rather than increased, IL-10+ cell frequencies in both CD4+ and CD8+ T cells following in vitro stimulation in a dose- and time-dependent manner. Blockade of IL-17, IFNγ, IL-6R or CD80/CD86-mediated co-stimulation did not significantly regulate IL-10 expression within CD4+ or CD8+ T cell subpopulations. We show that TNF blockade acts directly on effector CD4+ T cells, in the absence of monocytes or CD4+CD25highCD127low regulatory T cells and independently of IL-27, resulting in higher IL-10+ frequencies after 3 days in culture. IL-10/IL-10R blockade reduced the frequency of IL-10-expressing cells both in the presence and absence of TNF blockade. Addition of recombinant IL-10 alone was insufficient to drive an increase in IL-10+ CD4+ T cell frequencies in 3 day CD4+ T cell/monocyte co-cultures, but resulted in increased IL-10 expression at later time points in whole PBMC cultures. Together these data provide additional insights into the regulation of IL-10 expression in human T cells by TNF blockade. The maintenance of an IL-10+ phenotype across a broad range of effector T cell subsets may represent an underappreciated mechanism of action underlying this widely used therapeutic strategy.
<span class="paragraphSection"><div class="boxTitle">Aims</div>Migration of monocytes into the arterial wall contributes to arterial inflammation and atherosclerosis progression. Since elevated low-density lipoprotein cholesterol (LDL-C) levels have been associated with activation of plasma monocytes, intensive LDL-C lowering may reverse these pro-inflammatory changes. Using proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs) which selectively reduce LDL-C, we studied the impact of LDL-C lowering on monocyte phenotype and function in patients with familial hypercholesterolaemia (FH) not using statins due to statin-associated muscle symptoms.<div class="boxTitle">Methods and results</div>We assessed monocyte phenotype and function using flow cytometry and a trans-endothelial migration assay in FH patients (<span style="font-style:italic;">n</span> = 22: LDL 6.8 ± 1.9 mmol/L) and healthy controls (<span style="font-style:italic;">n</span> = 18, LDL 2.9 ± 0.8 mmol/L). Monocyte chemokine receptor (CCR) 2 expression was approximaterly three-fold higher in FH patients compared with controls. C–C chemokine receptor type 2 (CCR2) expression correlated significantly with plasma LDL-C levels (<span style="font-style:italic;">r</span> = 0.709) and was positively associated with intracellular lipid accumulation. Monocytes from FH patients also displayed enhanced migratory capacity <span style="font-style:italic;">ex vivo.</span> After 24 weeks of PCSK9 mAb treatment (<span style="font-style:italic;">n</span> = 17), plasma LDL-C was reduced by 49%, which coincided with reduced intracellular lipid accumulation and reduced CCR2 expression. Functional relevance was substantiated by the reversal of enhanced migratory capacity of monocytes following PCSK9 mAb therapy.<div class="boxTitle">Conclusions</div>Monocytes of FH patients have a pro-inflammatory phenotype, which is dampened by LDL-C lowering by PCSK9 mAb therapy. LDL-C lowering was paralleled by reduced intracellular lipid accumulation, suggesting that LDL-C lowering itself is associated with anti-inflammatory effects on circulating monocytes.</span>
Given the pace of advances in immunotherapy in recent years and physicians’ need to keep up with these developments, the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network® (NCCN®) announce a joint collaboration to publish practical clinical guidance on the management of side effects caused by immunotherapy.
The U.S. Food and Drug Administration today approved Siliq (brodalumab) to treat adults with moderate-to-severe plaque psoriasis. Siliq is administered as an injection.
Siliq’s safety and efficacy were established in three randomized, placebo-controlled clinical trials with a total of 4,373 adult participants with moderate-to-severe plaque psoriasis who were candidates for systemic therapy or phototherapy. More patients treated with Siliq compared to placebo had skin that was clear or almost clear, as assessed by scoring of the extent, nature and severity of psoriatic changes of the skin.
Suicidal ideation and behavior, including completed suicides, have occurred in patients treated with Siliq during clinical trials. Siliq users with a history of suicidality or depression had an increased incidence of suicidal ideation and behavior compared to users without this history. A causal association between treatment with Siliq and increased risk of suicidal ideation and behavior has not been established.
The most common adverse reactions reported with the use of Siliq include joint pain (arthralgia), headache, fatigue, diarrhea, throat pain (oropharyngeal pain), nausea, muscle pain (myalgia), injection site reactions, influenza, low white blood cell count (neutropenia) and fungal (tinea) infections.
Effective clinical cancer immunotherapies, such as administration of the cytokine IL-2, adoptive cell transfer (ACT) and the recent success of blockade of the checkpoint modulators CTLA-4 and PD-1, have been developed without clear identification of the immunogenic targets expressed by human cancers in vivo. Immunotherapy of patients with cancer through the use of ACT with autologous lymphocytes has provided an opportunity to directly investigate the antigen recognition of lymphocytes that mediate cancer regression in humans. High-throughput immunological testing of such lymphocytes in combination with improvements in deep sequencing of the autologous cancer have provided new insight into the molecular characterization and incidence of anti-tumor lymphocytes present in patients with cancer. Here we highlight evidence suggesting that T cells that target tumor neoantigens arising from cancer mutations are the main mediators of many effective cancer immunotherapies in humans.
Therapeutic monoclonal antibodies [mAbs] have become molecules of choice to treat autoimmune disorders, inflammatory diseases and cancer. Moreover, bispecific/multispecific antibodies that target more than one antigen or epitope on a target cell or recruit effector cells [T cell, natural killer (NK) cell or Macrophage cell] towards target cells have shown great potential to maximize the benefits of antibody therapy. In the past decade, many novel concepts to generate bispecific and multispecific antibodies have evolved successfully into a range of formats from full bispecific immunoglobulin gammas [IgGs] to antibody fragments. Impressively, antibody fragments such as bispecific T-cell engager [BiTE], bispecific killer cell engager [BiKE], trispecific killer cell engager [TriKE], tandem diabody [Tandab] and dual-affinity-retargeting [DART] are showing exciting results in terms of recruiting and activating self-immune effector cells to target and lyse tumor cells. Promisingly, Fc antigen binding fragment [Fcab] and monomeric antibody or half antibody may be particularly advantageous to target solid tumours owing to their small size and thus good tissue penetration potential while, on the other hand, keeping crystallizable fragment [Fc] related effector functions such as antibody-dependent cellular cytotoxicity [ADCC], complement-dependent cytotoxicity [CDC], antibody dependent cell-mediated phagocytosis [ADCP] and extended serum half-life via interaction with neonatal Fc receptor [FcRn]. This review, therefore, focuses on the progress of Fc engineering in generating bispecific molecules and on the use of small antibody fragment as scaffolds for therapeutic development.