Exceptional response and multisystem autoimmune-like toxicities associated with the same T cell clone in a patient with

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Exceptional response and multisystem autoimmune-like toxicities associated with the same T cell clone in a patient with uveal melanoma treated with immune checkpoint inhibitors

Abstract
Balancing the potential for durable remissions with autoimmune-like toxicities is a key clinical challenge in the use of immune checkpoint inhibitors (ICI). Certain toxicities are associated with an increased response rate; however, the molecular underpinnings of this association are poorly understood. Here, we report a patient with wide spread uveal melanoma who had an exceptional response to treatment with ipilimumab and nivolumab, but suffered severe immune-related sequelae, including central serous retinopathy with retinal detachment, tinnitus, and vitiligo resembling Vogt-Koyanagi-Harada disease, and refractory enteritis. TCR-sequencing of the primary tumor, a hepatic metastasis, duodenal biopsy and peripheral blood mononuclear cells, identified the identical T cell clone in all four tissues. This case provides preliminary evidence for cross-reactivity as a mechanism for the association between effect and toxicity of ICIs.

Introduction
Uveal melanoma (UM) comprises < 3% of all melanomas with an incidence of 5–10 cases/million [1] and underlying biology that is distinct from cutaneous melanoma (CM). In the last decade, the interrogation of the genetic landscape [2] and advances in immuno-oncology [3] have led to a remarkable improved survival rate of 40–60% [4] in patients with metastatic CM. In contrast, patients with UM rarely (ORR 0–2.6%) [5, 6] respond to ICIs, including anti-CTLA-4 and anti-PD1 monotherapies, and show low response rate (15.8%) to the combination [7]. Intrinsic resistance to ICIs in UM may be related to various mechanisms, including a low somatic mutation rate [8] and paucity of tumor infiltrating lymphocytes [9]. In CM, ICI-related skin toxicities, such as rash and vitiligo, correlate with increased tumor response and prolonged survival [10]. The immunological underpinnings for this phenomenon in patients remain poorly understood. Delineating underlying mechanisms may help to identify approaches for dissociating treatment benefits and risks.

Here we report a patient with metastatic UM who experienced an exceptional response to dual blockade of PD-1 and CTLA-4. This response was accompanied by severe and unique immune-related adverse events (irAEs). Integrated analysis of several tissues, including primary tumor, a liver metastasis, inflamed duodenum and peripheral blood using whole-exome, transcriptome and T cell receptor (TCR) sequencing, and multiplexed immunofluorescence identified a dominant T cell clone. This report suggests that tumor-reactive T cell clones may play a role in mediating toxicity in healthy tissues.

https://jitc.biomedcentral.com/articles ... 019-0533-0

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Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors



Abstract

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology.

Keywords: CD25; Fc gamma receptors; Treg depletion; anti-CD25; anti-PD-1; inhibitory Fc receptor; regulatory T cells; tumor immunotherapy; tumor microenvironment.




https://pubmed.ncbi.nlm.nih.gov/28410988/

By binding to specific proteins the Fc region ensures that each antibody generates an appropriate immune response for a given antigen. The Fc region also binds to various cell receptors, such as Fc receptors, and other immune molecules, such as complement proteins.

The receptors for the Fc portion of immunoglobulin, Fc receptors (FcRs), are important initiators of antibody mediated defense against harmful pathogens and are also key players in both the pathogenesis and severity of immune complex (IC) mediated autoimmune diseases.

Fc receptors recognize microbes that have been bound by antibodies. The interaction between the bound antibodies and the cell surface Fc receptor activates the immune cell to kill the microbe. This example shows the phagocytosis of an opsonized microbe

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