Antagonist antibodies to programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) have shown remarkable activity in multiple tumor types. Recent US Food and Drug Administration ...approval of such agents for advanced melanoma, non-small cell lung cancer, and renal cell carcinoma has hastened the need to better characterize their unique toxicity profiles.
To provide a clinical and pathologic description of the lichenoid mucocutaneous adverse effects seen in patients receiving anti-PD-1/PD-L1 treatment.
Patients with advanced cancer who were referred to dermatology at Yale-New Haven Hospital, a tertiary care hospital, after developing cutaneous adverse effects while receiving an anti-PD-1 or PD-L1 antibody therapy either as monotherapy or in combination with another agent were identified. Medical records from 2010 to 2015 and available skin biopsy specimens were retrospectively reviewed.
Patient demographic characteristics, concurrent medications, therapeutic regimen, type of disease, previous oncologic therapies, clinical morphology of cutaneous lesions, treatment of rash, peripheral blood eosinophil count, tumor response, and skin histologic characteristics if biopsies were available.
Patients were 13 men and 7 women, with a mean (range) age of 64 (46-86) years. The majority of cases (16 80%) had a clinical morphology consisting of erythematous papules with scale in a variety of distributions. Biopsies were available from 17 patients; 16 (94%) showed features of lichenoid interface dermatitis. Eighteen patients were treated with topical corticosteroids, and only 1 patient required discontinuation of anti-PD-1/PD-L1 therapy. Only 4 of 20 patients (20%) developed peripheral eosinophilia. Sixteen patients (80%) were concurrently taking medications that have been previously reported to cause lichenoid drug eruptions.
Papular and nodular eruptions with scale, as well as mucosal erosions, with lichenoid features on histologic analysis were a distinct finding seen with anti-PD-1/PD-L1 therapies and were generally manageable with topical steroids. Concurrent medications may play a role in the development of this cutaneous adverse effect.
High-throughput sequencing of T cell receptors to define and quantify T cell populations emerges as a diagnostic tool with the remarkable ability to discriminate between CTCL and benign inflammatory ...conditions (Kirsch et al., this issue).
Extracorporeal photochemotherapy (ECP) is a cancer immunotherapy for cutaneous T-cell lymphoma (CTCL) operative in more than 350 centers worldwide. Although its efficacy and favorable safety profile ...have driven its widespread use, elucidation of its underlying mechanism has been difficult. In this study, we identify the principal contributors to the anticancer immunotherapeutic effects of ECP, with the goal of enhancing potency and broadening applicability to additional malignancies. First, we scaled down the clinical ECP leukocyte-processing device to mouse size. Second, we used that miniaturized device to produce a cellular vaccine that regularly initiated therapeutic antimelanoma immunity. Third, we individually subtracted key factors from either the immunizing inoculum or the treated animal to ascertain their contribution to the
antimelanoma response. Platelet-signaled monocyte-to-dendritic cell (DC) differentiation followed by sorting/processing/presentation of tumor antigens derived from internalized apoptotic tumor cells were absolute requirements. As in clinical ECP, immunogenic cell death of tumor cells was finely titrated by DNA cross-linkage mediated by photoactivated 8-methoxypsoralen (8-MOPA). ECP-induced tumor-loaded DC were effective immunotherapeutic agents only if they were spared exposure to 8-MOPA, indicating that healthy DC are required for ECP. Infusion of responder T cells into naïve tumor-challenged mice established the protective role of stimulated T-cell antitumor immunity. Collectively, these results reveal that selective antitumor effects of ECP are initiated by tumor antigen-loaded, ECP-induced DC, which promote potent collaboration between CD4 and CD8 tumor-specific T cells. These mechanistic insights suggest potential therapeutic applicability of ECP to solid tumors in addition to CTCL.
These findings identify principal cellular contributors to the anticancer immunotherapeutic impact of ECP and suggest this treatment may be applicable to a broad spectrum of immunogenic malignancies.
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Current treatments for T cell malignancies encounter issues of disease relapse and off-target toxicity. Using T cell receptor (TCR)Vβ2 as a model, here we demonstrate the rapid generation of an ...off-the-shelf allogeneic chimeric antigen receptor (CAR)-T platform targeting the clone-specific TCR Vβ chain for malignant T cell killing while limiting normal cell destruction. Healthy donor T cells undergo CRISPR-induced TRAC, B2M and CIITA knockout to eliminate T cell-dependent graft-versus-host and host-versus-graft reactivity. Second generation 4-1BB/CD3zeta CAR containing high affinity humanized anti-Vβ scFv is expressed efficiently on donor T cells via both lentivirus and adeno-associated virus transduction with limited detectable pre-existing immunoreactivity. Our optimized CAR-T cells demonstrate specific and persistent killing of Vβ2+ Jurkat cells and Vβ2+ patient derived malignant T cells, in vitro and in vivo, without affecting normal T cells. In parallel, we generate humanized anti-Vβ2 antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) by Fc-engineering for NK cell ADCC therapy.
Mycosis Fungoides and Sezary Syndrome Foss, Francine M; Girardi, Michael
Hematology/oncology clinics of North America,
04/2017, Letnik:
31, Številka:
2
Journal Article
Recenzirano
Mycosis fungoides and the Sezary syndrome (SS) are rare lymphomas of CD4
helper T cells. There is stagewise progression from patch/plaques to thicker tumor lesions/diffuse erythroderma. Blood ...involvement is a characteristic of SS. Outcomes are related to the extent of skin, blood, lymph node, and visceral organ involvement. Patients with limited patch and plaque disease are treated with skin-directed therapies. More advanced/refractory disease is treated with skin-directed therapies and oral or systemic immunomodulatory agents. Single-agent chemotherapies are used against tumors, refractory plaques, and lymph node and visceral involvement. Allogeneic stem cell transplantation is a potentially curative strategy for advanced/resistant disease.
Background The condition that came to be known as nephrogenic systemic fibrosis (NSF) was first reported in 2000 and, in 2001, was termed “nephrogenic fibrosing dermopathy.” Since then, NSF has been ...the subject of a wide-ranging multidisciplinary medical investigation that has proven an indisputable link to renal disease and a compelling association with the increasing use of gadolinium-containing magnetic resonance imaging contrast agents in the renally impaired. Objective Although precise causation and risk factors continue to be elucidated, the need for reproducible prospective epidemiologic data demands clear and objective criteria for the diagnosis of NSF. Methods Experts in NSF diagnosis used their experience and the resources of the Yale International NSF Registry to develop a clinicopathological diagnostic system for NSF. Results A consensus scoring system incorporating a clinical and histopathological atlas was devised to guide and standardize the evaluation and diagnosis of NSF. Limitations There is no laboratory test that can be used as a gold standard to diagnose NSF. To overcome this, we relied on classic clinicopathological presentations, published sources, and consensus clinical expertise to ensure the integrity of the study population. Conclusion The clinicopathological definition of NSF provides guidance to physicians for the evaluation and diagnosis of NSF. Clinical, laboratory, and histopathological features comprise a schema that excludes conditions mimicking NSF while facilitating its reproducible and accurate diagnosis, even among physicians with little prior clinical experience with this entity. This definition can serve as a working diagnostic standard for future research and as the basis for adjudicating borderline cases.
Whereas the vast majority of T cells express a T-cell receptor (TCR) composed of αβ heterodimers, a smaller population expresses a γδ TCR. In contrast to αβ T cells, γδ T cells show less TCR ...diversity, are particularly enriched at epithelial surfaces and appear to respond to self-molecules that signal potential danger or cellular stress. In addition, various subsets of γδ T cells have shown antitumor and immunoregulatory activities. This review considers what has been discovered about the important cutaneous functions of γδ T cells through the study of mutant mice and offers perspectives on the roles of γδ T cells in human disease.
BACKGROUNDResponse rates of approved systemic therapies for cutaneous T-cell lymphoma (CTCL) hover near 30%, suggesting unmet need. This study describes real-world treatment patterns and response ...rates of extracorporeal photopheresis (ECP) in CTCL patients.METHODSA chart review was conducted in the United States of adults with CTCL who initiated ECP between January 1, 2017, and February 28, 2019, and received at least three months of ECP treatment as monotherapy or concomitant therapy. Clinical outcomes were collected quarterly for up to 18 months.RESULTSThe 52 patients were predominantly Caucasian. Half were male; median age was 69 years. Most patients had Sézary syndrome (50%) or mycosis fungoides (36.5%). Nearly 40% of patients had stage IV disease; 33% had lymph node involvement. Nineteen patients (36.5%) achieved response (>50% reduction in BSA affected); median time to response was 6.5 months. The percentage of patients rated as at least minimally improved was 59.5% at 6 months (N = 22), 75.0% at 9 months (N = 24), and 60.0% at 12 months (N = 15) after ECP initiation.CONCLUSIONSDespite the ECP treated population in this study being older and having more advanced-stage disease than recent trials, response rates were comparable. These real-world findings support ECP as an effective treatment option for CTCL patients.
Upregulation of the inducible gene products MICA (human) and Rae-1 (mouse) may promote tumor surveillance and autoimmunity by engaging the activating receptor NKG2D on natural killer (NK) cells and T ...cells. Nevertheless, sustained expression of MICA by tumors can also elicit NKG2D downregulation, perhaps indicating 'immunoevasion'. Investigating this paradox, we report here that constitutive Rae-1epsilon transgene expression in normal epithelium elicited local and systemic NKG2D downregulation, generalized but reversible defects in NK cell-mediated cytotoxicity and mild CD8(+) T cell defects. The extent of NKG2D downregulation correlated well with the incidence and progression of cutaneous carcinogenesis, emphasizing the utility of NKG2D as a marker of tumor resistance. Thus, NKG2D engagement is a natural mediator of immunosurveillance, which can be compromised by locally sustained ligand expression but potentially restored by innate immune activation.
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