Clinical and immunologic evaluation of three metastatic melanoma patients treated with autologous melanoma-reactive TCR-transduced T cells

We describe preliminary results from a Phase I clinical trial (NCT01586403) of adoptive cell therapy in which three patients received autologous CD4+ and CD8+ T cells transduced with a lentivirus carrying a tyrosinase-specific TCR and a marker protein, truncated CD34 (CD34t). This unusual MHC Class I-restricted TCR produces functional responses in both CD4+ and CD8+ T cells. Parameters monitored on transduced T cells included activation (CD25, CD69), inhibitory (PD-1, TIM-3, CTLA-4), costimulatory (OX40), and memory (CCR7) markers. For the clinical trial, T cells were activated, transduced, selected for CD34t+ cells, then re-activated, and expanded in IL-2 and IL-15. After lymphodepleting chemotherapy, patients were given transduced T cells and IL-2, and were followed for clinical and biological responses. Transduced T cells were detected in the circulation of three treated patients for the duration of observation (42, 523, and 255  days). Patient 1 tolerated the infusion well but died from progressive disease after 6 weeks. Patient 2 had a partial response by RECIST criteria then progressed. After progressing, Patient 2 was given high-dose IL-2 and subsequently achieved complete remission, coinciding with the development of vitiligo. Patient 3 had a mixed response that did not meet RECIST criteria for a clinical response and developed vitiligo. In two of these three patients, adoptive transfer of tyrosinase-reactive TCR-transduced T cells into metastatic melanoma p...
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research

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ConclusionsThis study provided an overall picture of ICI-induced vitiligo in daily medical practice on a large number of pharmacovigilance observations of case patients. Among the observations of ICI-induced vitiligo, the diagnosed cancer was melanoma for almost all patients. Most patients in the study experienced other associated adverse drug reactions (ADRs), such as colitis, pruritus, hypothyroidism, hyperthyroidism, thyroiditis, pancreatitis, and gastritis. Furthermore, our data suggest that the resolution of pembrolizumab- or nivolumab-induced vitiligo could be a marker of disease progression. Future studies evaluatin...
Source: Drug Safety - Category: Drugs & Pharmacology Source Type: research
We present a 48-year-old woman affected by metastatic uveal melanoma treated with nivolumab (3 mg/kg every 2 weeks). The patient had no previous history of autoimmune disease or dermatologic conditions. At the fourth month of treatment, on cutaneous examination, she presented multiple whitish vitiligo-like patches on the trunk, axillae, hands and face. Diagnosis of melanoma-associated leukoderma vitiliginous reaction was made. Over the following months, the melanoma-associated leukoderma lesions slowly progressed with cigarette paper-like appearance and indurated texture. A skin biopsy leaded the diagnosis of extragenital ...
Source: Anti-Cancer Drugs - Category: Cancer & Oncology Tags: Case Reports Source Type: research
ConclusionsImmunosuppression resulted in clinical remission of each irAE, highlighting the importance of vigilance for autoimmune complications in patients treated with checkpoint inhibition, even after immunotherapy cessation.
Source: Journal for Immunotherapy of Cancer - Category: Cancer & Oncology Source Type: research
Glycoprotein non-metastatic melanoma protein B (GPNMB) is a Type I transmembrane glycoprotein which has important roles in cancer and amyotrophic lateral sclerosis (ALS). In skin epidermis, GPNMB is mainly expressed in melanocytes and plays a critical role in pigmentation. Previously, we showed that GPNMB was highly expressed in keratinocytes from healthy donors, but decreased in vitiligo lesions. The function of keratinocyte-derived GPNMB is yet to be known. Therefore, we first confirmed GPNMB expression in cultured normal human epidermal keratinocytes, and oxidative stress (H2O2) down-regulated both membrane GPNMB and so...
Source: Journal of Investigative Dermatology - Category: Dermatology Authors: Tags: Photobiology and Pigmentation Source Type: research
Narrow-band ultraviolet B (NBUVB) phototherapy has been the mainstay in treatment of vitiligo, but its long-term safety in terms of photocarcinogenesis has not been established. We performed a nationwide population-based retrospective cohort study to investigate the risks of actinic keratosis (AK), Bowen ’s disease (BD), nonmelanoma skin cancers (NMSC), and melanoma, based on the number of NBUVB phototherapy sessions of patients with vitiligo. We obtained cohort data from the Korean National Health Insurance Claims database for the period January 2007 to December 2017.
Source: Journal of Investigative Dermatology - Category: Dermatology Authors: Tags: Clinical Research and Epidemiology Source Type: research
The objective of this study was to investigate the role of CLEC12B in melanoma. Expression of CLEC12B was assessed in melanoma cell lines, nevi and melanoma samples. Using a lentivirus construct we overexpressed (Ov) or downregulated (Sh) CLEC12B in melanoma cells lines to assess the effect of its modulation on proliferation and cell cycle. The signaling pathway involved was then studied.
Source: Journal of Investigative Dermatology - Category: Dermatology Authors: Tags: Melanoma and Other Skin Cancers Source Type: research
Nivolumab, a checkpoint inhibitor of programmed cell death receptor-1 (PD-1), is used in the treatment of metastatic melanoma and nonsmall cell lung cancer. Blockade of PD-1 receptor releases inhibition of T-cell activation and allows for an antitumor immune response. As with many immune-mediated therapeutics, the most common cutaneous immune-related adverse events reported in association with nivolumab are vitiligo, rash and pruritis. Other autoimmune and inflammatory skin conditions such as psoriasiform or lichenoid eruptions, autoimmune blistering disorders, and sarcoidosis have also been reported.
Source: Journal of the American Academy of Dermatology - Category: Dermatology Source Type: research
CONCLUSIONS: Unlike in Caucasians, the risk of skin cancer was increased in the Korean vitiligo population. Nonetheless, it is noteworthy that the skin cancer incidence in Korean vitiligo patients was lower than that of their Caucasian counterparts. Due to possible ethnic differences in the susceptibility to skin cancer, skin cancer surveillance in the vitiligo population may be adjusted to race. This article is protected by copyright. All rights reserved. PMID: 31233609 [PubMed - as supplied by publisher]
Source: The British Journal of Dermatology - Category: Dermatology Authors: Tags: Br J Dermatol Source Type: research
Hui Zhou, Xiaoyan Fu, Qian Li and Ting Niu* Department of Hematology and Research Laboratory of Hematology, West China Hospital, Sichuan University, Chengdu, China Background: Immune checkpoint inhibition therapy with monoclonal antibody against programmed cell death protein 1 (PD-1), including nivolumab and pembrolizumab, has demonstrated powerful clinical efficacy in the treatment of advanced cancers. However, there is no evidence-based systematic review on the safety and efficacy of anti-PD-1 antibody in treating lymphoma. Methods: To evaluate the safety and efficacy of nivolumab/pembrolizumab, we analyzed clin...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
Roser Calvo* Patient Safety, Safety Science, AstraZeneca Pharmaceuticals, Gaithersburg, MD, United States Immune-related hematological adverse events are amongst the rare but potentially life-threatening complications of immune checkpoint inhibitors. The spectrum of these toxicities is broadening as the number of patients exposed to these agents is increasing. Yet, they are still relatively unknown to many clinicians, possibly due to a lack of specific diagnostic criteria, which poses a challenge for their recognition and proper reporting, and partly due to their low incidence, often too low to be noted in most c...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
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