tacrolimus and Melanoma

Immune checkpoint inhibition with the anti-CTLA-4 antibody ipilimumab and the anti-PD-1 antibodies nivolumab and pembrolizumab has improved survival in metastatic melanoma, lung cancer and renal cancer. Use of these agents holds promise in other malignancies. The augmented immune response enabled by these agents has led to a particular group of side effects called immune-related adverse events (irAEs). The main irAEs include diarrhea, colitis, hepatitis, skin toxicities and endocrinopathies such as hypophysitis and thyroid dysfunction. The anti-PD-1 antibodies have a different toxicity profile to ipilimumab with fewer high grade events. This article identifies the rates of common and uncommon irAEs associated with each immune checkpoint inhibitor (ICPI) and their timing of onset, focusing mainly on the experience in melanoma and lung cancer. An approach to management for each class of irAE is provided.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Antineoplastic Agents; Carcinoma, Renal Cell; Chemical and Drug Induced Liver Injury; Colitis; CTLA-4 Antigen; Cyclosporine; Diarrhea; Drug Eruptions; Humans; Immunosuppressive Agents; Infliximab; Ipilimumab; Kidney Neoplasms; Lung Neoplasms; Melanoma; Mycophenolic Acid; Neoplasms; Nivolumab; Pituitary Diseases; Programmed Cell Death 1 Receptor; Skin Neoplasms; Tacrolimus; Thyroiditis

Cases of lymphoma or cutaneous cancer have been observed following use of topical calcineurin inhibitors (TCIs), but it is unclear whether TCI use increases cancer risk. We used published literature to assess the extent to which atopic dermatitis (AD) or TCI use is associated with lymphoma, melanoma, basal cell carcinoma and squamous cell carcinoma. We searched the literature and summarized the results of all studies that provided data on the absolute or relative frequency of any malignancy among patients with AD or eczema or among patients using TCIs. The relative risk for all lymphoma in broad populations of AD or eczema ranged from 0·7 to 1·8. Available data on lymphoma following TCI use were inconsistent and insufficient to draw a conclusion about the causal role of TCIs. We found no evidence indicating that melanoma or nonmelanoma skin cancer is associated with TCI use. A bias analysis showed that cutaneous T-cell lymphomas initially misdiagnosed and treated as AD would lead to overestimation of the association between TCI use and lymphoma. However, there are only sparse data on specific malignancies among TCI-treated patients. The short duration of typical TCI exposure hinders conclusions about longer exposure. There is insufficient evidence in the epidemiological literature to infer whether TCIs do or do not cause malignancy.

Topics: Administration, Topical; Calcineurin Inhibitors; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Dermatitis, Atopic; Dermatologic Agents; Humans; Lymphoma; Melanoma; Risk Factors; Skin Neoplasms; Tacrolimus

Within the last decade, healthcare providers have had a larger selection of effective novel topical immunomodulatory agents to treat many dermatologic conditions. Novel mechanisms of action of newer topical agents have facilitated differentiation from well-established topical agents such as corticosteroids and 5-fluorouracil. Further, because of a growing understanding of the immune mechanisms within the skin, the opportunity has arisen to use the body's immune system to effectively treat many dermatologic conditions, such as condyloma acuminata, actinic keratosis, basal cell carcinoma, and atopic dermatitis, while maintaining a favorable safety profile. Imiquimod 5% cream, an immune response modifier, is safe and effective in the treatment of condyloma acuminata, actinic keratosis, and primary superficial basal cell carcinoma (sBCC). Pimecrolimus cream 1% and tacrolimus ointment (0.1% and 0.03%) are safe and effective in the treatment of atopic dermatitis. This review highlights newer data on approved and investigational indications for these topical immunomodulatory agents.

Topics: Adjuvants, Immunologic; Administration, Topical; Aminoquinolines; Condylomata Acuminata; Dermatitis, Atopic; Dermatitis, Seborrheic; Humans; Hutchinson's Melanotic Freckle; Imiquimod; Keratosis; Melanoma; Membrane Glycoproteins; Receptors, Cell Surface; Skin Diseases; Skin Diseases, Viral; Skin Neoplasms; Tacrolimus; Toll-Like Receptors

Immune-related hepatitis is an adverse effect following treatment with immune-checkpoint inhibitors, such as ipilimumab, nivolumab and pembrolizumab. International guidelines advise on the use of corticosteroids as first-line treatment, although guidance on how to treat cases resistant to corticosteroids is limited. We aimed to evaluate the presentation and management of patients with grade 3-4 immune-related hepatitis, following treatment with immune-checkpoint inhibitors for stage 4 or unresectable or stage 3 melanoma, with a particular focus on steroid-refractory cases.. A retrospective observational review of patients developing immune-related hepatitis whilst undergoing treatment with immune checkpoint inhibitors for advanced melanoma from July 2014 to February 2020 at a tertiary oncology centre.. Forty-one patients developed immune-related hepatitis, of which 83% had been treated with the combination of ipilimumab and nivolumab. The median time to onset of IR-hepatitis was 47 days (range: 4-476), and the median time to peak alanine aminotransferase was 71 days (range: 4-478). Four patients had resolution of grade 3 immune-related hepatitis without the introduction of corticosteroids. A total of 37 patients were treated with corticosteroids. A total of 12 required oral treatment only and 13 were successfully managed as outpatients. Six patients had steroid-refractory immune-related hepatitis; and all received tacrolimus, with one also receiving mycophenolate mofetil and infliximab.. This study describes the largest UK series of immune-related hepatitis patients in the literature. We present two important deviations from current guidelines. Firstly, there is some evidence that withholding steroids is possible in grade 3-4 immune-related hepatitis. Secondly, tacrolimus can be used successfully to manage patients resistant to corticosteroids, with the early introduction most beneficial to reduce time on steroids.

Topics: Hepatitis; Humans; Immune Checkpoint Inhibitors; Ipilimumab; Melanoma; Nivolumab; Retrospective Studies; Tacrolimus

One key reason for T cell exhaustion is continuous antigen exposure. Early exhausted T cells can reverse exhaustion and differentiate into fully functional memory T cells if removed from persisting antigen stimulation. Therefore, this study viewed T cell exhaustion as an over-activation status induced by chronic antigen stimuli. This study hypothesized that blocking TCR signal intermittently to terminate over-activation signal can defer the developmental process of T cell exhaustion. In this study, melanoma-bearing mice were treated with tacrolimus (FK506) every 5 days. The tumor size and tumor-infiltrating lymphocytes (TILs) were analyzed. We found that intermittent administration of tacrolimus significantly inhibited tumor growth, and this effect was mediated by CD8+T cells. Intermittent tacrolimus treatment facilitated the infiltration of CD8+TILs. RNA-seq and quantitative RT-PCR of sorted CD8+TILs showed the expression of Nr4a1 (an exhaustion-related transcription factor) and Ctla4 (a T cell inhibitory receptor) was remarkably downregulated. These results indicated that intermittently blocking TCR signal by tacrolimus can promote anti-tumor immunity and inhibit the tumor growth in melanoma-bearing mice, inhibiting the transcription of several exhaustion-related genes, such as Nr4a1 and Ctla4.

Topics: Animals; CD8-Positive T-Lymphocytes; CTLA-4 Antigen; Lymphocytes, Tumor-Infiltrating; Melanoma; Mice; Tacrolimus

The efficacy of tofacitinib (TOF) in the early diagnosis of melanoma differentiation-associated gene 5 (MDA5)-related interstitial lung disease (ILD) has been described. However, whether TOF exposure is associated with a reduced 1-year mortality rate remains undetermined.. Patients diagnosed with MDA5-ILD receiving TOF or tacrolimus (TAC) treatment were included. A Cox proportional hazards model, which was adjusted for age, sex, smoking history, anti-MDA5 antibody titers, and concurrent use of other steroid-sparing agents, was performed to compare all-cause mortality and to investigate the risk factors predicting 1-year mortality rates in the 2 treatment groups.. During the study period, 26 patients were treated with TOF and 35 were treated with TAC. The 6-month (38.5% vs 62.9%;. Our observational study showed that TOF use might have a potential effect on improving the outcomes of MDA5-ILD. Future clinical trials are needed to assess the long-term efficacy and tolerability of TOF.

Topics: Autoantibodies; Dermatomyositis; Humans; Interferon-Induced Helicase, IFIH1; Lung Diseases, Interstitial; Melanoma; Retrospective Studies; Tacrolimus

Mucosal melanoma, or so-called mucosal-oral melanoma is a rare but serious diagnostic and therapeutic problem. The "primary mixed" mucocutaneous forms of melanoma, which affect both the mucosa and the adjacent skin, are also particularly problematic and rare. Given that the staging, diagnosis, and treatment of mucosal (oral) melanoma differs from that of cutaneous melanoma, staging in mixed melanoma (primary mucocutaneous melanoma) as well as decisions for each subsequent diagnostic and therapeutic step should be individualized and modified according to the recommendations of the respective two classifications (for cutaneous but also mucosal melanomas), while at the same time or at least to a large extent overlapping with them. In practice, the following paradoxes occur during staging - there are melanomas with the same tumor thickness, but in different stages, which should be treated in a different, consensus-based way. At the same time, it would be appropriate for the surgical interventions to be in accordance with the patient's wishes for minimal trauma/reduced risk of developing facial disproportion. We present the case of a 69-year-old patient with a newly-developed lesion in the area of the mucosa of the upper lip and adjacent skin, which was identified as a primary mucocutaneous form of melanoma after surgical removal. The complex pathogenesis of the disease is discussed herein, emphasizing the role of UV radiation, iatrogenic immunosuppression with mycophenolate mofetil, tacrolimus, and prednisolone (due to severe glomerulonephritis leading to kidney transplantation), as well as the potential possible but speculative pathogenetic role of acetyl salicylic acid, etc. Primary mucosal and mucocutaneous forms of melanoma remain a challenge for clinicians, and steps for their diagnosis and treatment should be an expression of multidisciplinary, consensual solutions.

Topics: Aged; Humans; Melanoma; Mouth Neoplasms; Mycophenolic Acid; Prednisolone; Salicylic Acid; Skin Neoplasms; Tacrolimus

Melanoma is the most malignant form of skin cancer with high metastatic potential. Nuclear factor of activated T-cells (NFATs) are discovered as transcription factors that regulate the expression of proinflammatory cytokines and other genes during the immune response. Among five NFAT members, NFAT3 is exclusively not expressed in immune cells and its role in progression of different types of cancer remains controversial. Our previous study showed that NFAT3 was highly expressed in skin cancer compared with normal skin tissues and critical for melanoma cell survival and tumor growth. Here, we reported that knockdown of NFAT3 expression, as well as treatment with the calcineurin (CaN) inhibitors, tacrolimus (FK506) or ascomycin (FK520) inhibits melanoma cell migration and invasion, and also proliferation and colony formation. Mechanistic studies revealed that FK506 or FK520 blocked the nuclear translocation and reduced the transcriptional activity of NFAT3. These data support that the antimelanoma effect of FK506 and FK520 is partially mediated by inhibiting the oncogenic factor NFAT3, suggesting that therapeutics based on NFAT3 inhibition may be effective in clinical melanoma treatment.

Topics: Calcineurin Inhibitors; Cell Culture Techniques; Cell Line, Tumor; Cell Movement; Cell Proliferation; Humans; Immunosuppressive Agents; Melanoma; Neoplasm Invasiveness; NFATC Transcription Factors; Tacrolimus

Topics: Autoimmunity; Black People; Diagnosis, Differential; Female; Humans; Hypopigmentation; Immunosuppressive Agents; Melanoma; Middle Aged; Tacrolimus; Treatment Outcome; Vitiligo

The Allgemeines Krankenhaus Informations Management (AKIM) project was started at the Vienna General Hospital (VGH) several years ago. This led to the introduction of a new hospital information system (HIS), and the installation of the expert system platform (EXP) for the integration of Arden-Syntax-based clinical decision support systems (CDSSs). In this report we take a look at the milestones achieved and the challenges faced in the creation and modification of CDSSs, and their integration into the HIS over the last three years.. We introduce a three-stage development method, which is followed in nearly all CDSS projects at the Medical University of Vienna and the VGH. Stage one comprises requirements engineering and system conception. Stage two focuses on the implementation and testing of the system. Finally, stage three describes the deployment and integration of the system in the VGH HIS. The HIS provides a clinical work environment for healthcare specialists using customizable graphical interfaces known as parametric medical documents. Multiple Arden Syntax servers are employed to host and execute the CDSS knowledge bases: two embedded in the EXP for production and development, and a further three in clinical routine for production, development, and quality assurance.. Three systems are discussed; the systems serve different purposes in different clinical areas, but are all implemented with Arden Syntax. MONI-ICU is an automated surveillance system for monitoring healthcare-associated infections in the intensive care setting. TSM-CDS is a CDSS used for risk prediction in the formation of cutaneous melanoma metastases. Finally, TacroDS is a CDSS for the manipulation of dosages for tacrolimus, an immunosuppressive agent used after kidney transplantation. Problems in development and integration were related to data quality or availability, although organizational difficulties also caused delays in development and integration.. Since the inception of the AKIM project at the VGH and its ability to support standards such as Arden Syntax and integrate CDSSs into clinical routine, the clinicians' interest in, and demand for, decision support has increased substantially. The use of Arden Syntax as a standard for CDSSs played a substantial role in the ability to rapidly create high-quality CDSS systems, whereas the ability to integrate these systems into the HIS made CDSSs more popular among physicians. Despite these successes, challenges such as lack of (consistent and high-quality) electronic data, social acceptance among healthcare personnel, and legislative issues remain. These have to be addressed effectively before CDSSs can be more widely accepted and adopted.

Topics: Artificial Intelligence; Cross Infection; Decision Support Systems, Clinical; Expert Systems; Hospital Information Systems; Humans; Intensive Care Units; Kidney Transplantation; Medical Informatics; Melanoma; Neoplasm Metastasis; Programming Languages; Risk Assessment; Tacrolimus

Immune-checkpoint inhibitors have been approved for the treatment of metastatic melanoma based on several phase III trials. Patients after organ transplantation and patients with impaired renal function were excluded from these studies. Recently, allograft rejections were reported in organ transplant recipients receiving PD-1 blocking antibodies.. Four patients with metastatic melanoma and impaired kidney function (baseline serum creatinine 1.79-2.59 mg/dl) were treated with immune-checkpoint blockers, of which one was a kidney-transplant recipient receiving immunosuppressive therapy with tacrolimus and prednisolone. The patient was initially treated with the anti-CTLA-4 antibody ipilimumab after detailed explanation of the potential risk of allograft rejection. Upon disease progression, therapy was switched to the anti-PD-1 antibody nivolumab. The other three patients were treated with nivolumab or pembrolizumab, two of them after previous therapy with ipilimumab.. The patients received a median of six doses (range 3-21) of anti-PD-1 antibodies and 3-4 doses of ipilimumab. Kidney function tests remained stable throughout the course of checkpoint blockade. In the kidney transplant recipient, neither ipilimumab nor nivolumab led to an allograft rejection. Responses to anti-PD-1 treatment were divergent with two patients showing disease progression, one achieving a mixed response and one experiencing a complete response.. These cases show that checkpoint inhibitors can be a safe therapeutic option in patients with impaired kidney function. Furthermore, we report the first organ transplant patient with malignant melanoma who received ipilimumab followed by nivolumab without experiencing a kidney allograft rejection.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Agents; CTLA-4 Antigen; Graft Rejection; Humans; Immunosuppressive Agents; Ipilimumab; Kidney Failure, Chronic; Kidney Transplantation; Male; Melanoma; Middle Aged; Nivolumab; Patient Safety; Prednisolone; Programmed Cell Death 1 Receptor; Skin Neoplasms; Tacrolimus

The aim of this study was to analyze the distribution of malignancies in patients after heart transplantation (HTX) and to evaluate the risk factors including immunosuppressive therapy with regard to the development of malignancies and survival. Special emphasis was placed on the effects of a mammalian target of rapamycin (mTOR) containing immunosuppressive regimen.. A total of 381 patients (age ≥18 years) receiving HTX were included in the present analysis. All patients were followed-up at the University of Heidelberg Heart Center, Heidelberg, Germany. Data were retrieved from the Heidelberg Registry for Heart Transplantation being collected between 1989 and 2014. According to center standard, all patients received induction therapy with anti-thymocyte globulin guided by T-cell monitoring since 1994. The initial immunosuppressive regimen consisting of cyclosporine A (CsA) and azathioprine (AZA) was replaced by CsA and mycophenolate mofetil (MMF) in 2001 and by tacrolimus (TAC) and MMF in 2006. Additionally, mTOR inhibitors (everolimus/sirolimus) were applied since 2003.. Mean recipient age at HTX was 51.2±10.5 years and the mean follow-up period after HTX was 9.7±5.9 years. During follow-up, 130 patients developed a neoplasm (34.1% of total). Subgroup analysis revealed 58 patients with cutaneous malignancy only (15.2%), 56 patients with noncutaneous malignancy only (14.7%), and 16 patients with both cutaneous and noncutaneous malignancy (4.2%). Statistically significant risk factors associated with an increased risk of malignancy after HTX were older age (P<0.0001), male recipients (P=0.0008), dyslipidemia (P=0.0263), diabetes mellitus (P=0.0003), renal insufficiency (P=0.0247), and >1 treated rejection episode (TRE) in the first year after HTX (P=0.0091). Administration of CsA (P=0.0195), AZA (P=0.0008), or steroids (P=0.0018) for >1 year after HTX was associated with increased development of malignancy, whereas administration of MMF (P<0.0001) or mTOR inhibitors (P<0.0001) was associated with a lower risk for development of malignancy. Additionally, 5-year follow-up of cutaneous malignancy recurrence (P=0.0065) and noncutaneous malignancy mortality (P=0.0011) was significantly lower in patients receiving an mTOR inhibitor containing therapy after the development of a malignancy.. This study highlights the complexity of risk factors including immunosuppression with regard to the development of malignancies after HTX. mTOR-inhibitor-based immunosuppression is associated with a better outcome after HTX, particularly in cases with noncutaneous malignancy.

Topics: Adult; Azathioprine; Cyclosporine; Female; Follow-Up Studies; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Melanoma; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Neoplasms; Risk Factors; Skin Neoplasms; Survival Analysis; Tacrolimus

Topics: Administration, Oral; Aged; Antibodies, Monoclonal; Antineoplastic Agents; Dacarbazine; Drug Administration Schedule; Fluorodeoxyglucose F18; Humans; Immunosuppressive Agents; Ipilimumab; Kidney Transplantation; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Male; Melanoma; Middle Aged; Mycophenolic Acid; Platinum Compounds; Positron-Emission Tomography; Prednisone; Radiopharmaceuticals; Skin Neoplasms; Tacrolimus; Temozolomide; Tomography, X-Ray Computed; Treatment Outcome

ABCB5, an ATP-binding cassette (ABC) transporter, is highly expressed in melanoma cells, and may contribute to the extreme resistance of melanomas to chemotherapy by efflux of anti-cancer drugs. Our goal was to determine whether we could functionally express human ABCB5 in the model yeast Saccharomyces cerevisiae, in order to demonstrate an efflux function for ABCB5 in the absence of background pump activity from other human transporters. Heterologous expression would also facilitate drug discovery for this important target. DNAs encoding ABCB5 sequences were cloned into the chromosomal PDR5 locus of a S. cerevisiae strain in which seven endogenous ABC transporters have been deleted. Protein expression in the yeast cells was monitored by immunodetection using both a specific anti-ABCB5 antibody and a cross-reactive anti-ABCB1 antibody. ABCB5 function in recombinant yeast cells was measured by determining whether the cells possessed increased resistance to known pump substrates, compared to the host yeast strain, in assays of yeast growth. Three ABCB5 constructs were made in yeast. One was derived from the ABCB5-β mRNA, which is highly expressed in human tissues but is a truncation of a canonical full-size ABC transporter. Two constructs contained full-length ABCB5 sequences: either a native sequence from cDNA or a synthetic sequence codon-harmonized for S. cerevisiae. Expression of all three constructs in yeast was confirmed by immunodetection. Expression of the codon-harmonized full-length ABCB5 DNA conferred increased resistance, relative to the host yeast strain, to the putative substrates rhodamine 123, daunorubicin, tetramethylrhodamine, FK506, or clorgyline. We conclude that full-length ABCB5 can be functionally expressed in S. cerevisiae and confers drug resistance.

Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Clorgyline; Daunorubicin; Humans; Melanoma; Rhodamine 123; Rhodamines; Saccharomyces cerevisiae; Tacrolimus

Oxygen-dependent radiosensitivity of tumour cells reflects direct oxidative damage to DNA, but non-nuclear mechanisms including signalling pathways may also contribute. Mitochondria are likely candidates because not only do they integrate signals from each of the main kinase pathways but mitochondrial kinases responsive to oxidative stress communicate to the rest of the cell. Using pharmacological and immunochemical methods, we tested the role of mitochondrial permeability transition (MPT) and the Bcl-2 proteins in oxygen-dependent radiosensitivity. Drug-treated or untreated cervical cancer HeLa, breast cancer MCF-7 and melanoma MeWo cell lines were irradiated at 6.2 Gy under normoxic and hypoxic conditions then allowed to proliferate for 7 days. The MPT blocker cyclosporin A (2 microM) strongly protected HeLa but not the other two lines against oxygen-dependent radiosensitivity. By contrast, bongkrekic acid (50 microM), which blocks MPT by targeting the adenine nucleotide transporter, had only marginal effect and calcineurin inhibitor FK-506 (0.1 microM) had none. Nor was evidence found for the modulation of oxygen-dependent radiosensitivity by Bax/Bcl-2 signalling, mitochondrial ATP-dependent potassium (mitoK(ATP)) channels or mitochondrial Ca(2+) uptake. In conclusion, calcineurin-independent protection by cyclosporin A suggests that MPT but not mitoK(ATP) or the mitochondrial apoptosis pathway plays a causal role in oxygen-dependent radiosensitivity of HeLa cells. Targeting MPT may therefore improve the effectiveness of radiotherapy in some solid tumours.

Topics: Anti-Bacterial Agents; bcl-2-Associated X Protein; Bongkrekic Acid; Breast Neoplasms; Cell Line, Tumor; Cyclosporine; Female; Humans; Immunosuppressive Agents; Melanoma; Mitochondria; Oxidative Stress; Radiation Tolerance; Tacrolimus; Uterine Cervical Neoplasms

Topics: Administration, Topical; Biopsy; Child; Disease Progression; Female; Forearm; Humans; Immunosuppressive Agents; Melanoma; Skin; Skin Neoplasms; Tacrolimus; Vitiligo

Topics: Aged; Anastomosis, Surgical; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Daclizumab; Drug Therapy, Combination; Ear Neoplasms; Ear, External; Female; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Melanoma; Microsurgery; Mycophenolic Acid; Plastic Surgery Procedures; Scalp; Skin Neoplasms; Surgical Flaps; Tacrolimus; Transplantation, Homologous

Topics: Anemia, Aplastic; Cyclosporine; Female; Humans; Immunosuppressive Agents; Male; Melanoma; Remission Induction; Sirolimus; Tacrolimus