A Review of Immune-Mediated Adverse Events in Melanoma

ABSTRACT This study described the rate of vaccine reactions in a population of dogs receiving vaccines after diagnosis of primary immune-mediated hemolytic anemia (IMHA). A secondary objective was to describe the time elapsed between vaccination and initial diagnosis of IMHA. A medical record search identified cases meeting criteria for primary IMHA. Owners and referring veterinarians were surveyed regarding vaccination of the dog following diagnosis. Referring veterinarians were surveyed regarding vaccination prior to diagnosis of IMHA. A completed survey was returned in 44 cases. Twenty-two dogs received vaccinations after diagnosis, and 22 dogs did not. The median time elapsed between vaccination and initial diagnosis was 280 days. No dog was vaccinated within 30 days of diagnosis. Two of the following possible reactions were noted out of 22 dogs vaccinated: vomiting and urticarial eruption in a dog administered a rabies and canine distemper vaccine, and recurrent anemia in a dog administered a rabies vaccine. The rate of vaccine reactions was higher than previously reported, although the time period evaluated was longer than in previous studies. The relationship between initial vaccination and development of IMHA, and between vaccination and vaccine reaction, in this population is uncertain and may reflect coincidence or differences in susceptibility.

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Adverse effects of immuno-oncology drugs—Awareness, diagnosis, and management: A literature review of immune-mediated adverse events

Indian Journal of Cancer ◽

10.4103/ijc.ijc_448_19 ◽

2019 ◽

Vol 56 (5) ◽

pp. 10

Author(s):

Shyam Aggarwal

Keyword(s):

Literature Review ◽

Adverse Effects ◽

Adverse Events ◽

Diagnosis And Management ◽

Immune Mediated

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The dual PI3Kδ/CK1ε inhibitor umbralisib exhibits unique immunomodulatory effects on CLL T cells

Blood Advances ◽

10.1182/bloodadvances.2020001800 ◽

2020 ◽

Vol 4 (13) ◽

pp. 3072-3084 ◽

Cited By ~ 2

Author(s):

Kamira Maharaj ◽

John J. Powers ◽

Alex Achille ◽

Melanie Mediavilla-Varela ◽

Wael Gamal ◽

...

Keyword(s):

Clinical Trials ◽

T Cells ◽

Adverse Events ◽

Safety Profile ◽

Lymphocytic Leukemia ◽

Casein Kinase 1 ◽

Pi3k Inhibitors ◽

Treg Number ◽

Immune Mediated ◽

And Function

Abstract The in-clinic phosphatidylinositol 3-kinase (PI3K) inhibitors idelalisib (CAL-101) and duvelisib (IPI-145) have demonstrated high rates of response and progression-free survival in clinical trials of B-cell malignancies, such as chronic lymphocytic leukemia (CLL). However, a high incidence of adverse events has led to frequent discontinuations, limiting the clinical development of these inhibitors. By contrast, the dual PI3Kδ/casein kinase-1-ε (CK1ε) inhibitor umbralisib (TGR-1202) also shows high rates of response in clinical trials but has an improved safety profile with fewer severe adverse events. Toxicities typical of this class of PI3K inhibitors are largely thought to be immune mediated, but they are poorly characterized. Here, we report the effects of idelalisib, duvelisib, and umbralisib on regulatory T cells (Tregs) on normal human T cells, T cells from CLL patients, and T cells in an Eμ-TCL1 adoptive transfer mouse CLL model. Ex vivo studies revealed differential effects of these PI3K inhibitors; only umbralisib treatment sustained normal and CLL-associated FoxP3+ human Tregs. Further, although all 3 inhibitors exhibit antitumor efficacy in the Eμ-TCL1 CLL model, idelalisib- or duvelisib-treated mice displayed increased immune-mediated toxicities, impaired function, and reduced numbers of Tregs, whereas Treg number and function were preserved in umbralisib-treated CLL-bearing mice. Finally, our studies demonstrate that inhibition of CK1ε can improve CLL Treg number and function. Interestingly, CK1ε inhibition mitigated impairment of CLL Tregs by PI3K inhibitors in combination treatment. These results suggest that the improved safety profile of umbralisib is due to its role as a dual PI3Kδ/CK1ε inhibitor that preserves Treg number and function.

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Severe haematological complications during treatment with natalizumab

Multiple Sclerosis Journal ◽

10.1177/1352458512442262 ◽

2012 ◽

Vol 18 (11) ◽

pp. 1644-1646 ◽

Cited By ~ 10

Author(s):

L Midaglia ◽

M Rodriguez Ruiz ◽

D Muñoz-García

Keyword(s):

Multiple Sclerosis ◽

Adverse Events ◽

Progressive Multifocal Leukoencephalopathy ◽

Immune Thrombocytopenic Purpura ◽

Safety Profile ◽

Temporal Relationship ◽

Careful Monitoring ◽

Thrombocytopenic Purpura ◽

Immune Mediated ◽

Immunosuppressant Treatment

The safety profile of natalizumab has been widely discussed due to several cases of progressive multifocal leukoencephalopathy, reported worldwide. Since the launch of natalizumab, 32 patients have been treated at our centre. In this context, we describe two cases (6.25%), one of immune-mediated acute haemolytic anaemia (IAHA) and another of immune thrombocytopenic purpura during treatment with natalizumab. The temporal relationship between drug administration and the nature of the haematological complications, confirmed with the serological findings in the case of the IAHA, suggests that natalizumab is the most probable cause for these adverse events. Although very uncommon, the haematological complications are severe enough to justify a close and careful monitoring for all patients with multiple sclerosis treated with an immunosuppressant treatment.

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A case report of psoriasis flare following immunotherapy: Report of an important entity and literature review

SAGE Open Medical Case Reports ◽

10.1177/2050313x19897707 ◽

2020 ◽

Vol 8 ◽

pp. 2050313X1989770 ◽

Cited By ~ 2

Author(s):

Anastasia Politi ◽

Dimas Angelos ◽

Davide Mauri ◽

George Zarkavelis ◽

George Pentheroudakis

Keyword(s):

Adverse Events ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Skin Lesions ◽

Inflammatory Disorder ◽

Immune Mediated ◽

Programmed Death ◽

History Of ◽

Programmed Death 1 ◽

Cessation Of Treatment

Immune checkpoint inhibitors, such as anti-cytotoxic T-lymphocyte–associated antigen-4 and anti-programmed death-1, are a type of cancer immunotherapy approved for late-stage malignancy treatment. However, such therapies often induce immune-related adverse events. During anti-programmed death-1 blockade therapy, the most commonly reported adverse effects are skin toxicities, such as psoriasis—a chronic immune-mediated inflammatory disorder affecting the skin. We present the clinical characteristics of flared psoriasis in one patient under anti-programmed death-1 therapy who was diagnosed with T2N2M0/IIIB squamous lung carcinoma with a history of psoriasis for the past 5 years, exacerbated after the first cycle of nivolumab. After the third cycle, the extensive skin plaques necessitated treatment cessation. Following the discontinuation of anti-programmed death-1 treatment, skin lesions were treated locally. Possibly, anti-programmed death-1 immunotherapy can trigger immune-mediated diseases, such as psoriasis. Physicians should be alert to immune-related adverse events. Continuation or permanent cessation of treatment depends on the severity and reversibility of immune-related adverse events.

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Immune-Mediated Adverse Events Associated with Ipilimumab CTLA-4 Blockade Therapy: The Underlying Mechanisms and Clinical Management

Scientifica ◽

10.1155/2013/857519 ◽

2013 ◽

Vol 2013 ◽

pp. 1-19 ◽

Cited By ~ 73

Author(s):

Ahmad Tarhini

Keyword(s):

T Cell ◽

Adverse Events ◽

T Cell Activation ◽

Cell Activation ◽

Treatment Guidelines ◽

Cell Mediated Immunity ◽

Low Grade ◽

Immune Mediated ◽

Organ Systems ◽

Treatment Naïve

Immunomodulation with the anti-CTLA-4 monoclonal antibody ipilimumab has been shown to extend overall survival (OS) in previously treated and treatment-naive patients with unresectable stage III or IV melanoma. Blockade of CTLA-4 signaling with ipilimumab prolongs T-cell activation and restores T-cell proliferation, thus amplifying T-cell-mediated immunity and the patient's capacity to mount an effective antitumor immune response. While this immunostimulation has unprecedented OS benefits in the melanoma setting, it can also result in immune-mediated effects on various organ systems, leading to immune-related adverse events (irAEs). Ipilimumab-associated irAEs are common and typically low grade and manageable, but can also be serious and life threatening. The skin and gastrointestinal tract are most frequently affected, while hepatic, endocrine, and neurologic events are less common. With proper management, most irAEs resolve within a relatively short time, with a predictable resolution pattern. Prompt and appropriate management of these irAEs is essential and treatment guidelines have been developed to assist oncologists and their teams. Implementation of these irAE management algorithms will help ensure that patients are able to benefit from ipilimumab therapy with adequate control of toxicities.

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Debilitating Skin Toxicity Associated with Pembrolizumab Therapy in an 81-Year-Old Female with Malignant Melanoma

Case Reports in Oncology ◽

10.1159/000452944 ◽

2016 ◽

Vol 9 (3) ◽

pp. 833-839 ◽

Cited By ~ 6

Author(s):

Muhammad O. Khokhar ◽

Jacob Kettle ◽

Amruth R. Palla

Keyword(s):

Malignant Melanoma ◽

Adverse Effects ◽

Adverse Events ◽

Drug Toxicity ◽

Immune Therapy ◽

Skin Toxicity ◽

Significant Potential ◽

Immune Mediated ◽

Related Drug

Frequently described immune-mediated adverse effects of immune therapy include dermatological complications, hepatitis, colitis, pneumonitis, and endocrinopathies. As utilization of pembrolizumab and related agents continues to expand both in the available indications as well as duration of exposure, there remains a significant potential to uncover previously undescribed adverse events. From a dermatological standpoint, 39% of patients receiving pembrolizumab therapy experience some form of skin-related drug toxicity [Naidoo et al.: Ann Oncol 2015;26: 2375–2391]. We describe a case of pembrolizumab-induced disabling autoimmune ectodermal toxicity.

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An FDA analysis of the association between adverse events and outcome in patients with urothelial cancer receiving a programmed death protein 1 or programmed death ligand 1 (anti-PD-1/L1) antibody.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.4549 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 4549-4549

Author(s):

Chana Weinstock ◽

Virginia Ellen Maher ◽

Laura L. Fernandes ◽

Shenghui Tang ◽

Sundeep Agrawal ◽

...

Keyword(s):

Overall Survival ◽

Adverse Events ◽

Urothelial Cancer ◽

Locally Advanced ◽

Study Drug ◽

Drug Approval ◽

Systemic Corticosteroids ◽

Immune Mediated ◽

Programmed Death ◽

The Relationship

4549 Background: To assess the relationship between tumor response rate, overall survival, and the development of related adverse events of special interest (AESIs) or related immune-mediated adverse events (imAEs) in patients with urothelial cancer treated with anti-PD-1/L1 antibodies. Methods: We examined seven trials that led to drug approval and which included 1747 patients with metastatic or locally advanced urothelial cancer treated with an anti-PD-1/L1 antibody. Five trials enrolled patients who had received prior platinum-based therapy and two enrolled patients who were cisplatin-ineligible. The datasets were searched for AESIs, related AESIs, imAEs, and related imAEs. The relationship to study drug was determined by the Investigator. Immune-mediated adverse events were defined as AESIs treated with topical or systemic corticosteroids. Results: In these exploratory analyses, a related AESI was reported in 64% of responding patients and in 34% of patients who did not respond to the anti-PD-1/L1 antibody while a related imAE occurred in 28% and 12% of patients who did and did not respond to study drug, respectively. In a responder analysis, an increase in overall survival was seen in patients with related AESIs compared to those with no related AESI [hazard ratio (HR) 0.42; 95% CI: 0.37, 0.49]. Fifty-seven percent of responding patients with a related AESI reported a related AESI prior to documentation of response. Conclusions: Patients who responded to treatment with an anti-PD-1/L1 antibody were more likely to report a related AESI or related imAE. This relationship did not appear to be due to the increased duration of exposure in responding patients. Systemic corticosteroid use did not appear to affect the duration of response.

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Checkpoint inhibitor (CPI) experienced patients (pts) from COSMUS-1: A clinical observational study of talimogene laherparepvec (T-VEC) in United States practice.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.8_suppl.142 ◽

2019 ◽

Vol 37 (8_suppl) ◽

pp. 142-142 ◽

Cited By ~ 1

Author(s):

Matthew Perez ◽

Thomas Amatruda ◽

Robert Martin Conry ◽

Charlotte Eielson Ariyan ◽

Anupam M. Desai ◽

...

Keyword(s):

Adverse Events ◽

Real World ◽

Pathologic Complete Response ◽

Complete Response ◽

Real World Data ◽

Clinicopathologic Characteristics ◽

Immune Mediated ◽

Group A ◽

Previously Treated ◽

Group B

142 Background: T-VEC, a modified oncolytic herpes virus, is an intralesional therapy for unresectable advanced melanoma. COSMUS-1, a recently presented observational chart review study from 7 US academic sites, described metastatic melanoma treatment (tx) patterns and safety of T-VEC in the real-world setting (Perez et al, SMR 2018). In this analysis, we evaluated T-VEC use in pts after prior CPI use or with CPI from COSMUS-1. Methods: Of 76 pts treated with T-VEC (first dose 27Nov2015-15Dec2016), 33 pts had received pembrolizumab, nivolumab and/or ipilimumab (ie, CPI) prior to or with T-VEC and were analyzed for demographics, clinicopathologic characteristics, outcomes, and adverse events. Two groups were identified: Group A, CPI then T-VEC only and Group B, CPI with T-VEC. Results: There were 21 pts in A and 12 pts in B; in B, all received TVEC + CPI with (1) prior CPI, n = 5, (2) prior CPI and additional CPI after combination, n = 1, (3) as combination only, n = 4, or (4) as combination followed by CPI only, n = 2. In A and B, respectively, mean age was 72 yrs and 63 yrs; 12 (57%) and 9 (75%) were men; 17 (81%) and 9 (75%) had ECOG 0-1,10 (48%) and 4 (33%) had Stage IIIB-IVM1a, and 11 (52%) and 7 (58%) had Stage IVM1b/c. Two pts (both in B) remained on T-VEC by study end. 21 (100%) pts in A and 10 (83%) pts in B discontinued T-VEC (most common, respectively: 10 pts and 3 pts due to disease progression, 4 pts and 2 pts due to physician decision). 2 pts had no injectable lesions left (in A) and 1 pt (in A) had pathologic complete response (CR). Adverse events of interest were reported in 7 pts (33%) in A and 6 pts (50%) in B; most common events in A and B, respectively, were immune-mediated events (n = 3 and 6) which included flu-like symptoms (fever, chills, rigor; n = 2 and 5) and injection site complications (n = 5 and 2). No herpetic infections were reported in pts. Conclusions: These real-world data suggest that T-VEC is well tolerated and can be administered in pts previously treated with a CPI, both those who switched to T-VEC or those where T-VEC was added on. One pt achieved a pathologic CR.

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