Douglas Johnson

• MD, MSCI
• Professor (Full) at Vanderbilt University

Importance Immune checkpoint inhibitors (ICIs) are efficacious in many cancer types but can produce immune-related adverse events (irAEs). As such, patients with preexisting autoimmune disorders are often excluded from clinical trials, although subsequent studies have shown that many of these patients have acceptable ICI tolerance. The safety and e...

9528 Background: Adjuvant PD1 treatment improves clinical outcomes in high-risk resected melanoma. We have shown that adjuvant PD1 can lead to irAEs that become chronic in up to 46% of treated patients (pts). We performed longer follow-up (f/u) to further characterize chronic irAEs from adjuvant PD1 treatment and assessed risk factors to determine...

e24083 Background: Immune-mediated diarrhea and colitis (IMDC) is a common toxicity to immune checkpoint inhibition (ICI) that is becoming increasingly common. Studies exploring the clinical course and outcomes of IMDC have been limited to relative small sample sizes ( < 200). We therefore aimed to provide a comprehensive account of the clinical, e...

This is a case with melanoma treated with adjuvant nivolumab. His course was complicated with hypothyroidism, mucositis and rash, with onset of treatment refractory gastritis and psoriasis which required biologic treatment. Ultimately this patient achieved remission from additional biologic treatment although still requires low-dose prednisone for...

With the increasing use of immune checkpoint inhibitors (ICIs) in combination regimens and in earlier stages of advanced melanoma, the effective management of immune-related adverse events (irAEs) is key to balancing immunotherapy efficacy and toxicity. Conflicting evidence exists on possible detrimental effects of immunosuppression with corticoste...

Ophthalmic immune-related adverse events (Eye-irAEs) from immune checkpoint inhibitors can cause visual morbidity. The absence of standardized definitions for Eye-irAEs not only impedes the development of evidence-based treatments but also progress in translational research. The objective of this study was to develop consensus guidance for an appro...

Background Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, but ICI myocarditis (ICI-M) remains a potentially fatal complication. The clinical implications and predictors of left ventricular ejection fraction (LVEF) <50% in ICI-M are not well understood. Objectives The aim of this study was to identify factors associated with...

Purpose Immune checkpoint inhibitors (ICIs) are increasingly used to treat advanced malignancy but can induce immune-related adverse events (irAE). The mechanisms behind these sporadic and sometimes life-threatening irAEs remain largely unexplored. Here, we present a case report and in-depth molecular analysis of an erythema nodosum (EN) like irAE...

This cohort study describes the morphologic classification, histopathologic characteristics, treatments, and outcomes of chronic cutaneous immune-related adverse events occurring in adjuvant or metastatic setting.

Background Large language models (LLMs) have emerged as transformative technologies, revolutionizing natural language understanding and generation across various domains, including medicine. In this study, we investigated the capabilities, limitations, and generalizability of Generative Pre-trained Transformer (GPT) models in analyzing unstructured...

Background Data on the safety profiles and clinical outcomes of patients with solid tumors and cardiac metastasis treated with immune checkpoint inhibitors (ICIs) are limited. Methods This is an international multicenter retrospective study of patients with cancer and cardiac metastasis at baseline. Patients who had received ≥1 dose of ICI were in...

Tumours of the appendix - a vestigial digestive organ attached to the colon - are rare. Although we estimate that around 3,000 new appendiceal cancer cases are diagnosed annually in the USA, the challenges of accurately diagnosing and identifying this tumour type suggest that this number may underestimate true population incidence. In the current a...

PURPOSE MAP2K1/MEK1 mutations are potentially actionable drivers in cancer. MAP2K1 mutations have been functionally classified into three groups according to their dependency on upstream RAS/RAF signaling. However, the clinical efficacy of mitogen-activated protein kinase (MAPK) pathway inhibitors (MAPKi) for MAP2K1-mutant tumors is not well define...

Immune checkpoint inhibitors (ICIs) have advanced the treatment of metastatic melanoma. However, some patients develop ICI-associated toxicities like hepatitis (ie, immune-mediated hepatitis; IMH). Although these toxicities usually resolve with steroids, steroid-refractory events may occur, which may be a major source of morbidity and mortality wit...

Introduction: Immune checkpoint inhibitors (ICIs) have advanced the treatment of metastatic melanoma by blocking immune system down-regulators enhancing T-cell-mediated anti-tumor responses. However, many ICIs induce immune-related adverse effects (irAEs) that can impact many organ systems. Areas covered: Strategies used to manage irAEs include...

Background Immune checkpoint inhibitors (ICIs) are associated with severe immune-related adverse events (s-irAEs) that result in hospitalization, emergency department (ED) visits, treatment discontinuation, or death. This study examined the impact of s-irAEs and their earliest management strategies on clinical outcomes in advanced non-small cell lu...

Background Tumor-associated macrophages (TAMs) play an essential role in the tumor microenvironment influencing tumor growth and metastasis, immunosuppression, tissue remodeling, and resistance to immune checkpoint blockade (ICB).¹Leukocyte Ig-like receptor subfamily B (LILRB) proteins are a family of immune checkpoint receptors that support the im...

Background Studies have suggested that immune checkpoint inhibitors (ICI) may exacerbate inflammatory and autoimmune conditions,1–3 but mouse-models and possibly preliminary human data have demonstrated some anti-inflammatory benefits.⁴ This study investigates the impact of ICIs on liver steatosis, using liver attenuation as a proxy, and liver enzy...

Background Circadian rhythms impact immune function; a previous study demonstrated that immunotherapy treatment times taking place later in the day correlated with poorer outcomes in patients with melanoma. However, this finding has not been replicated, and other infusion timing schemas are unexplored. The objective of this retrospective, cohort st...

Immune checkpoint therapies can drive antitumor responses and benefit patients but can also induce life-threatening immune-related adverse events such as myocarditis and myositis. These immune-related adverse events are rare but carry substantial morbidity and mortality. In this issue, Siddiqui and colleagues use single-cell RNA and T-cell receptor...

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, improving outcomes for many patients. However, toxicities termed immune-related adverse events (irAEs) are limitations of these revolutionary treatments. These irAEs may resolve with treatment or ICI cessation (acute) or persist many months beyond therapy cessation (chronic). Ac...

The NCCN Guidelines for Cutaneous Melanoma (termed Melanoma: Cutaneous ) provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients. These NCCN Guidelines Insights focus on the update to neoadjuvant systemic therapy options and summarize the new clinical data evaluated by the NCCN panel for the recommended t...

Identifying patients likely to benefit from immune checkpoint inhibitor (ICI) treatment remains a crucial goal for melanoma. The objective of this study is to assess the association between primary tumor features and immunotherapy response and survival in advanced melanoma patients. In this single-center retrospective cohort study, disease characte...

Background: Myocarditis (MC) secondary to ICIs is a severe immune-related adverse event (irAE) and may co-occur with myositis (MYS) and myasthenia gravis (MG), presenting as the triple M overlap syndrome (TMOS). Limited data have been reported on TMOS as a fatal irAE complication. We sought to understand the clinical complexities of TMOS and applie...

Background Immune checkpoint inhibitor (ICI)-induced myocarditis is a rare immune-related adverse event (irAE) with a fatality rate of 40%–46%. However, irMyocarditis can be asymptomatic. Thus, improved monitoring, detection and therapy are needed. This study aims to generate knowledge on pathogenesis and assess outcomes in cancer centers with inte...

Background Tebentafusp, a bispecific (gp100×CD3) ImmTAC, significantly improved overall survival (OS) outcomes for HLA-A*02:01+ adult patients with untreated metastatic uveal melanoma (mUM) and showed promising survival in previously treated mUM with 1-year OS of 62% in the primary analysis of study IMCgp100-102. Here we report long-term outcomes f...

Background: Immune-checkpoint inhibitors (ICI) are associated with life-threatening myocarditis but milder presentations are increasingly recognized. The same autoimmune process that causes ICI-myocarditis can manifest concurrent generalized myositis, myasthenia-like syndrome, and respiratory muscle failure. Prognostic factors for this 'cardiomyoto...

Background Anti-Program-Death-1 (PD-1) is a standard adjuvant therapy for patients with resected melanoma. We hypothesized that there are discrepancies in survival, recurrence pattern and toxicity to adjuvant PD-1 between different ethnicities and melanoma subtypes. Objective We performed a multicenter cohort study incorporating 6 independent inst...

10582 Background: IrAEs are prevalent in patients treated with immune checkpoint inhibitors (ICI) and mimic classical autoimmune diseases. IrAE risk prediction could improve clinical decision making and patient safety for ICI-treated patients. Classical autoimmune diseases show strong associations with germline polymorphisms and with Human Leukocyt...

2643 Background: Myocarditis (MC) secondary to ICIs is a severe immune-related adverse event (irAE) and may co-occur with myositis (MYS) and myasthenia gravis (MG), presenting as the triple M overlap syndrome (TMOS). Limited data have been reported on TMOS as a fatal irAE complication. We sought to understand the clinical complexities of TMOS and a...

2653 Background: Patients with pre-existing NAID often flare with ICIs; neurological (neuro) immune related adverse events (irAEs) are often morbid or fatal, and little is known about safety of ICI in pts with NAID and other neuro conditions (e.g. Parkinson’s). Thus, we aimed to determine their safety and efficacy in these contexts. Methods: We ret...

2516 Background: Endocrine immune related adverse events (irAEs), including thyroid dysfunction (ICI-T), diabetes mellitus (ICI-DM) and hypophysitis (ICI-HP), caused by treatment with immune checkpoint inhibitors (ICIs) are largely irreversible and pose a burden to cancer patients. Variation in HLA predisposes to many autoimmune conditions, but dat...

9540 Background: Treatment (tx) of advanced melanoma during pregnancy represents a major challenge. While management of early-stage melanoma is similar to non-pregnant patients (pts), very little data is available on outcome or tx guidelines for pregnant pts with advanced stage. Therefore, we collected real world management data, to ultimately deve...

e21521 Background: Immune checkpoint inhibitors (ICI) are the standard treatment for patients (pts) with MM. However, only a subset of pts respond to ICIs. Temozolomide (TEM) is used in refractory settings but with low objective response rates and no clear overall survival benefit. The efficacy of combined ICI + TEM is not well described. Methods:...

9529 Background: Tebentafusp (gp100 x CD3) has demonstrated an overall survival (OS) benefit in mUM. Benefit was observed in patients (pts) who achieved a RECIST v1.1 partial response (PR), stable disease (SD) and even progressive disease (PD) (Nathan 2021). In Phase (Ph) 1, some melanoma pts had SD with tumor reduction > 10% that was confirmed at...

Background Artificial intelligence (AI) chatbots have become a major source of general and medical information, though their accuracy and completeness are still being assessed. Their utility to answer questions surrounding immune-related adverse events (irAEs), common and potentially dangerous toxicities from cancer immunotherapy, are not well defi...

The systemic therapeutic landscape for cutaneous melanoma continues to evolve, with numerous diverse options currently available. Several clinical trials have resulted in approvals from the FDA and subsequent revisions to the NCCN Guidelines, which reflect the most up-to-date, evidence-based data relating to the evaluation and management of these m...

The first-line treatment for metastatic melanoma is immune checkpoint blockade (ICB), but it fails in many patients and may have serious adverse events. We showed that rigosertib (RGS), a RAS-pathway inhibitor, promotes CD40 upregulation on melanoma cells and synergizes with ICB in preclinical melanoma models. However, residual disease still occurr...

With an increasing number of patients eligible for immune checkpoint inhibitors, the incidence of immune-related adverse events (irAEs) is on the rise. Dermatologic immune-related adverse events (D-irAEs) are the most common and earliest to manifest, often with important downstream consequences for the patient. Current guidelines lack clarity in te...

Background: Electronic health records (EHR) are increasingly used for studying multimorbidities. However, concerns about accuracy, completeness, and EHRs being primarily designed for billing and administration raise questions about the consistency and reproducibility of EHR-based multimorbidity research. Methods: Utilizing phecodes to represent the...

Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event of treatment with immune checkpoint inhibitors (ICI). We hypothesize that genetic susceptibility to Crohn’s disease (CD) and ulcerative colitis (UC) predisposes to IMC. In this study, we first develop a polygenic risk scores for CD (PRSCD) and UC (PRSUC) in cancer-free ind...

PURPOSE MAP2K1/MEK1 mutations are potentially actionable drivers in cancer. MAP2K1 mutations have been functionally classified into three groups according to their dependency on upstream RAS/RAF signaling. However, the clinical efficacy of MAPK pathway inhibitors (MAPKi) for MAP2K1 mutant tumors is not well defined. We sought to characterize the ge...

The advent of effective immunotherapy, specifically cytotoxic T-lymphocyte associated protein 4 and programmed cell death 1 inhibitors, as well as targeted therapy including BRAF/MEK inhibitors, has dramatically changed the prognosis for metastatic melanoma patients. Up to 50% of patients may experience long-term survival currently. Despite these a...

PURPOSE Although immune checkpoint inhibitors (ICIs) have improved outcomes in certain patients with cancer, they can also cause life-threatening immunotoxicities. Predicting immunotoxicity risks alongside response could provide a personalized risk-benefit profile, inform therapeutic decision making, and improve clinical trial cohort selection. We...

Background Immune checkpoint inhibitor (ICI) gastrointestinal toxicity (gastritis, enteritis, colitis) is a major cause of morbidity and treatment-related death. Guidelines agree steroid-refractory cases warrant infliximab, however best management of infliximab-refractory ICI gastrointestinal toxicity (IRIGItox) is unknown. Methods We conducted an...

Simple Summary Immune checkpoint inhibitors are increasingly being used in the treatment of a variety of cancers, both alone and in combination with other cancer therapies. Side effects often include skin reactions, which may occur more frequently in therapeutic regimens consisting of multiple immune checkpoint inhibitors. We conducted a systematic...

Background: Despite a 5 to 20-fold higher risk of Hodgkin lymphoma (HL) in people with HIV (PWH) than the general population, PWH were excluded from clinical trials that led to the approval of anti-PD-1 agents (PD-1) in HL. PD-1 have overall response rates (ORR) of 65-70% in the general population and are used in all lines of HL therapy. Several pr...

Background Despite the remarkable success of immunotherapy in treating melanoma, understanding of the underlying mechanisms of resistance remains limited. Emerging evidence suggests that upregulation of tumor-specific major histocompatibility complex-II (tsMHC-II) serves as a predictive marker for the response to anti-programmed death-1 (PD-1)/prog...

Background Both dabrafenib/trametinib (D/T) and anti-PD-1 monotherapy (PD-1) are approved adjuvant therapies for patients with stage III BRAF V600-mutant melanoma. However, there is still a lack of head-to-head comparative data. We aimed to describe efficacy and toxicity outcomes for these two standard therapies across melanoma centers. Methods Th...

Background Treatment of melanoma with immune checkpoint inhibitors (ICI) has dramatically changed outcomes.¹ Although ICI lack the traditional risks of cytotoxic chemotherapy, up to 50% of treated patients will experience an immune related adverse event (irAE).² Currently, we are unable to predict which patients will have an irAE. Additionally, som...

Background Combination immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed death protein 1 (PD-1) have induced durable responses in many malignancies but produce high grade immune related adverse events (irAEs) in up to half of patients. Given this high rate of toxicity, there is a growi...

Immune checkpoint inhibitors (ICI) have transformed the therapeutic landscape in oncology. However, ICI can induce uncommon life-threatening autoimmune T-cell-mediated myotoxicities, including myocarditis and myositis. The thymus plays a critical role in T cell maturation. Here we demonstrate that thymic alterations are associated with increased in...

Background: Geriatric patients (≥80 years) are underrepresented in immune checkpoint inhibitor (ICIs) clinical trials. However, their unique biology may affect their response to ICIs. There are currently no established biomarkers of the response to ICIs in adult patients with cancer that can help with patient selection. Methods: We built a multi...

Since the first approval for immune checkpoint inhibitors (ICIs) for the treatment of cutaneous melanoma more than a decade ago, immunotherapy has completely transformed the treatment landscape of this chemotherapy-resistant disease. Combination regimens including ICIs directed against programmed cell death protein 1 (PD-1) with anti-cytotoxic T ly...

Importance Natural language processing tools, such as ChatGPT (generative pretrained transformer, hereafter referred to as chatbot), have the potential to radically enhance the accessibility of medical information for health professionals and patients. Assessing the safety and efficacy of these tools in answering physician-generated questions is cr...

Immune checkpoint inhibitors (ICIs) have revolutionized the field of anti-cancer therapy over the last decade; they provide durable clinical responses against tumors by inhibiting immune checkpoint proteins that canonically regulate the T cell-mediated immune response. Despite their success in many primary tumors and soft tissue metastases, ICIs fu...

Introduction: Myocarditis associated with immune checkpoint inhibitors presents with an often-severe clinical phenotype with arrhythmias and concurrent myositis. This condition tends to occur early after treatment onset and is associated with a high fatality rate. Diagnosis may be challenging, and treatment algorithms are still evolving. Areas co...

In this randomized phase 2 trial, blockade of cytotoxic T-lymphocyte protein 4 (CTLA-4) with continuation of programmed death protein 1 (PD-1) blockade in patients with metastatic melanoma who had received front-line anti-PD-1 or therapy against programmed cell death 1 ligand 1 and whose tumors progressed was tested in comparison with CTLA-4 blocka...

Introduction The emergence of immune checkpoint inhibitors (ICIs) has improved survival outcomes in patients with metastatic melanoma, while potentially increasing the use of systemic therapy near the end of life (EOL). Yet, less is known on how to facilitate treatment decision making and identify patients who might benefit from early palliative ca...

Importance: Anti-programmable cell death-1 (anti-PD-1) improves relapse-free survival when used as adjuvant therapy for high-risk resected melanoma. However, it can lead to immune-related adverse events (irAEs), which become chronic in approximately 40% of patients with high-risk melanoma treated with adjuvant anti-PD-1. Objective: To determine...

Immune checkpoint inhibitors have transformed cancer therapy, but their optimal use is still constrained by lack of response and toxicity. Biomarkers of response may facilitate drug development by allowing appropriate therapy selection and focusing clinical trial enrollment. However, aside from PD‐L1 staining in a subset of tumors and rarely mismat...

The discovery and development of novel treatments that harness the patient's immune system and prevent immune escape has dramatically improved outcomes for patients across cancer types. However, not all patients respond to immunotherapy, acquired resistance remains a challenge, and responses are poor in certain tumors which are considered to be imm...

The management of metastatic melanoma patients that fail multiple lines of systemic therapy remains a significant challenge. There is limited literature regarding combination of anti-PD-1 and temozolomide, or of other chemotherapy agents, in melanoma. Here, we present a series of 3 patients with metastatic melanoma and their responses to nivolumab...

Introduction: Immune checkpoint inhibitors (ICIs) have become a pillar of treatment for numerous cancers with increasing use in combination with other ICIs and in earlier stages of disease treatment. Although effective, ICI use is accompanied by a milieu of potentially bothersome or even life-threatening toxicities known as immune-related adverse...

6604 Background: The impact of severe adverse event (sAE) management (mgmt) on clinical outcomes in cancer patients (pts) receiving immune checkpoint inhibitor (ICI) therapy has not been fully examined. We aimed to evaluate the association between mgmt of sAEs and overall survival (OS) in pts receiving ICIs for advanced non-small cell lung cancer (...

3138 Background: Tumor mutation burden (TMB) correlates with immunotherapy response, but outcomes still vary in high TMB cancers, and many high TMB tumors lack T cell infiltration. Here, we assessed gene expression signatures of high TMB, including both inflamed and non-inflamed tumors (defined by interferon-γ [IFN-γ] gene signatures). Methods: Gen...

9528 Background: Preclinical models support the combination of immune checkpoint inhibitors (ICI) with targeted therapy (TT), suggesting a synergistic effect; however, clinical trials evaluating the efficacy of triplet combination in first-line setting showed limited advantage compared to TT only. Early data from the phase II TRIDeNT (NCT02910700)...

9591 Background: Adjuvant anti-PD1 improves relapse-free survival in high-risk, resected melanoma, but can lead to irAEs, which become chronic in up to 41% of patients (Patrinely et al, JAMA Onc 2021). Given the expanding use of anti-PD-1 in earlier settings in many tumors, it is imperative to assess their long-term effects. We aimed to determine t...

Purpose Sclerosing mesenteritis (SM), a fibroinflammatory process of the mesentery, can rarely occur after immune checkpoint inhibitor (ICI) therapy; however, its clinical significance and optimal management are unclear. We aimed to assess the characteristics and disease course of patients who developed SM following ICI therapy at a single tertiary...

Purpose: Compared with people living without HIV (PWOH), people living with HIV (PWH) and cancer have traditionally been excluded from immune checkpoint inhibitor (ICI) trials. Furthermore, there is a paucity of real-world data on the use of ICIs in PWH and cancer. Methods: This retrospective study included PWH treated with anti-PD-1- or anti-PD...