PD-1 directed immunotherapy alters Tfh and humoral immune responses to seasonal influenza vaccine.

Anti-programmed death-1 (anti-PD-1) immunotherapy reinvigorates CD8 T cell responses in patients with cancer but PD-1 is also expressed by other immune cells, including follicular helper CD4 T cells (Tfh) which are involved in germinal centre responses. Little is known, however, about the effects of anti-PD-1 immunotherapy on noncancer immune responses in humans. To investigate this question, we examined the impact of anti-PD-1 immunotherapy on the Tfh-B cell axis responding to unrelated viral antigens. Following influenza vaccination, a subset of adults receiving anti-PD-1 had more robust circulating Tfh responses than adults not receiving immunotherapy. PD-1 pathway blockade resulted in transcriptional signatures of increased cellular proliferation in circulating Tfh and responding B cells compared with controls. These latter observations suggest an underlying change in the Tfh-B cell and germinal centre axis in a subset of immunotherapy patients. Together, these results demonstrate dynamic effects of anti-PD-1 therapy on influenza vaccine responses and highlight analytical vaccination as an approach that may reveal underlying immune predisposition to adverse events.

Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response.

Tumour cells evade immune surveillance by upregulating the surface expression of programmed death-ligand 1 (PD-L1), which interacts with programmed death-1 (PD-1) receptor on T cells to elicit the immune checkpoint response1,2. Anti-PD-1 antibodies have shown remarkable promise in treating tumours, including metastatic melanoma2-4. However, the patient response rate is low4,5. A better understanding of PD-L1-mediated immune evasion is needed to predict patient response and improve treatment efficacy. Here we report that metastatic melanomas release extracellular vesicles, mostly in the form of exosomes, that carry PD-L1 on their surface. Stimulation with interferon-γ (IFN-γ) increases the amount of PD-L1 on these vesicles, which suppresses the function of CD8 T cells and facilitates tumour growth. In patients with metastatic melanoma, the level of circulating exosomal PD-L1 positively correlates with that of IFN-γ, and varies during the course of anti-PD-1 therapy. The magnitudes of the increase in circulating exosomal PD-L1 during early stages of treatment, as an indicator of the adaptive response of the tumour cells to T cell reinvigoration, stratifies clinical responders from non-responders. Our study unveils a mechanism by which tumour cells systemically suppress the immune system, and provides a rationale for the application of exosomal PD-L1 as a predictor for anti-PD-1 therapy.

T-cell invigoration to tumour burden ratio associated with anti-PD-1 response.

Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (Tex cells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating Tex cells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade.

Management of Immunotherapy-Related Toxicities, Version 1.2022, NCCN Clinical Practice Guidelines in Oncology.

The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions, consisting of medical and hematologic oncologists with expertise across a wide range of disease sites, and experts from the areas of dermatology, gastroenterology, endocrinology, neurooncology, nephrology, cardio-oncology, ophthalmology, pulmonary medicine, and oncology nursing. The content featured in this issue is an excerpt of the recommendations for managing toxicities related to CAR T-cell therapies and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to immune checkpoint inhibitors, visit NCCN.org.

NCCN Guidelines Insights: Management of Immunotherapy-Related Toxicities, Version 1.2020.

The NCCN Guidelines for Management of Immunotherapy-Related Toxicities provide interdisciplinary guidance on the management of immune-related adverse events (irAEs) resulting from cancer immunotherapy. These NCCN Guidelines Insights describe symptoms that may be caused by an irAE and should trigger further investigation, and summarize the NCCN Management of Immunotherapy-Related Toxicities Panel discussions for the 2020 update to the guidelines regarding immune checkpoint inhibitor-related diarrhea/colitis and cardiovascular irAEs.

Lupus-like cutaneous reaction following pembrolizumab: An immune-related adverse event associated with anti-PD-1 therapy.

PD-1 (programmed cell death-1) inhibitors, used to treat metastatic melanoma and other malignancies, are associated with development of immune-related adverse events in the skin. Such reactions include morbilliform eruptions, vitiligo, alopecia areata and bullous pemphigoid. In this report, we describe a patient who developed a lupus-like cutaneous reaction in the setting of pembrolizumab therapy for metastatic melanoma, adding to the spectrum of reactions which may be observed in association with PD-1 inhibitor therapy.

Onco-Primary Care of Patients Receiving Immune Checkpoint Inhibitors.

Primary clinicians foster long-term relationships with patients and play key roles in the treatment journey for patients with cancer. Primary clinicians are important members of the multidisciplinary team, and are central in coordinating and providing supportive care. The use of immune checkpoint inhibitors in adjuvant/neoadjuvant treatments and metastatic disease requires an awareness of their long-term survival benefits and immune-related adverse events (irAEs). Primary clinicians collaborate with the oncology care team to increase irAE awareness and identify institutional and individualized approaches to manage irAEs. IrAEs can develop at any time and present with a spectrum of symptoms, making them difficult to differentiate from other conditions. IrAE management relies on early recognition, close monitoring, and intervention with corticosteroids and/or dose interruption. Delayed irAEs underscore the importance of continued clinical vigilance following treatment, as primary clinicians are patients' most enduring point of contact. Primary clinicians have a critical role in supporting the care of patients with cancer and ensuring appropriate irAE recognition, monitoring, and intervention. Long-term continuity of care is critical for the immuno-oncology patient journey.

FDG PET/CT Imaging 1 Week after a Single Dose of Pembrolizumab Predicts Treatment Response in Patients with Advanced Melanoma.

PURPOSE: Immunologic response to anti-programmed cell death protein 1 (PD-1) therapy can occur rapidly with T-cell responses detectable in as little as one week. Given that activated immune cells are FDG avid, we hypothesized that an early FDG PET/CT obtained approximately 1 week after starting pembrolizumab could be used to visualize a metabolic flare (MF), with increased tumor FDG activity due to infiltration by activated immune cells, or a metabolic response (MR), due to tumor cell death, that would predict response. PATIENTS AND METHODS: Nineteen patients with advanced melanoma scheduled to receive pembrolizumab were prospectively enrolled. FDG PET/CT imaging was performed at baseline and approximately 1 week after starting treatment. FDG PET/CT scans were evaluated for changes in maximum standardized uptake value (SUVmax) and thresholds were identified by ROC analysis; MF was defined as >70% increase in tumor SUVmax, and MR as >30% decrease in tumor SUVmax. RESULTS: An MF or MR was identified in 6 of 11 (55%) responders and 0 of 8 (0%) nonresponders, with an objective response rate (ORR) of 100% in the MF-MR group and an ORR of 38% in the stable metabolism (SM) group. An MF or MR was associated with T-cell reinvigoration in the peripheral blood and immune infiltration in the tumor. Overall survival at 3 years was 83% in the MF-MR group and 62% in the SM group. Median progression-free survival (PFS) was >38 months (median not reached) in the MF-MR group and 2.8 months (95% confidence interval, 0.3-5.2) in the SM group (P = 0.017). CONCLUSIONS: Early FDG PET/CT can identify metabolic changes in melanoma metastases that are potentially predictive of response to pembrolizumab and significantly correlated with PFS.

Advanced Practice Provider Model for Urgent Oncology Care.

Inherent to the cancer disease trajectory are heightened risks for a plethora of comorbid diagnoses. As the treatment landscape for oncology therapeutics continues to rapidly advance, patients are living longer and potentially experiencing more symptoms requiring rapid assessment. Prompt assessment and intervention for cancer or cancer treatment-related symptoms is imperative to achieve patient comfort and obtain the best overall patient outcomes. Traditionally, these patients were frequently referred to the emergency department (ED) when same-day clinic appointments were not obtainable. In order to decrease ED utilization and provide same-day urgent care for oncology patients, the Abramson Cancer Center established an advanced practice provider-led Oncology Evaluation Center where cancer patients are able to receive same-day assessment, symptom relief, and ultimately prevent unnecessary ED visits.

Diverse cutaneous side effects associated with BRAF inhibitor therapy: a clinicopathologic study.

BACKGROUND: Vemurafenib, a novel selective small molecule inhibitor of BRAF, has recently been shown to be effective in the treatment of melanomas harboring the BRAF V600E mutation. Similar to the broad-spectrum RAF inhibitor sorafenib, vemurafenib induces development of squamous cell carcinomas and keratoacanthomas as a side effect of therapy. OBJECTIVE: We sought to detail additional cutaneous adverse effects of vemurafenib and a similar BRAF inhibitor, dabrafenib. METHODS: We evaluated the clinical and histologic feature of skin side effects developing on vemurafenib or dabrafenib therapy in 14 patients. RESULTS: Eight patients developed one or more squamous cell carcinomas, and 11 patients formed benign verrucous keratoses. Eight patients developed single lesions and/or widespread eruptions with histopathologic findings of acantholytic dyskeratosis, consistent with warty dyskeratomas and Darier- or Grover-like rashes, respectively. One patient developed palmoplantar hyperkeratosis, and darkening of existing nevi and new nevi within 2 months of starting vemurafenib. Side effects presented as early as 1 week after beginning therapy, with a mean time of onset of 12.6 weeks in our cohort. LIMITATIONS: This study was limited by the small number of cases, all from a single institution. CONCLUSION: Selective BRAF inhibitor therapy is associated with the development of malignant and benign growths, including keratoacanthoma-like squamous cell carcinomas, warty dyskeratomas, and verrucous keratoses, along with widespread eruptions with histologic features of acantholytic dyskeratosis. Given the potential for malignant lesions to develop on treatment, awareness of potential adverse effects of these agents is necessary, and a low threshold for biopsy of new growths is recommended.

Side effects in melanoma patients receiving adjuvant interferon alfa-2b therapy: a nurse's perspective.

PURPOSE: The aim of this review was to examine the toxicity profile of adjuvant interferon (IFN) alfa-2b in melanoma patients from a nursing perspective and to summarize practical information to guide the effective management of common IFN toxicities to improve patient comfort. METHODS: This is a narrative summary of both research and review articles identified by searching PubMed, National Cancer Institute, and American Cancer Society websites. It also assesses recognized guidelines on the management of adjuvant IFN toxicity relevant to nurses who are caring for patients receiving adjuvant IFN therapy. RESULTS: Adjuvant high-dose IFN alfa-2b (HDI) as compared with observation significantly prolongs relapse-free survival in patients with melanoma at high risk for recurrence after surgical resection; however, treatment compliance and patient quality of life can be compromised by its toxicity profile. HDI toxicities affect a number of organ systems and the majority of patients will experience some side effects. Common toxicities such as flu-like symptoms, fatigue, anorexia, neuropsychiatric symptoms, and laboratory abnormalities are discussed, along with both pharmacological and nonpharmacological management strategies. CONCLUSIONS: The considerable side effects of HDI can be managed using established strategies. Oncology nurses play a significant role in the management of patients with melanoma receiving adjuvant HDI, and their prompt recognition of side effects, together with an understanding of effective pharmacological and nonpharmacological interventions, will improve patient comfort; this has the potential to positively influence treatment adherence and completion of the recommended treatment course.

IL-8 and cathepsin B as melanoma serum biomarkers.

Melanoma accounts for only a small portion of skin cancer but it is associated with high mortality. Melanoma serum biomarkers that may aid early diagnosis or guide therapy are needed clinically. However, studies of serum biomarkers have often been hampered by the serum interference that causes false readouts in immunological tests. Here we show that, after using a special buffer to eliminate the serum interference, IL-8 and cathepsin B levels were significantly elevated in melanoma patients (p < 0.05). More importantly, the combination of IL-8 and cathepsin B were also studied as a prognosis marker for melanoma mortality. Our study provides a novel approach to examine serum biomarkers.

Automated Text-Based Symptom Monitoring With Rapid Clinician Triage for Patients With Cancer and Suspected or Confirmed COVID-19.

PURPOSE: Patients with cancer are at greater risk of developing severe symptoms from COVID-19 than the general population. We developed and tested an automated text-based remote symptom-monitoring program to facilitate early detection of worsening symptoms and rapid assessment for patients with cancer and suspected or confirmed COVID-19. METHODS: We conducted a feasibility study of Cancer COVID Watch, an automated COVID-19 symptom-monitoring program with oncology nurse practitioner (NP)-led triage among patients with cancer between April 23 and June 30, 2020. Twenty-six patients with cancer and suspected or confirmed COVID-19 were enrolled. Enrolled patients received twice daily automated text messages over 14 days that asked "How are you feeling compared to 12 hours ago? Better, worse, or the same?" and, if worse, "Is it harder than usual for you to breathe?" Patients who responded worse and yes were contacted within 1 hour by an oncology NP. RESULTS: Mean age of patients was 62.5 years. Seventeen (65%) were female, 10 (38%) Black, and 15 (58%) White. Twenty-five (96%) patients responded to ≥ 1 symptom check-in, and overall response rate was 78%. Four (15%) patients were escalated to the triage line: one was advised to present to the emergency department (ED), and three were managed in the outpatient setting. Median time from escalation to triage call was 11.5 minutes. Four (15%) patients presented to the ED without first escalating their care via our program. Participant satisfaction was high (Net Promoter Score: 100, n = 4). CONCLUSION: Implementation of an intensive remote symptom monitoring and rapid NP triage program for outpatients with cancer and suspected or confirmed COVID-19 infection is possible. Similar tools may facilitate more rapid triage for patients with cancer in future pandemics.

A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma.

Immunologic responses to anti-PD-1 therapy in melanoma patients occur rapidly with pharmacodynamic T cell responses detectable in blood by 3 weeks. It is unclear, however, whether these early blood-based observations translate to the tumor microenvironment. We conducted a study of neoadjuvant/adjuvant anti-PD-1 therapy in stage III/IV melanoma. We hypothesized that immune reinvigoration in the tumor would be detectable at 3 weeks and that this response would correlate with disease-free survival. We identified a rapid and potent anti-tumor response, with 8 of 27 patients experiencing a complete or major pathological response after a single dose of anti-PD-1, all of whom remain disease free. These rapid pathologic and clinical responses were associated with accumulation of exhausted CD8 T cells in the tumor at 3 weeks, with reinvigoration in the blood observed as early as 1 week. Transcriptional analysis demonstrated a pretreatment immune signature (neoadjuvant response signature) that was associated with clinical benefit. In contrast, patients with disease recurrence displayed mechanisms of resistance including immune suppression, mutational escape, and/or tumor evolution. Neoadjuvant anti-PD-1 treatment is effective in high-risk resectable stage III/IV melanoma. Pathological response and immunological analyses after a single neoadjuvant dose can be used to predict clinical outcome and to dissect underlying mechanisms in checkpoint blockade.

Timing of Onset of Adverse Cutaneous Reactions Associated With Programmed Cell Death Protein 1 Inhibitor Therapy.

Importance: An increasing number of cutaneous adverse reactions resulting from use of programmed cell death protein 1 (PD-1) inhibitors have been described, but with relatively little focus to date on the timing of these reactions. Objective: To determine the timing of cutaneous drug reactions after initiation of PD-1 inhibitor therapy. Design, Setting, and Participants: This retrospective observational study included patients referred to an academic dermatology clinic by an oncologist from January 1, 2014, through February 28, 2018, with at least 1 skin biopsy specimen of a skin reaction associated with PD-1 inhibitor use. Participants were included if they had a biopsy-proven cutaneous reaction in response to a PD-1 inhibitor used alone or in combination with ipilimumab. Exposures: All patients included in this study received pembrolizumab, nivolumab, or nivolumab with ipilimumab as immunotherapy for cancer. Main Outcomes and Measures: The main outcome measure was time to onset of biopsy-proven cutaneous reactions that occurred during or after use of pembrolizumab or nivolumab. Results: A total of 17 patients (12 men, 5 women; mean [SD] age, 68.6 [11.1] years) were identified who presented with cutaneous adverse reactions associated with PD-1 inhibitor therapy; these reactions included lichenoid dermatitis, bullous pemphigoid, erythema multiforme, eczema, lupus, and sarcoidosis. Twelve patients presented with reactions at least 3 months after beginning pembrolizumab or nivolumab therapy. The skin reactions presented a median (range) of 4.2 months (0.5-38.0 months) after drug initiation. In 5 cases, the cutaneous adverse reactions attributed to the PD-1 inhibitor therapy developed after the drug therapy was terminated. Conclusions and Relevance: Diverse cutaneous adverse reactions secondary to PD-1 inhibitor use may present with delayed onsets and even after discontinuation of therapy. Dermatologists should be aware of the potential for delayed presentations of cutaneous adverse reactions.

PD-1 Inhibitor Therapy: Consensus Statement From the Faculty of the Melanoma Nursing Initiative on Managing Adverse Events
.

BACKGROUND: Programmed cell death protein 1 (PD-1) inhibitor therapies are now a standard treatment for advanced melanoma and other tumor types. The immune-related adverse events (irAEs) associated with PD-1 inhibitor therapy are drastically different from the AEs associated with chemotherapy. Because these irAEs reflect immune system activation rather than side effects of therapy, nurses should be cognizant of the range of organ systems potentially affected as well as likely clinical presentations.
. OBJECTIVES: This article presents consensus statements to guide nurses in the recognition and management of irAEs associated with PD-1 inhibitor monotherapy for advanced melanoma.
. METHODS: Members of the Melanoma Nursing Initiative discussed the current literature and clinical experience regarding nursing interventions related to irAEs associated with PD-1 inhibitor therapy.
. FINDINGS: The care step pathways provided for select irAEs represent a proactive, comprehensive nursing care plan to support optimal outcomes for patients receiving PD-1 inhibitor therapy.

Improving the Safety of Oral Chemotherapy at an Academic Medical Center.

PURPOSE: Over the last decade, the use of oral chemotherapy (OC) for the treatment of cancer has dramatically increased. Despite their route of administration, OCs pose many of the same risks as intravenous agents. In this quality improvement project, we sought to examine our current process for the prescription of OC at the Abramson Cancer Center of the University of Pennsylvania and to improve on its safety. METHODS: A multidisciplinary team that included oncologists, advanced-practice providers, and pharmacists was formed to analyze the current state of our OC practice. Using Lean Six Sigma quality improvement tools, we identified a lack of pharmacist review of the OC prescription as an area for improvement. To address these deficiencies, we used our electronic medical system to route OC orders placed by treating providers to an oncology-specific outpatient pharmacist at the Abramson Cancer Center for review. RESULTS: Over 7 months, 63 orders for OC were placed for 45 individual patients. Of the 63 orders, all were reviewed by pharmacists, and, as a result, 22 interventions were made (35%). Types of interventions included dosage adjustment (one of 22), identification of an interacting drug (nine of 22), and recommendations for additional drug monitoring (12 of 22). CONCLUSION: OC poses many of the same risks as intravenous chemotherapy and should be prescribed and reviewed with the same oversight. At our institution, involvement of an oncology-trained pharmacist in the review of OC led to meaningful interventions in one third of the orders.

Acute visual loss after ipilimumab treatment for metastatic melanoma.

BACKGROUND: Ipilimumab, a humanized CLTA-4 antibody is a standard therapy in the treatment of advanced melanoma. While ipilimumab provides an overall survival benefit to patients, it can be associated with immune related adverse events (IrAEs). CASE PRESENTATION: Here we describe a patient treated with ipilimumab who experienced known IrAEs, including hypophysitis, as well as a profound vision loss due to optic neuritis. There are rare reports of optic neuritis occurring as an adverse event associated with ipilimumab treatment. Furthermore, the patient experienced multiple complications from high dose steroids used to manage his IrAEs. CONCLUSIONS: This case highlights the need for recognition of atypical immune mediated processes associated with newer checkpoint inhibitor therapies including ipilimumab.

What you are missing could matter: a rare, complex BRAF mutation affecting codons 599, 600, and 601 uncovered by next generation sequencing.

Testing for somatic mutations in tumor samples is becoming standard practice in a number of tumor types where targeted therapies are available. Since clinical care is dependent on the identification of the presence or absence of specific mutations, it is important that these mutations be identified consistently and accurately. Here we identify in a patient with metastatic melanoma a novel, complex mutation involving BRAF c.1798A>T (p.T599T), c.1799T>A (p.V600E), and c.1803A>T (p.K601N) that was identified by next generation sequencing but not by standard testing methods. The patient was started on a combination therapy inhibiting both BRAF and MEK, and demonstrated a dramatic clinical response. This case highlights the need for improved methods of mutation testing in tumor samples and exposes a pitfall in allele-specific testing methods that can be overcome using next generation sequencing.