Multicentric Assessment of Safety and Efficacy of Combinatorial Adjuvant Brain Metastasis Treatment by Intraoperative Radiation Therapy and Immunotherapy.

PURPOSE: After surgical resection of brain metastases (BMs), intraoperative radiation therapy (IORT) provides a promising alternative to adjuvant external beam radiation therapy by enabling superior organ-at-risk preservation, reduction of in-hospital times, and timely admission to subsequent systemic treatments, which increasingly comprise novel targeted immunotherapeutic approaches. We sought to assess the safety and efficacy of IORT in combination with immune checkpoint inhibitors (ICIs) and other targeted therapies (TTs). METHODS AND MATERIALS: In a multicentric approach incorporating individual patient data from 6 international IORT centers, all patients with BMs undergoing IORT were retrospectively assessed for combinatorial treatment with ICIs/TTs and evaluated for toxicity and cumulative rates, including wound dehiscence, radiation necrosis, leptomeningeal spread, local control, distant brain progression (DBP), and estimated overall survival. RESULTS: In total, 103 lesions with a median diameter of 34 mm receiving IORT combined with immunomodulatory systemic treatment or other TTs were included. The median follow-up was 13.2 (range, 1.2-102.4) months, and the median IORT dose was 25 (range, 18-30) Gy prescribed to the applicator surface. There was 1 grade 3 adverse event related to IORT recorded (2.2%). A 4.9% cumulative radiation necrosis rate was observed. The 1-year local control rate was 98.0%, and the 1-year DBP-free survival rate was 60.0%. Median time to DBP was 5.5 (range, 1.0-18.5) months in the subgroup of patients experiencing DBP, and the cumulative leptomeningeal spread rate was 4.9%. The median estimated overall survival was 26 (range, 1.2 to not reached) months with a 1-year survival rate of 74.0%. Early initiation of immunotherapy/TTs was associated with a nonsignificant trend toward improved DBP rate and overall survival. CONCLUSIONS: The combination of ICIs/TTs with IORT for resected BMs does not seem to increase toxicity and yields encouraging local control outcomes in the difficult-to-treat subgroup of larger BMs. Time gaps between surgery and systemic treatment could be shortened or avoided. The definitive role of IORT in local control after BM resection will be defined in a prospective trial.

Leveraging health care technology to improve health outcomes and reduce outcome disparities in AYA leukemia.

Significant improvements have occurred for adolescent and young adult (AYA) B-cell acute lymphoblastic leukemia (B-ALL) patients following the widespread adoption of "pediatric-inspired" treatment regimens for AYA patients cared for in adult oncology settings. However, for AYA patients, aged 15 to 39, an outcomes gap remains in B-ALL, necessitating the incorporation of novel therapies into up-front treatment regimens. As a result, clinical trial enrollment remains the current standard of care for AYA B-ALL across disease subtypes when available and accessible. Currently, several up-front trials are looking to incorporate the use of inotuzumab, blinatumomab, and chimeric antigen receptor T-cell therapy into existing chemotherapy backbones for AYA patients, as well as tyrosine kinase inhibitors for both Philadelphia-positive (Ph+) and Ph-like B-ALL. In addition to ongoing attempts to improve up-front treatments by incorporating immunotherapy and targeted approaches, the increased use of next generation sequencing for measurable residual disease evaluation has led to superior risk-stratification and a decreased need to pursue consolidative hematopoietic stem cell transplantation during the first complete remission for many patients.

Changes in Health Care Costs, Survival, and Time Toxicity in the Era of Immunotherapy and Targeted Systemic Therapy for Melanoma.

Importance: Melanoma treatment has evolved during the past decade with the adoption of adjuvant and palliative immunotherapy and targeted therapies, with an unclear impact on health care costs and outcomes in routine practice. Objective: To examine changes in health care costs, overall survival (OS), and time toxicity associated with primary treatment of melanoma. Design, Setting, and Participants: This cohort study assessed a longitudinal, propensity score (PS)-matched, retrospective cohort of residents of Ontario, Canada, aged 20 years or older with stages II to IV cutaneous melanoma identified from the Ontario Cancer Registry from January 1, 2018, to March 31, 2019. A historical comparison cohort was identified from a population-based sample of invasive melanoma cases diagnosed from the Ontario Cancer Registry from January 1, 2007, to December 31, 2012. Data analysis was performed from October 17, 2022, to March 13, 2023. Exposures: Era of melanoma diagnosis (2007-2012 vs 2018-2019). Main Outcomes and Measures: The primary outcomes were mean per-capita health care and systemic therapy costs (Canadian dollars) during the first year after melanoma diagnosis, time toxicity (days with physical health care contact) within 1 year of initial treatment, and OS. Standardized differences were used to compare costs and time toxicity. Kaplan-Meier methods and Cox proportional hazards regression were used to compare OS among PS-matched cohorts. Results: A PS-matched cohort of 731 patients (mean [SD] age, 67.9 [14.8] years; 437 [59.8%] male) with melanoma from 2018 to 2019 and 731 patients (mean [SD] age, 67.9 [14.4] years; 440 [60.2%] male) from 2007 to 2012 were evaluated. The 2018 to 2019 patients had greater mean (SD) health care (including systemic therapy) costs compared with the 2007 to 2012 patients ($47 886 [$55 176] vs $33 347 [$31 576]), specifically for stage III ($67 108 [$57 226] vs $46 511 [$30 622]) and stage IV disease ($117 450 [$79 272] vs $47 739 [$37 652]). Mean (SD) systemic therapy costs were greater among 2018 to 2019 patients: stage II ($40 823 [$40 621] vs $10 309 [$12 176]), III ($55 699 [$41 181] vs $9764 [$12 771]), and IV disease ($79 358 [$50 442] vs $9318 [$14 986]). Overall survival was greater for the 2018 to 2019 cohort compared with the 2007 to 2012 cohort (3-year OS: 74.2% [95% CI, 70.8%-77.2%] vs 65.8% [95% CI, 62.2%-69.1%], hazard ratio, 0.72 [95% CI, 0.61-0.85]; P < .001). Time toxicity was similar between eras. Patients with stage IV disease spent more than 1 day per week (>52 days) with physical contact with the health care system by 2018 to 2019 (mean [SD], 58.7 [43.8] vs 44.2 [26.5] days; standardized difference, 0.40; P = .20). Conclusions and Relevance: This cohort study found greater health care costs in the treatment of stages II to IV melanoma and substantial time toxicity for patients with stage IV disease, with improvements in OS associated with the adoption of immunotherapy and targeted therapies. These health system-wide data highlight the trade-off with adoption of new therapies, for which there is a greater economic burden to the health care system and time burden to patients but an associated improvement in survival.

Immunotherapy for keratinocyte cancers. Part I: Immune-related epidemiology, risk factors, pathogenesis, and immunotherapy management of keratinocyte cancers.

The important role of the immune system in the surveillance and control of keratinocyte cancers (KCs), namely squamous and basal cell carcinomas, is increasingly appreciated, as new immunotherapies have recently become available. As the field of immunotherapy is rapidly evolving, this review synthesizes key concepts and highlights important cellular components within the immune system responsible for attacking KCs. We review the most current data on the epidemiology, risk factors, and immunotherapy management for KCs. Patients will seek advice from dermatologists to help explain why immunotherapies work for KCs and whether they might be appropriate for different clinical scenarios. Collaboration with medical colleagues across different disciplines to evaluate KCs for response to immunotherapy and early recognition of immune-related adverse events will help to optimize patient outcomes.

Patient-reported outcome (PRO)-based symptom assessment in patients with advanced lung cancer receiving first-line combination immunotherapy: a protocol for a multicenter, prospective, observational study.

BACKGROUND: Immunotherapy is currently applied in the first-line treatment regimens for numerous advanced cancers, especially advanced lung cancer. Immune-related adverse events (irAEs) resulting from immunotherapy can vary in severity and cause a substantial symptom burden to patients. However, there are limited data on symptom burden in patients with advanced lung cancer following immunotherapy. To address this deficit, this study aims to provide insight into the symptom burden and severity through patient-reported outcome measurements and conduct an analysis of temporal trends and clinical consequences of symptom burden in patients with advanced lung cancer receiving combination immunotherapy. METHODS: We will prospectively recruit 168 eligible patients from 14 hospitals in China. Eligible patients will be aged ≥ 18 years, pathologically diagnosed with locally advanced or stage IV primary lung cancer without surgical indications, and agreed to receive immunotherapy in combination with other therapies. The primary outcome of this study is the symptom burden of patients during the immunotherapy course. Longitudinal symptom data will be collected using the MD Anderson Symptom Inventory-Lung Cancer module (MDASI-LC) and the symptomatic irAEs scale at baseline (once before treatment) and weekly after treatment, until 1 month after the last treatment cycle has been completed. The trajectory of symptom burden following combination immunotherapy will be depicted, and by linking it to clinical outcomes (the secondary outcome and exploratory outcome of this study), the consequence of symptom burden in patients with advanced lung cancer receiving combination immunotherapy will be examined further. DISCUSSION: This study intends to establish longitudinal symptom trajectories in patients with lung cancer receiving immunotherapy, and explore its association with clinical outcomes. These findings may serve as an important reference for clinicians in the symptomatic management of patients with lung cancer receiving immunotherapy. TRIAL REGISTRATION NUMBER: ChiCTR2200061540. Registered on June 28, 2022.

Assessment of Symptoms and Adverse Events Related to Immunotherapy in Patients With Cancer: An Integrative Review.

CONTEXT: Clinical practice guidelines advocate for routine assessment of symptoms and adverse events during immunotherapy treatment of cancer. Outside the clinical trial setting, there are few examples of such assessment in practice. OBJECTIVES: To identify, appraise, and synthesize the available literature regarding the assessment of immune-related symptoms and adverse events in patients with cancer beyond the clinical trial setting. Specifically, we aimed to identify the measurement instruments used, who completes these and when. METHODS: We completed an integrative review following established methods including a systematic literature search of electronic databases, a dual process for screening, quality appraisal, and data extraction. We included primary studies (retrospective or prospective) reporting the use of instruments or strategies to assess symptoms or adverse events in patients with cancer treated with immunotherapy. Outcomes of interest included: 1) how immune-related symptoms and adverse events were assessed; 2) types of assessment instruments; 3) frequency of instrument use and mode of administration; 4) the reported duration and intensity of symptoms and 5) adverse events and associated management strategies. Data were synthesized narratively. RESULTS: We screened 2138 articles and included 16 articles representing 2553 patients with cancer undergoing immunotherapy. All articles were published between 2018 and 2022 and were of sound methodological quality. Seven studies were retrospective chart reviews, and the remaining studies prospectively collected data, with seven collecting patient reported outcomes. In studies where data were collected at more than one time point (n = 6), weekly assessment during immunotherapy was the most common frequency. The potential for implementation of assessment into routine clinical practice was described in just four studies. CONCLUSION: Despite recommendations from clinical practice guidelines for routine assessment of symptoms and adverse events during immunotherapy treatment for cancer, there are few examples of how this is undertaken in clinical practice. The use of patient reported outcome measures to assess toxicity from immunotherapy is uncommon but offers the potential to identify symptoms early and facilitate timely intervention. Our review highlights the available instruments, how they have been used and the need for more applied research in this field to optimize patient outcomes.

Immune-induced pneumonia in patients with advanced solid tumors treated with immunotherapy: a real-world assessment.

Aim: To investigate the computed tomography (CT) and clinical characteristics of immunotherapy-induced pneumonitis (IIP) in patients with advanced solid tumors. Patients & methods: CT and clinical data of 254 patients with advanced solid tumors treated with immune checkpoint inhibitors in our hospital were collected retrospectively. Results: The incidences of IIP in patients with non-small-cell lung cancer, lymphoma and gastrointestinal tumors were 19% (19/100), 9.8% (6/61) and 6.2% (4/65), respectively. The median onset time for all 31 IIP patients was 44 days (interquartile range: 24-65). Most IIP patients (21/31) had grade 1-2 disease. Multifocal ground-glass opacities (seen in 21/31 patients) were the main CT findings of IIP. Conclusion: Patients should be alerted to the risk of IIP, an adverse reaction that has a relatively low incidence but which is sometimes life-threatening.

The study aimed to investigate the clinical and computed tomography (CT) features of immunotherapy-induced pneumonitis (IIP) in patients with advanced solid tumors. To describe these characteristics, clinical and CT information of 254 patients with advanced solid tumors who were treated with drugs called immune checkpoint inhibitors were collected. The incidences of IIP in patients with non-small-cell lung cancer, lymphoma and gastrointestinal tumors were 19% (19/100), 9.8% (6/61) and 6.2% (4/65), respectively. The median time taken to develop IIP for all 31 IIP patients was 44 days. Most IIP patients had mild or moderate (grade 1­2) disease. The main CT findings of IIP were abnormalities called multifocal ground-glass opacities (21/31). Most IIP patients can recover well after glucocorticoid discontinuation. This real-world study was done to raise physicians' awareness of the possible development of IIP, an adverse reaction with a relatively low incidence but which is sometimes life-threatening, to highlight the variety of CT manifestations, and to provide advice on regulating the timing and method of glucocorticoid therapy.

Cognitive assessment in patients treated by immunotherapy: the prospective Cog-Immuno trial.

BACKGROUND: The discovery of the importance of the immune system and its role in oncogenesis led to the development of immunotherapy, a treatment that represents a major advance in oncology management. Due to the recent nature of immunotherapy, little is known about its side effects and their impact on quality of life. To date, there is no published study that accurately assesses the impact of immunotherapy on cognition, mood and/or fatigue in patients treated for cancer, despite potential neurological toxicities. The purpose of this study is to prospectively assess the incidence of cognitive impairment and cognitive complaints among cancer patients naïve for immunotherapy without concomitant anti-cancer treatment. METHODS: The Cog-Immuno trial is a multicentre longitudinal study addressing patients with cancer candidate to receive immunotherapy alone (n = 100). Immunotherapy treatment will include either anti-PD1/PDL1 or anti-CTLA4 monotherapy or combination therapy. Cognitive and quality of life assessment, electrocardiogram (ECG) and biological tests will be performed at baseline, thereafter 3, and 6 months after immunotherapy initiation. The primary endpoint is the proportion of patients treated by immunotherapy who will experience a decline in cognitive performances or in Montreal Cognitive Assessment (MoCA) score within 3 months after inclusion. Secondary endpoints concern: anxiety, depression, fatigue, clinical characteristics, biological data and neurophysiological measures (heart rate variability and hemispheric lateralization). A pre-clinical study will be conducted in cancer bearing mice receiving checkpoint inhibitors (ICI) with the evaluation of cognitive functions and emotional reactivity, collection of blood samples and investigation of neurobiological mechanisms from brain slices. DISCUSSION: Assessing and understanding the incidence and the severity of cognitive impairment and its impact on quality of life in cancer patients treated by immunotherapy is a major issue. The results of this study will provide information on the impact of these treatments on cognitive functions in order to help the physicians in the choice of the treatment. TRIAL REGISTRATION: NCT03599830, registered July 26, 2018. PROTOCOL VERSION: Version 5.1 dated from 2020/10/02.

Pharmacist's role in immune-related adverse events management: real-world incidence and risk evaluation from immunotherapy.

OBJECTIVES: The challenge of using immune checkpoint inhibitors (ICI) is the immune-related adverse events (irAEs). Nonetheless, there is scarce evidence regarding the irAEs in Thailand. The primary aims of this study are to assess the incidence as well as risk factors of irAEs among cancer patients in Wattanosoth hospital. METHODS: This was a cross-sectional retrospective chart review for the 3-year period (2017-2019). Data were collected after initiating the approved ICIs and patients were then followed for 12 months. The outcomes included incidences of irAEs, adverse events management, and tumor objective response. Bivariate analysis was performed for factors that might be associated with irAEs occurrences. RESULTS: Data from 91 patients was collected. There was a 49.5% overall irAEs incidence. The most frequent irAE to occur affected the endocrine system (29.85%). In addition, we identified that odds ratios of irAEs development increased in patients who had four or more ICI cycles or had a serum creatinine level higher than 1.2 mg/dl, (OR: 1.75; 95% CI 1.1611:2.6256, P = 0.0074) and (OR: 1.58; 95% CI: 1.0628:2.3574; P = 0.0238), respectively. The emergence of irAEs may be a sign of tumor objective responses (OR: 1.79; 95% CI 1.0035:3.1889; P = 0.0486). CONCLUSION: This study demonstrates that irAEs are common in patients treated with ICIs. In addition, our study identifies that number of cycles and serum creatinine influence the development of irAEs. Hence, prompt recognition and an adequate monitoring plan should be cautiously taken into consideration.

Immunotherapy-induced Colitis: A Comprehensive Review of Epidemiology, Clinical Presentation, Diagnostic Workup, and Management Plan.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of a variety of malignancies including advanced melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancers among others. Since their introduction, there has been significant improvement in survival and prognosis in patients with advanced malignancies. Unfortunately, improved outcomes have come at a price of significant immune-related adverse events, with those of the gastrointestinal tract being the most common. Gastrointestinal immune-related adverse events frequently present as diarrhea and colitis, the severity of which can range from mild diarrhea to fulminant colitis with intestinal perforation. Currently, management of ICI-induced colitis is primarily guided by retrospective studies and expert opinion. A significant number of ICI-induced colitis responds to high-dose corticosteroids; however, some patients require further therapy with biologics. There is limited information on the factors which may predispose patients to ICI-induced colitis. Future research elucidating these risk factors along with development of a scoring system could allow for risk-stratification of patients before initiation of ICI therapy. Such a system may help clinicians and patients keep a high index of suspicion regarding ICI-induced colitis and could hopefully reduce the incidence of severe cases. Similarly, future studies should investigate protective factors against ICI-induced colitis, which could potentially allow more patients to safely benefit from ICI therapy.

Efficiency of Electronic Health Record Assessment of Patient-Reported Outcomes After Cancer Immunotherapy: A Randomized Clinical Trial.

Importance: Cancer immunotherapy causes a wide range of immune-related adverse events (irAEs) that require close and timely follow-up. Objectives: To compare the efficiency between electronic patient-reported outcomes (ePRO) and traditional follow-up models in cancer immunotherapy. Design, Setting, and Participants: This open-label randomized clinical trial was performed from September 1, 2019, to March 31, 2021. Patients were randomized to the ePRO model intervention or a control group by a computer system. A total of 28 Chinese tertiary care hospitals participated. Patients who were receiving cancer immunotherapy and could use smartphones or computers were eligible. A total of 300 patients were screened and 278 (92.7%) were enrolled. Interventions: The control group was followed up using traditional methods, including clinic visits every 21 days and telephone follow-up every 3 months. In the intervention group, the ePRO follow-up model included a questionnaire of common symptoms and an image recognition function to evaluate grades of typical irAEs. Patients completed questionnaires weekly and uploaded pictures of results between visits. When grade 1 or 2 irAEs occurred, standardized advice was sent automatically. If grade 3 or 4 irAEs were reported, the model alerted the health care team for assessment and intervention immediately. All patients were followed up for 6 months or until treatment completion. Main Outcomes and Measures: Incidence of serious (grades 3 to 4) irAEs, emergency department (ED) visits, quality of life (QOL), time spent implementing the ePRO model, rate of treatment discontinuation, and death were compared between groups post intervention. Results: A total of 278 patients (mean [SD] age, 58.8 [12.7 (range, 27-78)] years; 206 men [74.1%]) were included in the analysis, consisting of 141 in the intervention group and 137 in the control group. At the postintervention evaluation, the intervention group showed a reduced incidence of serious irAEs (29 of 141 [20.6%] vs 46 of 137 [33.6%]; hazard ratio [HR], 0.51 [95% CI, 0.30-0.88]; P = .01), fewer ED visits (23 of 141 [16.3%] vs 41 of 137 [29.9%]; HR, 0.46 [95% CI, 0.26-0.81]; P = .01), a lower rate of treatment discontinuation (5 of 141 [3.6%] vs 15 of 137 [11.0%]; HR, 0.30 [95% CI, 0.11-0.85]; P = .02), a higher QOL level (mean [SD] score, 74.2 [15.1; 95% CI, 71.7-76.9] vs 64.7 [28.5; 95% CI, 61.0-68.4]; P = .001), and less time implementing follow-up (mean [SD], 8.2 [3.9; 95% CI, 5.0-10.6] minutes vs 36.1 [15.3; 95% CI, 33.6-38.8] minutes; P < .001). However, there were no significant differences between groups in death rates (2 of 141 [1.4%] vs 5 of 137 [3.6%]; HR, 0.38 [95% CI, 0.07-1.99]; P = .28). Conclusions and Relevance: This randomized clinical trial found that the ePRO follow-up model can improve safety and QOL of patients receiving cancer immunotherapy as well as reduce time spent monitoring. This model may provide reliable information and management recommendations. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2100052819.

Cutaneous adverse events in 155 patients with metastatic melanoma consecutively treated with anti-CTLA4 and anti-PD1 combination immunotherapy: Incidence, management, and clinical benefit.

BACKGROUND: In response to the increased use of combination checkpoint inhibitors (CPIs) and the resulting increased cutaneous adverse events (CAEs), this study reviewed patients with melanoma treated with combination CPIs to characterize CAE features and their clinical impact, correlation to adverse events in other organs, and correlation to tumor response. METHODS: Patients from the authors' institutional database who received at least 1 dose of ipilimumab in combination with either nivolumab or pembrolizumab between January 1, 2012, and December 31, 2017, for stage IV or unresectable stage III melanoma were identified. The time to next treatment (TTNT) was calculated from the start of CPI therapy to the start of the next treatment or death, and the development of CAEs was tested in a time-dependent Cox regression to identify associations with TTNT. RESULTS: Eighty-one patients (52.3%) experienced a total of 92 CAEs, including eczematous dermatitis (25.0%), morbilliform eruption (22.8%), vitiligo (12.0%), and pruritus without rash (8.7%). The median times to the onset and resolution of CAEs were 21 days (range, 0-341 days) and 50 days (range, 1-352 days), respectively. Most CAEs resolved after patients entered the CPI maintenance phase and treatment with oral antihistamines with or without topical steroids. CPI discontinuation occurred in 4 patients (2.6%) because of CAEs, in 49 (31.6%) because of other immune-related adverse events, and in 20 (12.9%) because of melanoma progression or death. For patients definitively treated with CPIs (n = 134; 86.5%), TTNT was significantly longer with CAEs than without CAEs (hazard ratio, 0.567; 95% CI, 0.331-0.972; P = .039). CONCLUSIONS: CAEs were mostly reversible and rarely required therapy discontinuation. The development of CAEs was associated with a longer TTNT, and this suggested a possible clinical benefit.

Imaging of Cancer Immunotherapy: Response Assessment Methods, Atypical Response Patterns, and Immune-Related Adverse Events, From the AJR Special Series on Imaging of Inflammation.

The introduction of immunotherapy with immune-checkpoint inhibitors (ICIs) has revolutionized cancer treatment paradigms. Since FDA approval of the first ICI in 2011, multiple additional ICIs have been approved and granted marketing authorization, and many promising agents are in early clinical adoption. Due to the distinctive biologic mechanisms of ICIs, the patterns of tumor response and progression seen with immunotherapy differ from those observed with cytotoxic chemothera-pies. With increasing clinical adoption of immunotherapy, it is critical for radiologists to recognize different response patterns and common pitfalls to avoid misinterpretation of imaging studies or prompt premature cessation of potentially effective treatment. This review provides an overview of ICIs and their mechanisms of action and discusses anatomic and metabolic immune-related response assessment methods, typical and atypical patterns of immunotherapy response (including pseudoprogression, hyperprogression, dissociated response, and durable response), and common imaging features of immune-related adverse events. Future multicenter trials are needed to validate the proposed immune-related response criteria and identify the functional imaging markers of early treatment response and survival.

The Price of Success: Immune-Related Adverse Events from Immunotherapy in Lung Cancer.

Cancer immunotherapy has the goal of enhancing a patient's intrinsic immune processes in order to mount a successful immune response against tumor cells. Cancer cells actively employ tactics to evade, delay, alter, or attenuate the anti-tumor immune response. Immune checkpoint inhibitors (ICIs) modulate endogenous regulatory immune mechanisms to enhance immune system activation, and have become the mainstay of therapy in many cancer types. This activation occurs broadly and as a result, activation is supraphysiologic and relatively non-specific, which can lead to immune-related adverse events (irAEs), the frequency of which depends on the patient, the cancer type, and the specific ICI antibody. Careful assessment of patients for irAEs through history taking, physical exam, and routine laboratory assessments are key to identifying irAEs at early stages, when they can potentially be managed more easily and before progressing to higher grades or more serious effects. Generally, most patients with low grade irAEs are eligible for re-challenge with ICIs, and the use of corticosteroids to address an irAE is not associated with poorer patient outcomes. This paper reviews immune checkpoint inhibitors (ICIs) including their mechanisms of action, usage, associated irAEs, and their management.

Nonclinical safety assessment of engineered T cell therapies.

Over the last decade, immunotherapy has established itself as an important novel approach in the treatment of cancer, resulting in a growing importance in oncology. Engineered T cell therapies, namely chimeric antigen receptor (CAR) T cells and T cell receptor (TCR) T cell therapies, are platform technologies that have enabled the development of products with remarkable efficacy in several hematological malignancies and are thus the focus of intense research and development activity. While engineered T cell therapies offer promise in addressing currently intractable cancers, they also present unique challenges, including their nonclinical safety assessment. A workshop organized by HESI and the US Food and Drug Administration (FDA) was held to provide an interdisciplinary forum for representatives of industry, academia and regulatory authorities to share information and debate on current practices for the nonclinical safety evaluation of engineered T cell therapies. This manuscript leverages what was discussed at this workshop to provide an overview of the current important nonclinical safety assessment considerations for the development of these therapeutic modalities (cytokine release syndrome, neurotoxicity, on-target/off-tumor toxicities, off-target effects, gene editing or vector integration-associated genomic injury). The manuscript also discusses approaches used for hazard identification or risk assessment and provides a regulatory perspective on such aspects.

PET/CT metabolic patterns in systemic immune activation: A new perspective on the assessment of immunotherapy response and efficacy.

Despite advances in immunotherapy, extensive challenges remain in its clinical application. Positron emission tomography (PET)/computed tomography (CT) is widely used in the diagnosis and follow-up of malignant tumors and in the prediction of treatment outcomes. Successful cancer immunotherapy requires systemic immune activation. In addition to local immune responses, a systemic antitumor response involving primary and secondary lymphoid organs is required for tumor eradication. Immune-related adverse events (IRAEs) are considered to be a manifestation of excessive immune activation. PET/CT can monitor the metabolic changes in peripheral lymphoid organs and related organs. Thus, it can identify patients with effective immune activation and predict the efficacy and outcomes of immunotherapy. This review aimed to investigate the theoretical basis and feasibility of applying PET/CT for monitoring the immune activation status of peripheral lymphoid organs after immunotherapy and predict its effectiveness. Towards this goal, we reviewed the cellular components and structural composition of peripheral lymphoid organs, as well as their functions in the systemic immune response. We analyzed the theoretical basis and feasibility of applying PET/CT to monitor the immune activation status of peripheral lymphoid organs after immunotherapy to predict the effectiveness of immunotherapy.

Health-related quality-of-life assessment of patients with solid tumors on immuno-oncology therapies.

Immuno-oncology therapies have been approved for various solid tumors; however, the high cost of these treatments and their potential toxicities require a thorough assessment of their risks and benefits. Collection of data directly from patients through patient-reported outcome instruments can improve the precision and reliability of adverse event detection, assess tolerability of adverse events, and provide an evaluation of health-related quality of life (HRQOL) changes from immuno-oncology therapies. There is robust development in HRQOL tools specifically for patients treated with immuno-oncology agents. This review examines the history and basic concepts of HRQOL and patient-reported outcome assessments commonly used in oncological trials, highlighting the strengths and weaknesses of current approaches when applied to immunotherapies, as well as some of the current efforts to develop tools for this field and opportunities for future research. LAY SUMMARY: Immuno-oncology (IO) therapies are costly and carry potential toxicities known as immune-related adverse events. Evaluation of health-related quality of life (HRQOL) can impact the risk-benefit assessment of IO therapies. Integration of HRQOL end points and patient-reported outcome data for IO therapies are urgently needed. Ongoing robust development of patient-reported outcome tools specific to IO therapies are currently underway and will permit the evaluation of HRQOL for IO agents. Improvement in precision and reliability of HRQOL evaluation will enhance the ultimate true value of these expensive and effective drugs.