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As cancer immunotherapies continue to expand across all areas of oncology, it is imperative to establish a standardized approach for defining and capturing clinically important toxicities, such as cytokine release syndrome (CRS). In this paper, we provide considerations for categorizing the variety of adverse events that may accompany CRS and for recognizing that presentations of CRS may differ among various immunotherapies (e.g. , monoclonal antibodies, CAR T cell therapies and T cell engagers, which can include bispecific antibodies and other constructs). The goals of this paper are to ensure accurate and consistent identification of CRS in patients receiving immunotherapies in clinical studies to aid in reporting; enable more precise evaluation of the therapeutic risk–benefit profile and cross-study analyses; support evidence-based monitoring and management of important toxicities related to cancer immunotherapies; and improve patient care and outcomes. These efforts will become more important as the number and variety of molecular targets for immunotherapies broaden and as therapies with novel mechanisms continue to be developed. [ABSTRACT FROM AUTHOR]

• CAR-T therapy offers durable remissions in refractory hematological malignancies. • Meta-analyses show significant efficacy in various hematologic cancers. • CAR T-cell therapy improves quality of life for blood cancer patients. • Encouraging results in CD22-targeting CAR T-cell therapy for B-cell malignancies. • Long-term studies reveal durable remissions but also persistent adverse effects. Chimeric Antigen Receptor T-cell (CAR-T) therapy has emerged as a groundbreaking and highly promising approach for the management of cancer. This paper reviews the efficacy of CAR-T therapy in the treatment of various hematological malignancies, also, with a mention of its effect on solid tumors, for which they have not received FDA approval yet. Different common and uncommon side effects are also discussed in this paper, with attention to the effect of each drug separately. By reviewing the recommendations of the FDA for CAR-T therapy research, we have extensively discussed dose-limiting toxicities. This further highlights the need for precise dosing strategies, striking a balance between therapeutic benefits and potential risks. Additionally, we reviewed the long-term follow-up of patients receiving CAR-T therapy to gain valuable insights into response durability and late-onset effects. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T (CAR-T) cell therapy, a groundbreaking immunotherapy. However, it faces formidable challenges in treating solid tumors, grappling with issues like poor trafficking, limited penetration, and insufficient persistence within the tumor microenvironment (TME). CAR-T cells are engineered to express receptors that target specific cancer antigens, enhancing their ability to recognize and eliminate cancer cells. This review paper explores the intricate interplay between CAR-T therapy and radiotherapy (RT), investigating their synergistic potential. Radiotherapy, a standard cancer treatment, involves using high doses of radiation to target and damage cancer cells, disrupting their ability to grow and divide. We highlight that RT modulates the TME, augments antigen presentation, and promotes immune cell infiltration, bolstering CAR-T cell-mediated tumor eradication. Molecular insights shed light on RT-induced alterations in tumor stroma, T cell recruitment promotion, and induction of immunogenic cell death. Noteworthy, strategies, such as combining hypofractionated radiotherapy with myeloid-derived suppressor cell blockade, underscore innovative approaches to enhance CAR-T cell therapy in solid tumors. Bridging indications for RT and CAR-T cells in hematological malignancies are discussed, emphasizing scenarios where RT strategically enhances CAR-T cell efficacy. The paper critically evaluates the RT as a bridge compared to traditional chemotherapy, highlighting timing and dosage considerations crucial for optimizing CAR-T therapy outcomes. In summary, the paper provides valuable insights into the intricate molecular mechanisms activated by RT and innovative strategies to improve CAR-T cell therapy, fostering a deeper understanding of their combined potential in cancer treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

T cell exhaustion refers to a progressive state in which T cells become functionally impaired due to sustained antigenic stimulation, which is characterized by increased expression of immune inhibitory receptors, but weakened effector functions, reduced self-renewal capacity, altered epigenetics, transcriptional programme and metabolism. T cell exhaustion is one of the major causes leading to immune escape of cancer, creating an environment that supports tumor development and metastatic spread. In addition, T cell exhaustion plays a pivotal role to the efficacy of current immunotherapies for cancer. This review aims to provide a comprehensive view of roles of T cell exhaustion in cancer development and progression. We summerized the regulatory mechanisms that involved in T cell exhaustion, including transcription factors, epigenetic and metabolic reprogramming events, and various microenvironmental factors such as cytokines, microorganisms, and tumor autocrine substances. The paper also discussed the challenges posed by T cell exhaustion to cancer immunotherapies, including immune checkpoint blockade (ICB) therapies and chimeric antigen receptor T cell (CAR-T) therapy, highlightsing the obstacles encountered in ICB therapies and CAR-T therapies due to T cell exhaustion. Finally, the article provides an overview of current therapeutic options aimed to reversing or alleviating T cell exhaustion in ICB and CAR-T therapies. These therapeutic approaches seek to overcome T cell exhaustion and enhance the effectiveness of immunotherapies in treating tumors. [ABSTRACT FROM AUTHOR]

Abstract Recently cable cars have come to be considered as an urban transport alternative in many cities. After the successful implementation of Metrocable in Medellin, Colombia, in 2004, other Latin American cities developed projects to incorporate cable cars as part of their public transport network. The system in La Paz and El Alto is the longest urban cable car network in the world. It connects two geographically complex areas with about two million inhabitants and high rates of poverty. This paper provides quantitative evidence of the effect of the La Paz–EL Alto cable car on users' commuting time, which may have an important impact on many dimensions of people's lives. Because cable cars have only recently been used for urban transit, literature on the subject is scarce. No paper has addressed the case of La Paz and El Alto in Bolivia, as most previous studies have focused on anecdotical information of the case of Medellin. From a mobility survey carried out in La Paz-El Alto, we compare the average commuting travel times of using cable cars (treatment group) over other transport modes (control group). We estimate that travel by cable car cuts commuting times by an average of 22% over other transport modes. This translates into a daily reduction of nine minutes in travel time and an average net benefit of US$0.58 per commute. The effect holds across the distribution of commuting times: No matter how short or long the commute, it takes less time when the cable car network is used. Highlights • Many cities around the world have built cable car networks to improve urban mobility. • No quantitative assessment of time savings from cable cars has been made so far. • We provide quantitative evidence of the effect of cable car systems on urban mobility. • Travel time decreases by 22% on average when commutes are made by cable car. • The reduction in travel time translates into a net benefit of US$0.58 per commute. [ABSTRACT FROM AUTHOR]

In the contemporary landscape of oncology, immunotherapy, represented by immune checkpoint blockade (ICB) therapy, stands out as a beacon of innovation in cancer treatment. Despite its promise, the therapy's progression is hindered by suboptimal clinical response rates. Addressing this challenge, the modulation of the NLRP3 inflammasome-GSDMD-mediated pyroptosis pathway holds promise as a means to augment the efficacy of immunotherapy. In the pathway, the NLRP3 inflammasome serves as a pivotal molecular sensor that responds to inflammatory stimuli within the organism. Its activation leads to the release of cytokines interleukin 1β and interleukin 18 through the cleavage of GSDMD, thereby forming membrane pores and potentially resulting in pyroptosis. This cascade of processes exerts a profound impact on tumor development and progression, with its function and expression exhibiting variability across different tumor types and developmental stages. Consequently, understanding the specific roles of the NLRP3 inflammasome and GSDMD-mediated pyroptosis in diverse tumors is imperative for comprehending tumorigenesis and crafting precise therapeutic strategies. This review aims to elucidate the structure and activation mechanisms of the NLRP3 inflammasome, as well as the induction mechanisms of GSDMD-mediated pyroptosis. Additionally, we provide a comprehensive overview of the involvement of this pathway in various cancer types and its applications in tumor immunotherapy, nanotherapy, and other fields. Emphasis is placed on the feasibility of leveraging this approach to enhance ICB therapy within the field of immunotherapy. Furthermore, we discuss the potential applications of this pathway in other immunotherapy methods, such as chimeric antigen receptor T-cell (CAR-T) therapy and tumor vaccines. In our review, we systematically elucidate the composition and activation pathway of the NLRP3 inflammasome, along with the characteristics and activation pathway of GSDMD-mediated pyroptosis. We comprehensively delineate the dual effects of the three pivotal factors on tumors within the NLRP3 inflammasome-GSDMD-mediated pyroptosis pathway: inflammatory mediators, self-components, and pyroptosis. Furthermore, NLRP3 inflammasome-GSDMD-mediated pyroptosis is deeply involved in tumor therapy, especially in the emerging field of nano-therapy. The combination of these therapeutic approaches with immunotherapy provides new perspectives on cancer immunotherapy. [Display omitted] • Our paper elucidates the composition and activation pathways of the NLRP3 inflammasome and GSDMD-mediated pyroptosis. • We detail the dual effects of key factors influencing tumors within the NLRP3 inflammasome-GSDMD-mediated pyroptosis pathway. • NLRP3 inflammasome-GSDMD-mediated pyroptosis plays a crucial role in tumor therapy, particularly in nanotherapy and immunotherapy. [ABSTRACT FROM AUTHOR]

• Ultrasound combined with tumor immunotherapy made encouraging new progress in both basic research and clinical treatment. • Ultrasound can increase the delivery of immunomodulatory substances and enhance the effect of immunotherapy. • Ultrasound can be used to improve the body's immune response to tumors. Immunotherapy has become a revolutionary method for treating tumors, offering new hope to cancer patients worldwide. Immunotherapy strategies such as checkpoint inhibitors, chimeric antigen receptor T-cell (CAR-T) therapy, and cancer vaccines have shown significant potential in clinical trials. Despite the promising results, there are still limitations that impede the overall effectiveness of immunotherapy; the response to immunotherapy is uneven, the response rate of patients is still low, and systemic immune toxicity accompanied with tumor cell immune evasion is common. Ultrasound technology has evolved rapidly in recent years and has become a significant player in tumor immunotherapy. The introductions of high intensity focused ultrasound and ultrasound-stimulated microbubbles have opened doors for new therapeutic strategies in the fight against tumor. This paper explores the revolutionary advancements of ultrasound combined with immunotherapy in this particular field. [ABSTRACT FROM AUTHOR]

The American Society for Transplantation and Cellular Therapy (ASTCT) published its first white paper on indications for autologous and allogeneic hematopoietic cell transplantation (HCT) in 2015. It was identified at the time that periodic updates of indications would be required to stay abreast with state of the art and emerging indications and therapy. In recent years the field has not only seen an improvement in transplantation technology, thus widening the therapeutic scope of HCT, but additionally a whole new treatment strategy using modified immune effector cells, including chimeric antigen receptor T cells and engineered T-cell receptors, has emerged. The guidelines review committee of the ASTCT deemed it optimal to update the ASTCT recommendations for indications for HCT to include new data and to incorporate indications for immune effector cell therapy (IECT) where appropriate. The guidelines committee established a multiple stakeholder task force consisting of transplant experts, payer representatives, and a patient advocate to provide guidance on indications for HCT and IECT. This article presents the updated recommendations from the ASTCT on indications for HCT and IECT. Indications for HCT/IECT were categorized as (1) Standard of care, where indication is well defined and supported by evidence; (2) Standard of care, clinical evidence available, where large clinical trials and observational studies are not available but have been shown to be effective therapy; (3) Standard of care, rare indication, for rare diseases where demonstrated effectiveness exists but large clinical trials and observational studies are not feasible; (4) Developmental, for diseases where preclinical and/or early-phase clinical studies show HCT/IECT to be a promising treatment option; and (5) Not generally recommended, where available evidence does not support the routine use of HCT/IECT. The ASTCT will continue to periodically review these guidelines and update them as new evidence becomes available. [ABSTRACT FROM AUTHOR]

Failure analysis construction of car tyres is a highly demanding process requiring very specific methods of analysis. Industrial metrotomography is one of suitable analytical tool in this area. However, the method used for failure analysis construction of car tyres may have its limits. The paper provides a detailed research for the analysis of 5 typical types of damage occurring in car tyres, analysing the possibilities of such a technology as well as occurrence of undesirable phenomena. Results provided further on refer to occurrence of undesirable phenomenon such as various artifacts due to their construction, but also confirm suitability of application of the method for car tyres research of failure analysis. • The analysis of 5 typical types of damage occurring in car tyres. • Analysing the possibilities of a technology industrial metrotomography. • Investigation of processes of car tyres damaging. [ABSTRACT FROM AUTHOR]

Proffered Papers: Proffered papers 27: Novel technologies OC-0559: Predictors of Failures following Chimeric Antigen Receptor T-cell (CAR T) Therapy N. Figura, M. Jain, A. Sim, E. Dean, Y. Balagurunathan, J. Chavez, B. Shah, F. Khimani, A. Lazaryan, M. Davila, H. Liu, S. Kim, F. Locke, T. Robinson. [Extracted from the article]

Chimeric antigen receptor (CAR) T-cell therapy is one of the most remarkable advances in cancer therapy in the last several decades. More than 300 adoptive T-cell therapy trials are ongoing, which is a testament to the early success and hope engendered by this line of investigation. Despite the enthusiasm, application of CAR T-cell therapy to solid tumours has had little success, although positive outcomes are increasingly being reported for these diseases. In this Series paper, we discuss the short-term strategies to improve CAR T-cell therapy responses, particularly for solid tumours, by combining CAR T-cell therapy with radiotherapy through the use of careful monitoring and non-invasive imaging. Through the use of imaging, we can gain greater mechanistic insights into the cascade of events that must unfold to enable tumour eradication by CAR T-cell therapy. [ABSTRACT FROM AUTHOR]

• Between June 2014 and January 2019, we asked respondents when most cars in their country will drive fully automatically. • In 15 crowdsourcing surveys, we obtained answers from 18,970 people in 128 countries. • The median reported year was 2030, which is optimistic compared to what experts believe. • Respondents who completed multiple surveys were more likely to revise their estimate upward than downward. • People from more affluent countries reported a significantly earlier year. When fully automated cars will be widespread is a question that has attracted considerable attention from futurists, car manufacturers, and academics. This paper aims to poll the public's expectations regarding the deployment of fully automated cars. In 15 crowdsourcing surveys conducted between June 2014 and January 2019, we obtained answers from 18,970 people in 128 countries regarding when they think that most cars will be able to drive fully automatically in their country of residence. The median reported year was 2030. The later the survey date, the smaller the percentage of respondents who reported that most cars would be able to drive fully automatically by 2020, with 15–22% of the respondents providing this estimate in the surveys conducted between 2014 and 2016 versus 3–5% in the 2018 surveys. Respondents who completed multiple surveys were more likely to revise their estimate upward (39.4%) than downward (35.3%). Correlational analyses showed that people from more affluent countries and people who have heard of the Google Driverless Car (Waymo) or the Tesla Autopilot reported a significantly earlier year. Finally, we made a comparison between the crowdsourced respondents and respondents from a technical university who answered the same question; the median year reported by the latter group was 2040. We conclude that over the course of 4.5 years the public has moderated its expectations regarding the penetration of fully automated cars but remains optimistic compared to what experts currently believe. [ABSTRACT FROM AUTHOR]

Highlights • The human decision making in car following tasks based on Wiedemann is introduced. • A driving simulator study is executed to verify these mechanisms. • At higher velocities, decisions tend to be made based on time headway. • This verifies the Wiedemann mechanism. • At lower velocities, decisions are also made based on time to collision. Abstract In the present paper, a theory-based advancement of the car following model of Wiedemann is introduced. It is suitable for a more realistic simulation of human longitudinal guidance behaviour in the lower velocity range, like in urban traffic. The algorithm was identified and developed by means of a driving simulator study, which is introduced as well. While the decision making process in recent car following models based on Wiedemann is solely determined by the time headway to the leading vehicle, the results of the study show that information about time to collision is also used in the lower velocity range. This approach delivers a more realistic simulation of human car following behaviour, which can be integrated into driver models for microscopic traffic simulations and for the control of surrounding traffic in driving simulators. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Stable packaging cell lines have not yet met the growing demand for viral vectors. • Viral plasmid systems have been developed to improve viral titers and safety. • Stable packaging cell lines have been developed to improve viral titers and safety. Lentivirus and other retroviral vectors are useful tools to engineer chimeric antigen receptor (CAR) T cells which are designed to target tumor cells in the growing field of gene therapy. Several efforts have been made to improve vector packaging systems including plasmid systems and envelopes and develop stable packaging cell lines (PCLs) in order to improve the productivity and safety by eliminating cytotoxicity of HIV-1 genes and unnecessary homologous genomic regions. In this paper, we explored stable PCLs developed to date for the production of both lentiviral and retroviral vectors and addressed key features of the viral vector production systems and how the features can be further utilized and modified to meet the growing demand in clinical trials. [ABSTRACT FROM AUTHOR]

• Application and design strategy of different CAR cells in solid tumors. • Improving the CAR costimulatory domain architecture might overcome solid tumor immunosuppressive microenvironmental barriers. • CAR cell therapy will become an important part and the future direction of solid tumor immunotherapy. In addition to chimeric antigen receptor (CAR)-αβ T -cell therapy, CAR-NK, CAR-NKT, CAR-M and CAR-γδ T -cell therapy have gradually been applied to the treatment of solid tumors. Compared to hematological tumors, solid tumors have the characteristics of strong tumor heterogeneity, limited target antigen selection, and low T -cell infiltration to build immunosuppressive tumor microenvironment. These features would present great obstacles to CAR cell therapy. This paper comprehensively analyzed the application of different CAR cells to solid tumors and summarized the design principles of different CAR cells to provide the direction for the development of CAR cell therapy in solid tumors. [ABSTRACT FROM AUTHOR]

As genetically engineered cells, chimeric antigen receptor (CAR)-T cells express specific receptors on their surface to target and eliminate malignant cells. CAR proteins are equipped with elements that enhance the activity and survival of T cells. Once injected, CAR-T cells act as a "living drug" against tumor cells in the body. Up to now, CAR-T cell therapy has been demonstrated as a robust adoptive cell transfer (ACT) immunotherapeutic modality for eliminating tumor cells in refractory hematological malignancies. CAR-T cell therapy modality involves several steps, including the collecting of the blood from patients, the isolation of peripheral blood mononuclear cells (PBMCs), the enrichment of CD4+/CD8+ T cell, the genetic reprogramming, the expansion of modified T cells, and the injection of genetically engineered T cells. The production of CAR-T cells is a multi-step procedure, which needs precise and safety management systems, including good manufacturing practice (GMP), and in-line quality control and assurance. The current study describes the structure of CARs and concentrates on the next generations of CARs that are engaged in enhancing the anti-tumor responses and safety of the engineered T cells. This paper also highlights the important concerns in quality control and nonclinical research of CAR-T cells, as well as general insights into the manufacture, reprogramming, and application of CAR-T cells based on new and enhanced techniques for treating hematological malignancies. Besides, the application of the CRISPR-Cas9 genome editing technology and nanocarrier-based delivery systems containing CAR coding sequences to overcome the limitations of CAR-T cell therapy has also been explained. [Display omitted] [ABSTRACT FROM AUTHOR]

Cluster of differentiation 38 (CD38) is a multifunctional extracellular enzyme on the cell surface with NADase and cyclase activities. CD38 is not only expressed in human immune cells, such as lymphocytes and plasma cells, but also is abnormally expressed in a variety of tumor cells, which is closely related to the occurrence and development of tumors. T cells are one of the important immune cells in the body. As NAD consuming enzymes, CD38, ART2, SIRT1 and PARP1 are closely related to the number and function of T cells. CD38 may also influence the activity of ART2, SIRT1 and PARP1 through the CD38-NAD+ axis to indirectly affect the number and function of T cells. Thus, CD38-NAD+ axis has a profound effect on T cell activity. In this paper, we reviewed the role and mechanism of CD38+ CD4+ T cells / CD38+ CD8+ T cells in cellular immunity and the effects of the CD38-NAD+ axis on T cell activity. We also summarized the relationship between the CD38 expression level on T cell surface and disease prediction and prognosis, the effects of anti-CD38 monoclonal antibodies on T cell activity and function, and the role of anti-CD38 chimeric antigen receptor (CAR) T cell therapy in tumor immunity. This will provide an important theoretical basis for a comprehensive understanding of the relationship between CD38 and T cells. [Display omitted] • As a NAD consuming enzyme, CD38 is closely related to the number and function of T cells. • The expression of CD38 in CD4+ T cells and CD8+ T cell affects the function of CD4+T cell. • The expression level of CD38 on T cell surface is associated with disease prediction and prognosis. [ABSTRACT FROM AUTHOR]

• Oral submucous fibrosis (OSMF) is a fibrotic disease associated with myofibroblasts driven fibrosis. • Fibroblast activating factor (FAP) is expressed on such activated myofibroblasts. • Adoptive transfer of T cells that express a chimeric antigen receptor against FAP is proposed as a targeted immunotherapy for OSMF. • This therapy will reduce the fibrosis and down-regulate the myofibroblasts associated with malignant transformation events. Despite several advancements in understanding the pathogenesis of oral submucous fibrosis (OSMF), there is no definitive therapy for the complete remission of the disease process. This is attributed to the fact that any chronic fibrotic disease targeting myofibroblasts, the primary cells responsible for fibrosis is challenging. The betel quid-associated chemicals, predominantly, arecoline and arecaidine, advance the activation of resident fibroblasts to myofibroblasts in OSMF, resulting in uncontrolled and excessive production of collagen. The myofibroblasts, which are associated with the malignant transformation express fibroblast-activating protein (FAP) on their surface that could be selectively targeted for the treatment of OSMF. In the present paper, we propose that the adoptive transfer of T cells that express a chimeric antigen receptor against fibroblast activation protein (FAP CAR T cell therapy) results in a significant reduction in fibrosis and restoration of function in OSMF. The detailed procedural aspects of this therapy along with experimental designs are also discussed. Since myofibroblasts are involved in the malignant transformation of OSMF, the selective elimination of these cells will reduce the cancer development and ultimately the cancer burden. [ABSTRACT FROM AUTHOR]

Topic Signficance & Study Purpose/Background/Rationale We initially conducted a quality review of patients treated with CAR-T therapies and noted inconsistencies in cytokine release syndrome (CRS) and neurotoxicity grading due to data located in various areas within our EMR and fragmented documentation between the EMR and paper record. Consistent documentation of CAR T-cell toxicity amongst providers is important for assesment and management of toxicities post-infusion in cellular therapy programs. EMR flowsheets facilitate tracking and communication within the healthcare team and ensuring proper clinical documentation. Method, Interventions, & Analysis Key members from the Informatics and Adult Stem Cell Transplant Program collaborated to develop a flowsheet to capture all elements to grade, identify symptoms and toxicities. To enhace clinical documentation, we created a tool that brings in several flowsheet enteries to the notes and to guide providers for accruate grading of CRS and neurotoxicity related to CAR T-cell infusions for the Epic® EMR. Findings & Interpretation These electronic tools were developed during the planning phase of the CAR T-cell program. Two flowsheets were used by nurses to document CRS (Figure 1) and neurotoxicity (Figure 2) based on practice guidelines established by program leaders. The flowsheet enteries were added to provider's daily documentation through "smart phrases" (Figure 3) that captured grading of toxicities and guided clinical decision making. Discussion and Implications Development of tools to standardize symptomology reporting and effectively capture data is imperative for CAR T-cell therapy programs. EMR tools can facilitate management and streamline data collection for reporting of toxicities. As more patients receive this novel immunotherapy, it will be important to have tools in place to assist with tracking patient outcomes. The future goal is to have grading auto-generated to enhance real time care delivery with alert based warnings for worsening CRS or neurotoxicity, and for these tools to reflect current standards of care, including revised consensus criteria for grading and reporting of CAR-T toxicities currently being developed by the ASBMT. [ABSTRACT FROM AUTHOR]

In this paper, we introduce a decentralized car parking approach for vast car park areas based on cooperation among vehicles through vehicle-to-vehicle communication, called Cooperative Car Parking (CoPark). In CoPark, the task of finding car parking spaces inside a large car parking area is done via smart agents in vehicles opportunistically cooperating with each other to locate parking spaces as near as possible to the final destination with reduced searching time. We comprehensively investigate a range of car parking circumstances and situations in our simulations to evaluate the proposed CoPark approach. We show that by strategic cooperation between agents in the CoPark approach, greater satisfaction can be achieved in terms of individual and social benefits, in the form of reduced search times for car park spaces and reduced walking distances from where cars are parked to a destination building. • A new cooperative car parking approach, CoPark-WS, for cars to find parking spaces and to resolve contention for spaces. • The searching time and walking distance are considered in vehicle decisions in CoPark-WS. • The performance of CoPark-WS is evaluated via extensive simulations. • Results show promise for cooperative parking without centralized coordination. [ABSTRACT FROM AUTHOR]

The current and the new generation of Internet of Things (IoT) devices present several challenges, among them the software update of legacy and new devices using wireless connections. In this paper, we study a problem of scheduling massive Firmware-Over-The-Air updates for millions of connected cars. We model this problem as a new generic problem called Time- and Machine-Dependent Scheduling Problem (TMDSP) that resembles project scheduling problems with variable-intensity activities. In the TMDSP, jobs, machine utilization, and production rates vary over time. In each period, a given job can be executed by a subset of machines with different capacities and production rates. The objective is to deploy a feasible schedule with minimum total completion time. We explore solving the problem using several approaches among than Biased Random-Key Genetic Algorithm (BRKGA), Iterated Local Search (ILS), Simulating Annealing (SA), two variations of Tabu Search (TB), and traditional genetic algorithms (TGA), in addition to a Mixed Integer Programming (MIP) model. We test the proposed approaches on a synthetic benchmark and very large real instances in IoT space. While using a commercial solver and the MIP model, we are able to solve only a few real instances (with, at most, 1,976 cars and 9,116 sectors); on the other hand, BRKGA presents significantly better results when compared to ILS, MIP solver and a simple multi-start heuristic. • We study a problem of scheduling Firmware-Over-The-Air updates for connected cars. • We present a new problem called Time- and Machine-Dependent Scheduling Problem. • We propose several metaheuristics and an integer programming model. • Tests were performed on synthetic and real scenarios with massive number of cars. • Tests suggest that the biased random-key genetic algorithm has better performance. [ABSTRACT FROM AUTHOR]