Assessment of ChatGPT-3.5's Knowledge in Oncology: Comparative Study with ASCO-SEP Benchmarks.

BACKGROUND: ChatGPT (Open AI) is a state-of-the-art large language model that uses artificial intelligence (AI) to address questions across diverse topics. The American Society of Clinical Oncology Self-Evaluation Program (ASCO-SEP) created a comprehensive educational program to help physicians keep up to date with the many rapid advances in the field. The question bank consists of multiple choice questions addressing the many facets of cancer care, including diagnosis, treatment, and supportive care. As ChatGPT applications rapidly expand, it becomes vital to ascertain if the knowledge of ChatGPT-3.5 matches the established standards that oncologists are recommended to follow. OBJECTIVE: This study aims to evaluate whether ChatGPT-3.5's knowledge aligns with the established benchmarks that oncologists are expected to adhere to. This will furnish us with a deeper understanding of the potential applications of this tool as a support for clinical decision-making. METHODS: We conducted a systematic assessment of the performance of ChatGPT-3.5 on the ASCO-SEP, the leading educational and assessment tool for medical oncologists in training and practice. Over 1000 multiple choice questions covering the spectrum of cancer care were extracted. Questions were categorized by cancer type or discipline, with subcategorization as treatment, diagnosis, or other. Answers were scored as correct if ChatGPT-3.5 selected the answer as defined by ASCO-SEP. RESULTS: Overall, ChatGPT-3.5 achieved a score of 56.1% (583/1040) for the correct answers provided. The program demonstrated varying levels of accuracy across cancer types or disciplines. The highest accuracy was observed in questions related to developmental therapeutics (8/10; 80% correct), while the lowest accuracy was observed in questions related to gastrointestinal cancer (102/209; 48.8% correct). There was no significant difference in the program's performance across the predefined subcategories of diagnosis, treatment, and other (P=.16, which is greater than .05). CONCLUSIONS: This study evaluated ChatGPT-3.5's oncology knowledge using the ASCO-SEP, aiming to address uncertainties regarding AI tools like ChatGPT in clinical decision-making. Our findings suggest that while ChatGPT-3.5 offers a hopeful outlook for AI in oncology, its present performance in ASCO-SEP tests necessitates further refinement to reach the requisite competency levels. Future assessments could explore ChatGPT's clinical decision support capabilities with real-world clinical scenarios, its ease of integration into medical workflows, and its potential to foster interdisciplinary collaboration and patient engagement in health care settings.

HDACi-dependent Microenvironmental Normalization Overcomes Tumor Burden-induced T-cell Exhaustion.

PURPOSE: T-cell exhaustion limits immunotherapy for the treatment of solid tumors. Although immune checkpoint blockade and adoptive T-cell therapy (ACT) can mediate tumor regression, their potency is often determined by tumor burden. Here, we identified tumor burden-related pathway changes that are conducive to T-cell exhaustion. We then determined whether microenvironmental reprogramming via epigenetic modulation could reverse T-cell exhaustion and improve immunotherapeutic responsiveness. EXPERIMENTAL DESIGN: We developed a murine syngeneic tumor model wherein an increased burden ablated therapeutic responsiveness to ACT, which corresponded with systemic induction of T-cell exhaustion. Transcriptome analysis of these large tumors allowed us to characterize changes to immunosuppressive pathway expression during class I histone deacetylase inhibitor MS-275 treatment. We then measured the therapeutic impact of MS-275 during ACT and assessed T-cell exhaustion by transcriptome/phenotypic analysis. RESULTS: ACT durably regressed small tumors but failed to control large tumors, which were associated with systemic T-cell exhaustion and ablation of T-cell responses. Large tumors were defined by an immunosuppressive pathway signature. MS-275 reversed this pathway signature and promoted durable regression of large tumors during ACT. Prototypical exhaustion marker Tim-3 was selectively upregulated in transferred T cells despite displaying a reduced exhaustion signature. Instead, we observed enhanced activation-dependent signaling correlating with enrichment of the IL2-STAT5 signaling axis. Activated CD8+ T-cell responses were predominantly skewed toward terminal effector cell-like CD44+ Tim-3hi TCF1- CD127- KLRG1+ differentiation. CONCLUSIONS: Tumor burden-induced pathway changes can be reversed through epigenetic reprogramming, enabling the conversion from T-cell exhaustion to effector lineage differentiation.

Advancements in CAR-NK therapy: lessons to be learned from CAR-T therapy.

Advancements in chimeric antigen receptor engineered T-cell (CAR-T) therapy have revolutionized treatment for several cancer types over the past decade. Despite this success, obstacles including the high price tag, manufacturing complexity, and treatment-associated toxicities have limited the broad application of this therapy. Chimeric antigen receptor engineered natural killer cell (CAR-NK) therapy offers a potential opportunity for a simpler and more affordable "off-the-shelf" treatment, likely with fewer toxicities. Unlike CAR-T, CAR-NK therapies are still in early development, with few clinical trials yet reported. Given the challenges experienced through the development of CAR-T therapies, this review explores what lessons we can apply to build better CAR-NK therapies. In particular, we explore the importance of optimizing the immunochemical properties of the CAR construct, understanding factors leading to cell product persistence, enhancing trafficking of transferred cells to the tumor, ensuring the metabolic fitness of the transferred product, and strategies to avoid tumor escape through antigen loss. We also review trogocytosis, an important emerging challenge that likely equally applies to CAR-T and CAR-NK cells. Finally, we discuss how these limitations are already being addressed in CAR-NK therapies, and what future directions may be possible.

Safety and efficacy of autologous cell vaccines in solid tumors: a systematic review and meta-analysis of randomized control trials.

We conducted a systematic review and meta-analysis of randomized control trials to formally assess the safety and efficacy of autologous whole cell vaccines as immunotherapies for solid tumors. Our primary safety outcome was number, and grade of adverse events. Our primary efficacy outcome was clinical responses. Secondary outcomes included survival metrics and correlative immune assays. We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for studies published between 1946 and August 2020 using any autologous whole cell product in the treatment of any solid tumor. The Cochrane Randomized Controlled Trial risk of bias tool was used to assess risk of bias. Eighteen manuscripts were identified with a total of 714 patients enrolled in control and 808 in vaccine arms. In 698 patients receiving at least one dose of vaccine, treatment was well tolerated with a total of 5 grade III or higher adverse events. Clinical response was reported in a minority (n = 2, 14%) of studies. Autologous cell vaccines were associated with improved overall (HR 1.28, 95% CI 1.01-1.63) and disease-free survival (HR 1.33, 95% CI 1.05-1.67) over thirteen and ten trials respectively. Where reported, immune assays correlated well with clinical outcomes. Our results suggest that autologous whole cell vaccination is safe and efficacious in increasing survival in patients undergoing treatment for solid tumors.Registration: PROSPERO CRD42019140187.

When donor T cells attack: The curious case of liver transplant-associated acute graft-versus-host-disease.

Graft versus host disease is a rare but deadly complication of solid organ transplant. Clinical features of graft-versus-host-disease are non-specific, which may lead to delayed diagnosis as more common conditions including infections or drug reactions are considered. We describe a 54-year-old male patient who underwent liver transplantation for alcohol use disorder-related cirrhosis and developed acute graft-versus-host disease. Initial clinical presentation included dermatitis, bone marrow failure and enteritis. Results of skin biopsy and cytogenetic studies were consistent with liver transplant-associated acute graft-versus-host disease. The importance of this case is to highlight to transplant physicians and surgeons the challenges of diagnosing graft-versus-host-disease. In our case, pre-existing partnerships among the liver and hematopoietic stem cell transplant teams, transfusion medicine specialists, critical care specialists and facilitated timely communication relevant to confirming graft-versus-host disease. We propose an algorithm to assist in the workup of suspected graft-versus-host disease. Because this condition is characterized by high mortality, a high index of suspicion is imperative for prompt diagnosis and optimal management of the donor-recipient immune interaction when patients present with classic clinical features.

Current challenges in the manufacture of clinical-grade autologous whole cell vaccines for hematological malignancies.

Autologous whole cell vaccines use a patient's own tumor cells as a source of antigen to elicit an anti-tumor immune response in vivo. Recently, the authors conducted a systematic review of clinical trials employing these products in hematological cancers that showed a favorable safety profile and trend toward efficacy. However, it was noted that manufacturing challenges limit both the efficacy and clinical implementation of these vaccine products. In the current literature review, the authors sought to define the issues surrounding the manufacture of autologous whole cell products for hematological cancers. The authors describe key factors, including the acquisition, culture, cryopreservation and transduction of malignant cells, that require optimization for further advancement of the field. Furthermore, the authors provide a summary of pre-clinical work that informs how the identified challenges may be overcome. The authors also highlight areas in which future basic research would be of benefit to the field. The goal of this review is to provide a roadmap for investigators seeking to advance the field of autologous cell vaccines as it applies to hematological malignancies.

Safety and efficacy of autologous whole cell vaccines in hematologic malignancies: A systematic review and meta-analysis.

Autologous cell vaccines use a patient's tumor cells to stimulate a broad antitumor response in vivo. This approach shows promise for treating hematologic cancers in early phase clinical trials, but overall safety and efficacy remain poorly described. We conducted a systematic review assessing the use of autologous cell vaccination in treating hematologic cancers. Primary outcomes of interest were safety and clinical response, with secondary outcomes including survival, relapse rate, correlative immune assays and health-quality related metrics. We performed a search of MEDLINE, Embase and the Cochrane Register of Controlled Trials including any interventional trial employing an autologous, whole cell product in any hematologic malignancy. Risk of bias was assessed using a modified Institute of Health Economics tool. Across 20 single arm studies, only 341 of 592 enrolled participants received one or more vaccinations. Primary reasons for not receiving vaccination included rapid disease progression/death and manufacturing challenges. Overall, few high-grade adverse events were observed. One death was reported and attributed to a GM-CSF producing allogeneic cell line co-administered with the autologous vaccine. Of 58 evaluable patients, the complete response rate was 21.0% [95% CI, 10.4%-37.8%)] and overall response rate was 35.8% (95% CI, 24.4%-49.0%). Of 97 evaluable patients for survival, the 5-years overall survival rate was 64.9% (95% CI, 52.6%-77.2%) and disease-free survival was 59.7% (95% CI, 47.7%-71.7%). We conclude that, in hematologic malignancies, based on limited available data, autologous cell vaccines are safe and display a trend towards efficacy but that challenges exist in vaccine manufacture and administration.

Flattening the COVID-19 Curve With Natural Killer Cell Based Immunotherapies.

Natural Killer (NK) cells are innate immune responders critical for viral clearance and immunomodulation. Despite their vital role in viral infection, the contribution of NK cells in fighting SARS-CoV-2 has not yet been directly investigated. Insights into pathophysiology and therapeutic opportunities can therefore be inferred from studies assessing NK cell phenotype and function during SARS, MERS, and COVID-19. These studies suggest a reduction in circulating NK cell numbers and/or an exhausted phenotype following infection and hint toward the dampening of NK cell responses by coronaviruses. Reduced circulating NK cell levels and exhaustion may be directly responsible for the progression and severity of COVID-19. Conversely, in light of data linking inflammation with coronavirus disease severity, it is necessary to examine NK cell potential in mediating immunopathology. A common feature of coronavirus infections is that significant morbidity and mortality is associated with lung injury and acute respiratory distress syndrome resulting from an exaggerated immune response, of which NK cells are an important component. In this review, we summarize the current understanding of how NK cells respond in both early and late coronavirus infections, and the implication for ongoing COVID-19 clinical trials. Using this immunological lens, we outline recommendations for therapeutic strategies against COVID-19 in clearing the virus while preventing the harm of immunopathological responses.

Safety and efficacy of autologous tumour cell vaccines as a cancer therapeutic to treat solid tumours and haematological malignancies: a meta-analysis protocol for two systematic reviews.

INTRODUCTION: Autologous cancer cell vaccines are promising personalised immunotherapeutic options for solid and haematological malignancies that uses the patient's own cells to arm an immune response. Evidence suggests that among patients receiving these vaccines, those who mount an immune response against their own tumour cells have better prognosis, and a myriad of preclinical studies have demonstrated the same. Recently, two autologous cell vaccines Vigil and OncoVAX have made it to phase III clinical trials. Here, we outline a protocol to be used for two separate systematic reviews using a parallel approach for inclusion criteria, data extraction and analysis for autologous cell vaccines in (1) solid and (2) haematological malignancies. We aim to review evidence from controlled and uncontrolled interventional studies of autologous cell vaccines administered to patients with cancer to determine their historical efficacy (with or without associated adjuvants or modifications) with clinical response rates and safety outcomes being of particular importance. METHODS AND ANALYSIS: We will search MEDLINE (OVID interface, including In-Process and Epub Ahead of Print), Embase (OVID interface) and the Cochrane Central Register of Controlled Trials (Wiley interface) for articles published from 1947 until 30 July 2018 (date search was performed). Studies will be screened first by title and abstract, then by full-text in duplicate. Interventional trials that report the use of an autologous cell vaccine to patients with cancer of any age will be included. The primary outcomes of interest in this review are clinical response (complete or overall/objective response) and safety outcomes (adverse events). Secondary outcomes include immune response, disease-free survival and overall survival. The risk of bias within studies will be assessed using the appropriate Cochrane Risk of Bias tool. If appropriate, a random effects meta-analysis will be performed to synthesise the data and report summary estimates of effect. Statistical heterogeneity will be assessed using the I2 statistic. ETHICS AND DISSEMINATION: Ethics approval is not required for this systematic review protocol as the review will solely use published literature. Results will be submitted to peer-reviewed journals for publication and presented to relevant stakeholders and scientific meetings. PROSPERO REGISTRATION NUMBER: CRD42019140187.

Endogenous T cells prevent tumor immune escape following adoptive T cell therapy.

While the outcome of adoptive T cell therapy (ACT) is typically correlated with the functionality of the inoculated T cells, the role of the endogenous T cells is unknown. The success of checkpoint blockade therapy has demonstrated the potentially curative value of preexisting tumor-primed T cells in cancer treatment. Given the results from checkpoint blockade therapy, we hypothesized that endogenous T cells contribute to long-term survival following ACT. Here, we describe a therapeutic approach combining ACT with an oncolytic vaccine that allows simultaneous analysis of antitumor immunity mediated by transferred and endogenous T cells. We found that, in addition to promoting the expansion and tumor infiltration of the transferred T cells, oncolytic vaccines boosted tumor-primed host T cells. We determined that transferred T cells contributed to rapid destruction of large tumor masses while endogenous T cells concurrently prevented the emergence of antigen-loss variants. Moreover, while transferred T cells disappeared shortly after tumor regression, endogenous T cells secured long-term memory with a broad repertoire of antigen specificity. Our findings suggest that this combination strategy may exploit the full potential of ACT and tumor-primed host T cells to eliminate the primary tumor, prevent immune escape, and provide long-term protective memory.

Type I IFN blockade uncouples immunotherapy-induced antitumor immunity and autoimmune toxicity.

Despite its success in treating melanoma and hematological malignancies, adoptive cell therapy (ACT) has had only limited effects in solid tumors. This is due in part to a lack of specific antigen targets, poor trafficking and infiltration, and immunosuppression in the tumor microenvironment. In this study, we combined ACT with oncolytic virus vaccines (OVVs) to drive expansion and tumor infiltration of transferred antigen-specific T cells and demonstrated that the combination is highly potent for the eradication of established solid tumors. Consistent with other successful immunotherapies, this approach elicited severe autoimmune consequences when the antigen targeted was a self-protein. However, modulation of IFN-α/-ß signaling, either by functional blockade or rational selection of an OVV backbone, ameliorated autoimmune side effects without compromising antitumor efficacy. Our study uncovers a pathogenic role for IFN-α/-ß in facilitating autoimmune toxicity during cancer immunotherapy and presents a safe and powerful combinatorial regimen with immediate translational applications.

Enhanced susceptibility of cancer cells to oncolytic rhabdo-virotherapy by expression of Nodamura virus protein B2 as a suppressor of RNA interference.

Antiviral responses are barriers that must be overcome for efficacy of oncolytic virotherapy. In mammalian cells, antiviral responses involve the interferon pathway, a protein-signaling cascade that alerts the immune system and limits virus propagation. Tumour-specific defects in interferon signaling enhance viral infection and responses to oncolytic virotherapy, but many human cancers are still refractory to oncolytic viruses. Given that invertebrates, fungi and plants rely on RNA interference pathways for antiviral protection, we investigated the potential involvement of this alternative antiviral mechanism in cancer cells. Here, we detected viral genome-derived small RNAs, indicative of RNAi-mediated antiviral responses, in human cancer cells. As viruses may encode suppressors of the RNA interference pathways, we engineered an oncolytic vesicular stomatitis virus variant to encode the Nodamura virus protein B2, a known inhibitor of RNAi-mediated immune responses. B2-expressing oncolytic virus showed enhanced viral replication and cytotoxicity, impaired viral genome cleavage and altered microRNA processing in cancer cells. Our data establish the improved therapeutic potential of our novel virus which targets the RNAi-mediated antiviral defense of cancer cells.

Capitalizing on Cancer Specific Replication: Oncolytic Viruses as a Versatile Platform for the Enhancement of Cancer Immunotherapy Strategies.

The past decade has seen considerable excitement in the use of biological therapies in treating neoplastic disease. In particular, cancer immunotherapy and oncolytic virotherapy have emerged as two frontrunners in this regard with the first FDA approvals for agents in both categories being obtained in the last 5 years. It is becoming increasingly apparent that these two approaches are not mutually exclusive and that much of the therapeutic benefit obtained from the use of oncolytic viruses (OVs) is in fact the result of their immunotherapeutic function. Indeed, OVs have been shown to recruit and activate an antitumor immune response and much of the current work in this field centers around increasing this activity through strategies such as engineering genes for immunomodulators into OV backbones. Because of their broad immunostimulatory functions, OVs can also be rationally combined with a variety of other immunotherapeutic approaches including cancer vaccination strategies, adoptive cell transfer and checkpoint blockade. Therefore, while they are important therapeutics in their own right, the true power of OVs may lie in their ability to enhance the effectiveness of a wide range of immunotherapies.

Reciprocal cellular cross-talk within the tumor microenvironment promotes oncolytic virus activity.

Tumors are complex ecosystems composed of networks of interacting 'normal' and malignant cells. It is well recognized that cytokine-mediated cross-talk between normal stromal cells, including cancer-associated fibroblasts (CAFs), vascular endothelial cells, immune cells, and cancer cells, influences all aspects of tumor biology. Here we demonstrate that the cross-talk between CAFs and cancer cells leads to enhanced growth of oncolytic virus (OV)-based therapeutics. Transforming growth factor-ß (TGF-ß) produced by tumor cells reprogrammed CAFs, dampened their steady-state level of antiviral transcripts and rendered them sensitive to virus infection. In turn, CAFs produced high levels of fibroblast growth factor 2 (FGF2), initiating a signaling cascade in cancer cells that reduced retinoic acid-inducible gene I (RIG-I) expression and impeded the ability of malignant cells to detect and respond to virus. In xenografts derived from individuals with pancreatic cancer, the expression of FGF2 correlated with the susceptibility of the cancer cells to OV infection, and local application of FGF2 to resistant tumor samples sensitized them to virotherapy both in vitro and in vivo. An OV engineered to express FGF2 was safe in tumor-bearing mice, showed improved therapeutic efficacy compared to parental virus and merits consideration for clinical testing.