Efficacy and safety of targeted therapy plus immunotherapy combined with hepatic artery infusion chemotherapy (FOLFOX) for unresectable hepatocarcinoma

BACKGROUND The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma(HCC),and therapeutic strategies with multiple modes of delivery have been shown to be more efficacious than mono-therapy.However,the mechanisms underlying this innovative treatment modality have not been elucidated.AIM To evaluate the clinical efficacy of targeted therapy plus immunotherapy combined with hepatic arterial infusion chemotherapy(HAIC)of FOLFOX in patients with unresectable HCC.METHODS We enrolled 53 patients with unresectable HCC who received a combination of targeted therapy,immunotherapy,and HAIC of FOLFOX between December 2020 and June 2021 and assessed the efficacy and safety of the treatment regimen.RESULTS The objective response rate was 60.4%(32/53),complete response was 24.5%(13/53),partial response was 35.9%(19/53),and stable disease was 39.6%(21/53).The median duration of response and median progression-free survival were 9.1 and 13.9 months,respectively.The surgical conversion rate was 34.0%(18/53),and 1-year overall survival was 83.0%without critical complicating diseases or adverse events(AEs).CONCLUSION The regimen of HAIC of FOLFOX,targeted therapy,and immunotherapy was curative for patients with unresectable HCC,with no serious AEs and a high rate of surgical conversion.

Effects of postoperative treatment with chemotherapy and cellular immunotherapy on patients with colorectal cancer

BACKGROUND The outcome of surgical treatment for colorectal cancer(CRC)remains unsatis-factory and warrants further exploration and optimization.AIM To clarify the impact of chemotherapy plus cellular immunotherapy[dendritic cell-cytokine-induced killer(DC-CIK)cell immunotherapy]on patients after CRC surgery and to explore the mediating variables.METHODS A total cohort of 121 patients who underwent CRC surgery between January 2019 and April 2022 were selected.The sample comprised a control group of 55 pa-tients who received the XELOX chemotherapy regimen and a research group of 66 patients who received XELOX+DC-CIK immunotherapy.We performed compa-rative analyses of the clinical and pathological data of the two groups,including efficacy(2-year disease-free survival[DFS]rate),the incidence of adverse events(diarrhea,myelosuppression,gastrointestinal reactions,and peripheral neuritis),serum levels of tumor markers[carcinoembryonic antigens and carbohydrate an-tigens(CA)19-9 and CA242],and T-cell subsets[cluster of differentiation(CD)3+,CD3+CD4+,CD3+CD8+,natural killer(NK),and NK T cells].We also conducted preliminary univariate and mul-tivariate analyses of the variables that affected the efficacy of the treatments.RESULTS We found a significantly higher 2-year DFS rate of treatment efficacy in the research group than in the control group,with a statistically lower incidence of adverse events.Both groups showed a reduction in serum tumor markers after treatment but there was no marked intergroup difference.After treatment,the various T-cell subgroup indicators in the control group were significantly lower than those in the research group.The indices of T-cell subsets in the research group showed no significant change from preoperative levels.Univariate analysis revealed a significant correlation between TNM staging,tumor differentiation,and the rates of nonresponse to treatment in CRC patients after surgery.Multivariate results indicated that the treatment approach significantly affected the efficacy of postoperative CRC treatment.CONCLUSION We concluded that XELOX+DC-CIK immunotherapy for postsurgical CRC patients offers reduced rates of treatment-induced adverse events,extended 2-year DFS,enhanced immunity,and increased physiological antitumor responses.

Comparative effectiveness of immunotherapy and chemotherapy in patients with metastatic colorectal cancer stratified by microsatellite instability status

BACKGROUND Immunotherapy have demonstrated promising outcomes in patients with high microsatellite instability(MSI)(MSI-H)metastatic colorectal cancer.However,the comparative effectiveness of Immunotherapy and chemotherapy for patients with low MSI(MSI-L),and microsatellite stable(MSS)metastatic colorectal cancer remains unclear.AIM To investigate immunotherapy vs chemotherapy for treatment of MSI-L/MSS metastatic colorectal cancer,and to evaluate the success of immunotherapy against chemotherapy in managing MSI-H metastatic colorectal cancer during a follow-up of 50 months.METHODS We conducted a retrospective cohort study using the National Cancer Database(NCDB)to evaluate the overall survival(OS)of patients with metastatic colorectal cancer treated with immunotherapy or chemotherapy.The study population was stratified by MSI status(MSI-H,MSI-L,and MSS).Multivariable Cox proportional hazard models were used to assess the association between treatment modality and OS,adjusting for potential confounders.RESULTS A total of 21951 patients with metastatic colorectal cancer were included in the analysis,of which 2358 were MSI-H,and 19593 were MSI-L/MSS.In the MSI-H cohort,immunotherapy treatment(n=142)was associated with a significantly improved median OS compared to chemotherapy(n=860).After adjusting for potential confounders,immunotherapy treatment remained significantly associated with better OS in the MSI-H cohort[adjusted hazard ratio(aHR):0.57,95%confidence interval(95%CI):0.43-0.77,P<0.001].In the MSS cohort,no significant difference in median OS was observed between immunotherapy treatment and chemotherapy(aHR:0.94,95%CI:0.69-1.29,P=0.715).CONCLUSION In this population-based study using the NCDB,immunotherapy treatment was associated with significantly improved OS compared to chemotherapy in patients with MSI-H metastatic colorectal cancer,but not in those with MSI-L/MSS metastatic colorectal cancer.Further studies are warranted to determine the optimal therapeutic approach for patients with MSI-L/MSS metastatic colorectal cancer.

Successful conversion of advanced gastric cancer treated by immunotherapy combined with chemotherapy: A case report

Gastric cancer is one of the most common malignant tumors,for patients with advanced gastric cancer,the traditional treatment is mainly chemotherapy or combined targeted therapy;however,these have not achieved ideal efficacy.However,with the continuous deepening of research on molecular targeted drugs and immunosuppressants,the treatment of advanced gastric cancer patients has made new progress,and some new technologies have also been continuously emerged and applied,which brings hope for the treatment of advanced gastric cancer.Recently,several multicenter randomized controlled phase III studies on immunotherapy for advanced gastric cancer yielded encouraging results,demonstrating its superior efficacy in the treatment of advanced gastric cancer.However,prospective data to support the acceptance of surgery and the R0 removal rate following conversion therapy with immune checkpoint inhibitors are lacking.In this study,a 58-year-old woman with advanced gastric cancer and positive PD-L1 expression,negative HER-2 expression,and microsatellite stable status received immunochemotherapy combined with traditional Chinese medicine to achieve R0 resection and satisfactory efficacy.

Immunotherapy of gastric cancer:Present status and future perspectives

In this editorial,we comment on the article entitled“Advances and key focus areas in gastric cancer immunotherapy:A comprehensive scientometric and clinical trial review(1999-2023),”which was published in the recent issue of the World Journal of Gastroenterology.We focused on the results of the authors’bibliometric analysis concerning gastric cancer immunotherapy,which they analyzed in depth by compiling the relevant publications of the last 20 years.Before that,we briefly describe the most recent data concerning the epidemiological parameters of gastric cancer(GC)in different countries,attempting to give an interpretation based on the etiological factors involved in the etiopathogenesis of the neoplasm.We then briefly discuss the conservative treatment(chemotherapy)of the various forms of this malignant neoplasm.We describe the treatment of resectable tumors,locally advanced neoplasms,and unresectable(advanced)cases.Special attention is given to modern therapeutic approaches with emphasis on immunotherapy,which seems to be the future of GC treatment,especially in combination with chemotherapy.There is also a thorough analysis of the results of the study under review in terms of the number of scientific publications,the countries in which the studies were conducted,the authors,and the scientific centers of origin,as well as the clinical studies in progress.Finally,an attempt is made to draw some conclusions and to point out possible future directions.

Is the combination of immunotherapy with conventional chemotherapy the key to increase the efficacy of colorectal cancer treatment?

Colorectal cancer(CRC) is among the most prevalent and deadly neoplasms worldwide. According to GLOBOCAN predictions, its incidence will increase from 1.15 million CRC cases in 2020 to 1.92 million cases in 2040. Therefore, a better understanding of the mechanisms involved in CRC development is necessary to improve strategies focused on reducing the incidence, prevalence,and mortality of this oncological pathology. Surgery, chemotherapy, and radiotherapy are the main strategies for treating CRC. The conventional chemotherapeutic agent utilized throughout the last four decades is 5-fluorouracil, notwithstanding its low efficiency as a single therapy. In contrast, combining 5-fluorouracil therapy with leucovorin and oxaliplatin or irinotecan increases its efficiency. However, these treatments have limited and temporary solutions and aggressive side effects. Additionally, most patients treated with these regimens develop drug resistance, which leads to disease progression. The immune response is considered a hallmark of cancer;thus, the use of new strategies and methodologies involving immune molecules, cells, and transcription factors has been suggested for CRC patients diagnosed in stages Ⅲ and Ⅳ. Despite the critical advances in immunotherapy, the development and impact of immune checkpoint inhibitors on CRC is still under investigation because less than 25% of CRC patients display an increased 5-year survival. The causes of CRC are diverse and include modifiable environmental factors(smoking, diet, obesity, and alcoholism), individual genetic mutations, and inflammation-associated bowel diseases. Due to these diverse causes, the solutions likely cannot be generalized. Interestingly, new strategies, such as single-cell multiomics, proteomics, genomics, flow cytometry, and massive sequencing for tumor microenvironment analysis, are beginning to clarify the way forward. Thus,the individual mechanisms involved in developing the CRC microenvironment, their causes, and their consequences need to be understood from a genetic and immunological perspective. This review highlighted the importance of altering the immune response in CRC. It focused on drugs that may modulate the immune response and show specific efficacy and contrasted with evidence that immunosuppression or the promotion of the immune response is the answer to generating effective treatments with combined chemotherapeutic drugs.

Low-dose immunotherapy as a potentiator to increase the response with neo-adjuvant chemotherapy in oral cancers

Neo-adjuvant chemotherapy(NACT)is utilized in locally advanced oral cancers to reduce the tumor burden and downstage the tumor to be amenable for definitive surgical management.Its long-term results compared to upfront surgical resection was not encouraging.Immunotherapy has now been used not only in recurrence and metastatic setting but also in the locally advanced tumor management regimens.The purpose of this concept paper is to bring forward the rationale to use a fixed low-dose immunotherapy agent as a potentiator to the standard NACT regimen and recommend their future investigation in oral cancer management.

Peptide drugs: a new direction in cancer immunotherapy

Cancer immunotherapy has emerged as a promising approach in cancer treatment and is considered a major advancement after surgical interventions, radiotherapy, chemotherapy, and targeted therapy. The clinical use of immunotherapeutic drugs, particularly antibody-based drugs that target immune checkpoints, has notably increased~1.

Revolutionizing gastric cancer treatment:The potential of immunotherapy

Gastric cancer,a prevalent malignancy worldwide,ranks sixth in terms of frequency and third in fatality,causing over a million new cases and 769000 annual deaths.Predominant in Eastern Europe and Eastern Asia,risk factors include family medical history,dietary habits,tobacco use,Helicobacter pylori,and Epstein-Barr virus infections.Unfortunately,gastric cancer is often diagnosed at an advanced stage,leading to a grim prognosis,with a 5-year overall survival rate below 5%.Surgical intervention,particularly with D2 Lymphadenectomy,is the mainstay for early-stage cases but offers limited success.For advanced cases,the National Comprehensive Cancer Network recommends chemotherapy,radiation,and targeted therapy.Emerging immunotherapy presents promise,especially for unresectable or metastatic cases,with strategies like immune checkpoint inhibitors,tumor vaccines,adoptive immunotherapy,and nonspecific immunomodulators.In this Editorial,with regards to the article“Advances and key focus areas in gastric cancer immunotherapy:A comprehensive scientometric and clinical trial review”,we address the advances in the field of immunotherapy in gastric cancer and its future prospects.

Deep insight into the B-cell associated tertiary lymphoid structure and tumor immunotherapy

Bod et al.1 recently published a study in Nature that garnered attention to B cell-associated anti-tumor immunity and immunotherapy of melanoma and other tumors1.As a promising supplemental immunotherapy to mainstream methods that target T and natural killer(NK)cells,B cell-associated anti-tumor immunotherapy is promising。

Analysis of the impact of immunotherapy efficacy and safety in patients with gastric cancer and liver metastasis

BACKGROUND Gastric cancer(GC)is the fifth most common type of cancer and has the fourth highest death rate among all cancers.There is a lack of studies examining the impact of liver metastases on the effectiveness of immunotherapy in individuals diagnosed with GC.AIM To investigate the influence of liver metastases on the effectiveness and safety of immunotherapy in patients with advanced GC.METHODS This retrospective investigation collected clinical data of patients with advanced stomach cancer who had immunotherapy at our hospital from February 2021 to January 2023.The baseline attributes were compared using either the Chi-square test or the Fisher exact probability method.The chi-square test and Kaplan-Meier survival analysis were employed to assess the therapeutic efficacy and survival duration in GC patients with and without liver metastases.RESULTS The analysis comprised 48 patients diagnosed with advanced GC,who were categorized into two groups:A liver metastasis cohort(n=20)and a non-liver metastatic cohort(n=28).Patients with liver metastasis exhibited a more deteriorated physical condition compared to those without liver metastasis.The objective response rates in the cohort with metastasis and the cohort without metastasis were 15.0%and 35.7%(P>0.05),respectively.Similarly,the disease control rates in these two cohorts were 65.0%and 82.1%(P>0.05),respectively.The median progression-free survival was 5.0 months in one group and 11.2 months in the other group,with a hazard ratio of 0.40 and a significance level(P)less than 0.05.The median overall survival was 12.0 months in one group and 19.0 months in the other group,with a significance level(P)greater than 0.05.CONCLUSION Immunotherapy is less effective in GC patients with liver metastases compared to those without liver metastasis.

Present situation and prospect of immunotherapy for unresectable locally advanced esophageal cancer during peri-radiotherapy

Four major studies(Checkmate577,Keynote-590,Checkmate649 and Attraction-4)of locally advanced esophageal cancer published in 2020 have established the importance of immunotherapy,represented by anti-programmed death protein(PD)-1 in postoperative adjuvant treatment and advanced first-line treatment of locally advanced or advanced esophageal cancer and esophagogastric junction cancer,from the aspects of proof of concept,long-term survival,overall survival rate and progression-free survival.For unresectable or inoperable nonmetastatic esophageal cancer,concurrent radiotherapy and chemotherapy is the standard treatment recommended by various guidelines.Because its curative effect is still not ideal,it is necessary to explore radical radiotherapy and chemotherapy in the future,and it is considered to be promising to combine them with immunotherapeutic drugs such as anti-PD-1.This paper mainly discusses how to combine radical concurrent radiotherapy and chemotherapy with immunotherapy for unresectable local advanced esophageal cancer.

Hepatic arterial infusion chemotherapy with anti-angiogenesis agents and immune checkpoint inhibitors for unresectable hepatocellular carcinoma and meta-analysis

BACKGROUND Hepatic arterial infusion chemotherapy(HAIC)has been proven to be an ideal choice for treating unresectable hepatocellular carcinoma(uHCC).HAIC-based treatment showed great potential for treating uHCC.However,large-scale studies on HAIC-based treatments and meta-analyses of first-line treatments for uHCC are lacking.AIM To investigate better first-line treatment options for uHCC and to assess the safety and efficacy of HAIC combined with angiogenesis inhibitors,programmed cell death of protein 1(PD-1)and its ligand(PD-L1)blockers(triple therapy)under real-world conditions.METHODS Several electronic databases were searched to identify eligible randomized controlled trials for this meta-analysis.Study-level pooled analyses of hazard ratios(HRs)and odds ratios(ORs)were performed.This was a retrospective single-center study involving 442 patients with uHCC who received triple therapy or angiogenesis inhibitors plus PD-1/PD-L1 blockades(AIPB)at Sun Yat-sen University Cancer Center from January 2018 to April 2023.Propensity score matching(PSM)was performed to balance the bias between the groups.The Kaplan-Meier method and cox regression were used to analyse the survival data,and the log-rank test was used to compare the suvival time between the groups.RESULTS A total of 13 randomized controlled trials were included.HAIC alone and in combination with sorafenib were found to be effective treatments(P values for ORs:HAIC,0.95;for HRs:HAIC+sorafenib,0.04).After PSM,176 HCC patients were included in the analysis.The triple therapy group(n=88)had a longer median overall survival than the AIPB group(n=88)(31.6 months vs 14.6 months,P<0.001)and a greater incidence of adverse events(94.3%vs 75.4%,P<0.001).CONCLUSION This meta-analysis suggests that HAIC-based treatments are likely to be the best choice for uHCC.Our findings confirm that triple therapy is more effective for uHCC patients than AIPB.

Immunotherapy in combination with chemotherapy for Peutz-Jeghers syndrome with advanced cervical cancer:A case report

BACKGROUND Peutz-Jeghers syndrome(PJS)is a rare autosomal dominant disorder,and female patients may develop gynecologic tumours.The prognosis for such patients is poor and the specific pathogenesis remains uncertain.Therefore,there are currently no uniform treatment options.CASE SUMMARY Herein,we introduce the case of a 45-year-old female who was diagnosed with PJS for 45 years and cervical cancer for 3 years.Postoperative pathological examination showed metastases in the right external iliac lymph nodes.The patient was initially treated with a combination of doxorubicin and carboplatin chemotherapy and pelvic magnetic resonance showed that the metastases had grown.Subsequently,we performed whole exome sequencing in this patient and identified the relevant causative gene.In addition to the chemotherapy regimen,sindilizumab was administered and the patient was followed up.After 4 cycles of treatment,the metastases were substantially reduced and were not enlarged after six months of follow-up.This case report suggests that patients with PJS combined with cervical cancer may have a sustained response to immunecombination chemotherapy regimens.CONCLUSION Clinicians should be aware of the importance of immunotherapy in patients with PJS combined with advanced cervical cancer.

Immunotherapy for esophageal cancer:Where are we now and where can we go

Immune checkpoint inhibitor therapy has dramatically improved patient prognosis,and thereby transformed the treatment in various cancer types including esophageal squamous cell carcinoma(ESCC)in the past decade.Monoclonal antibodies that selectively inhibit programmed cell death-1(PD-1)activity has now become standard of care in the treatment of ESCC in metastatic settings,and has a high expectation to provide clinical benefit during perioperative period.Further,anti-cytotoxic T-lymphocyte–associated protein 4(CTLA-4)monoclonal antibody has also been approved in the treatment of recurrent/metastatic ESCC in combination with anti-PD-1 antibody.Well understanding of the existing evidence of immune-based treatments for ESCC,as well as recent clinical trials on various combinations with chemotherapy for different clinical settings including neoadjuvant,adjuvant,and metastatic diseases,may provide future prospects of ESCC treatment for better patient outcomes.

Advancements in Lynch Syndrome Management: Applying Immunotherapy for Therapeutic Success

Lynch syndrome is the fourth most common cancer in the United States, with an early age of onset and poor prognosis. Here, we present a unique case of a patient with progressive colon cancer due to a late diagnosis of Lynch syndrome showing excellent response to immunotherapy. A 59-year-old male with a history of rectal cancer 30 years ago came to the hospital due to a fever and further found a large necrotic colon mass. Biopsy was positive for colorectal cancer;however, due to the size of the tumor, the patient was deemed not a surgical candidate and offered hospice with palliative chemotherapy. Based on further workup, the patient was diagnosed with Lynch syndrome, with colon cancer determined to be responsive to Immunotherapy. He was started on JEMPERLI (Dosterlimab-gxly), and after three cycles of therapy, imaging and PET scan were repeated, showing decreased activity and extent of the tumor—a tremendous success.

New avenues for the treatment of immunotherapy-resistant pancreatic cancer

Pancreatic cancer(PC)is characterized by its extremely aggressive nature and ranks 14th in the number of new cancer cases worldwide.However,due to its complexity,it ranks 7th in the list of the most lethal cancers worldwide.The pathogenesis of PC involves several complex processes,including familial genetic factors associated with risk factors such as obesity,diabetes mellitus,chronic pancreatitis,and smoking.Mutations in genes such as KRAS,TP53,and SMAD4 are linked to the appearance of malignant cells that generate pancreatic lesions and,consequently,cancer.In this context,some therapies are used for PC,one of which is immunotherapy,which is extremely promising in various other types of cancer but has shown little response in the treatment of PC due to various resistance mechanisms that contribute to a drop in immunotherapy efficiency.It is therefore clear that the tumor microenvironment(TME)has a huge impact on the resistance process,since cellular and non-cellular elements create an immunosuppressive environment,characterized by a dense desmoplastic stroma with cancerassociated fibroblasts,pancreatic stellate cells,extracellular matrix,and immunosuppressive cells.Linked to this are genetic mutations in TP53 and immunosuppressive factors that act on T cells,resulting in a shortage of CD8+T cells and limited expression of activation markers such as interferon-gamma.In this way,finding new strategies that make it possible to manipulate resistance mechanisms is necessary.Thus,techniques such as the use of TME modulators that block receptors and stromal molecules that generate resistance,the use of genetic manipulation in specific regions,such as microRNAs,the modulation of extrinsic and intrinsic factors associated with T cells,and,above all,therapeutic models that combine these modulation techniques constitute the promising future of PC therapy.Thus,this study aims to elucidate the main mechanisms of resistance to immunotherapy in PC and new ways of manipulating this process,resulting in a more efficient therapy for cancer patients and,consequently,a reduction in the lethality of this aggressive cancer.

Shenqi Fuzheng injection alleviates chemotherapy-induced cachexia by restoring glucocorticoid signaling in hypothalamus

Chemotherapy-induced cachexia(CIC)is a debilitating condition characterized by weight loss,muscle atrophy,and anorexia[1].While peripheral mechanisms of cachexia have been extensively studied,the involvement of the central nervous system(CNS)in CIC is often overlooked.Chemotherapeutic drugs cause stress responses and inflammation,which may impact the hypothalamus and disrupt systemic energy and neuroendocrine functions.Understanding hypothalamic roles in regulating these processes can provide insights into CIC's mechanisms and aid in developing novel therapies.

Screening of Myocardial Cardiotoxicity Induced by Anticancer Chemotherapy and the Importance of Global Longitudinal Strain

Introduction: The improvement of survival in patients with cancer and the expansion of therapeutic options have led to the emergence of a new profile of cardiotoxicity, specifically associated with antimitotic agents. Our study aimed to assess the incidence of chemotherapy-induced myocardial toxicity in patients with cancer. Patients and Methods: We conducted a looking-forward longitudinal cohort study including all patients admitted to the Cardiology departments of Aristide le Dantec Hospital and Dalal Jamm National Hospital Centre for apre-chemotherapy check-up. The included patients did not undergo any pre-existing cardiopathy. Results: Over a period of two years ranging from January 2019 to December 2021, a total of 37 patients were included in the study. Notably, there was a female predominance (92%) with an average age of 49.7 years ± 13.69. Breast cancer accounted for 70% of the neoplasms. Laboratory findings revealed moderate anemia in 19 patients (51%). At inclusion, the left ventricle (LV) was of normal size (LV diastole at 44.46 ± 4.97 mm). The systolic function of the left ventricle was normal in all patients, with an average ejection fraction (EF) of 63.1% ± 5.80 and a mean global longitudinal strain (GLS) of −20.4% ± 2.58. The most commonly used agents were anthracyclines. During follow-up, 3 patients (8.1%) developed clinical symptoms of left heart failure, and LV dysfunction on echocardiography was observed in 5 (13.5%) patients, with a significant decrease in EF Conclusion: The incidence of cardiac toxicity is not negligible, hence the importance of early screening. Strain imaging is an essential tool that should be performed as part of the assessment before chemotherapy and re-evaluated during treatment.

Immunotherapy in type 1 diabetes:Novel pathway to the future ahead

Since the discovery of insulin over 100 years ago,the focus of research in the management of type 1 diabetes(T1D)has centered around glycemic control and management of complications rather than the prevention of autoimmune destruc-tion of pancreaticβcells.Fortunately,in recent years,there has been significant advancement in immune-targeted pharmacotherapy to halt the natural progres-sion of T1D.The immune-targeted intervention aims to alter the underlying pa-thogenesis of T1D by targeting different aspects of the immune system.The im-munotherapy can either antagonize the immune mediators like T cells,B cells or cytokines(antibody-based therapy),or reinduce self-tolerance to pancreaticβcells(antigen-based therapy)or stem-cell treatment.Recently,the US Food and Drug Administration approved the first immunotherapy teplizumab to be used only in stage 2 of T1D.However,the window of opportunity to practically implement this approved molecule in the selected target population is limited.In this Edito-rial,we briefly discuss the various promising recent developments in the field of immunotherapy research in T1D.However,further studies of these newer thera-peutic agents are needed to explore their true potential for prevention or cure of T1D.