Treatment Of Cytomegalovirus Infection Research Articles

Use of Specific T Lymphocytes in Treating Cytomegalovirus Infection in Hematopoietic Cell Transplant Recipients: A Systematic Review

Cytomegalovirus (CMV) poses a significant threat to post-hematopoietic cell transplantation (HCT). Control strategies include letermovir prophylaxis or ganciclovir pre-emptive therapy (PET). Without prophylaxis, 65–90% of seropositive recipients develop a clinically significant CMV infection. Due to PET drawbacks, letermovir prophylaxis is preferable, as it reduces CMV-related events and improves overall survival. However, refractory or resistant CMV-CS remains a challenge, with maribavir showing limited efficacy. This systematic review followed the Cochrane Manual and PRISMA guidelines and was registered in PROSPERO. Searches were conducted in PubMed, Scopus, Embase, and Web of Science. Out of 1895 identified records, 614 duplicates were removed, and subsequent screening excluded 1153 studies. Eleven included studies (2012–2024) involved 255 HCT recipients receiving adoptive immunotherapy (AI), primarily CMV-specific T-cell therapy. GvHD occurred in 1.82% of cases. Adverse events occurred in 4.4% of cases, while mild CRS was observed in 1.3% of patients. Efficacy, evaluated in 299 patients across eleven studies, showed an average response rate of 78.2%. CMV-CS recurrence was observed in 24.4% of 213 patients, and death due to CMV was reported in 9.7% of 307 patients across nine studies. Adoptive hCMV-specific T-cell immunotherapy appears to be a safe, effective alternative for refractory CMV-CS in HCT.

Efficacy and Safety of Valganciclovir in Congenital Cytomegalovirus Infection with Isolated Intrahepatic Cholestasis: A Randomized Controlled Trial.

Cytomegalovirus (CMV) infection affects the hepatic, neurologic, hematopoietic, respiratory, gastrointestinal, and other organs, resulting in a high mortality rate and long-term sequelae. It may cause acute or chronic hepatitis, or even lead to hepatic cirrhosis. Valganciclovir (VGCV) is an effective, safe, and well-tolerated treatment for congenital CMV infection, without any serious adverse effects. This study was conducted to evaluate the clinical, biochemical, and virological profiles of infants with CMV with intrahepatic cholestasis and to determine the outcomes with or without treatment with VGCV. Twenty infants aged <6 months diagnosed with congenital CMV infection with evidence of intrahepatic cholestasis were included in this study. Randomization was used to divide the study participants into 2 groups. The control group (n=10) was treated with only supportive management, and the intervention group (n=10) was treated with oral VGCV at 16 mg/kg/dose 12 hours a day for 6 weeks plus supportive treatments. Physical examinations and biochemical, serological, and virological tests were performed at the time of diagnosis and at the end of 6 weeks and 6 months. The control and intervention groups were compared in terms of clinical and laboratory parameters such as jaundice, dark urine, pale stool, hepatomegaly, total bilirubin, aminotransferases, gamma-glutamyl transferase, alkaline phosphatase, and CMV polymerase chain reaction load, which showed a significant reduction after treatment in the intervention group (p<0.05) with oral VGCV, with very few side effects, whereas the control group showed no significant changes. Oral VGCV can be used to effectively treat CMV infection with intrahepatic cholestasis without notable side effects.

NAVIGATING THE UNCHARTED WATERS: MANAGING CONCURRENT CYTOMEGALOVIRUS MYOCARDITIS AND ALLOGRAFT REJECTION IN A PATIENT WITH HEART TRANSPLANTATION

Abstract A 49–year–old female with hypertrophic cardiomyopathy underwent orthotopic heart transplantation. She was cytomegalovirus(CMV)–positive and received a heart from a CMV–negative donor, so prophylaptic therapy was not administered. Initial immunosuppression included cyclosporine and induction with Basiliximab in a steroid–free regimen. The first routine biopsy (EMB) showed mild focal cellular rejection (grade 1A) and C4d positivity with granular aspect. Mycophenolate mofetil (MMF) was added. The second EMB, 7 days later, showed mild diffuse cellular rejection (grade 1B) and diffuse C4d positivity. Anti–HLA donor–specific antibodies (DSA) had increased anti–B13 levels (MFI=21298) compared to pre–transplantation tests. Echocardiography showed a normal ejection fraction (LVEF) and mild concentric hypertrophy (LVH). Treatment included pulse methylprednisolone therapy (1 g/day for three days) followed by oral prednisone with a slow tapering regimen, and increased MMF. CMV count weekly monitored was negative. The next two EMBs performed one week apart from each other described a grade 1A mild focal pattern while the 5th EMB (1 month and 2 weeks post–transplant) showed a grade 1A rejection together with focal mild fibrosis and eosinophils, so we replaced cyclosporine with tacrolimus, increased MMF and prednisone. At this time, the patient had no overt clinical signs of CMV infection but a CMV–PCR of 100847 IU/mL so ganciclovir 5 mg/Kg bid was started and CMV–PCR decreased to 42308 IU/mL after 1 week. Subsequently, she developed sinus tachycardia, mildly reduced LVEF, moderate LVH and diastolic dysfunction. Troponin was elevated. A new EMB revealed interstitial edema, diffuse ischemic injury, and eosinophilic inclusions suggesting CMV myocarditis. Treatment involved down–titrating MMF and Prednisone, administering standard intravenous immunoglobulin (IVIG), and high–dose Ganciclovir (7.5 mg/Kg bid). Leukopenia subsequently led to Ganciclovir down–titration. In the next days, the patient improved, CMV cleared, and leukocyte count normalized. She was discharged on Tacrolimus, MMF, Prednisone and Valganciclovir. Subsequent tests showed no cellular or antibody–mediated rejection (AMR), no CMV inclusions, recovered cardiac function, and markedly reduced anti–B13 DSA (MFI 3000). This case raises some concerns: in this context, the use of IVIG in the treatment of CMV infection and AMR appears reasonable, in support of antiviral and immunosuppressive therapy.

Considerable differences in management of cytomegalovirus infection in patients with biliary atresia.

Patients with biliary atresia (BA)and ongoing cytomegalovirus (CMV)infection may have poorer outcomes after Kasai portoenterostomy than uninfected patients. Still, there is no consensus on the usefulness of viral testing and antiviral treatment (AVT). This study aims to explore the need for future research on AVT for CMV infection by assessing how CMV infection in BA patients is managed in different centers. An online questionnaire with 10 questions was offered to participants at an international congress on BA, organized in collaboration with the European Reference Network for rare liver diseases in 2022. Answers to questions were either dichotomic or multiple choices of different numeric intervals. Ongoing CMV infection was defined by detecting cytomegalovirus-immunoglobulin M (CMV-IgM) in serum or cytomegalovirus-deoxyribonucleic acid (CMV-DNA)by polymerase chain reaction in blood or urine. There were 43 respondents from 36 centers in 26 countries. The total number of BA patients per year was between 208 and 380 from centers with 0-5 to >20 BA patients yearly (median 6-10). CMV infection was tested in 27 centers (75%), of which 18 (67%) use AVT. The rate of CMV infection varied between 0%-5% and 40%-50% (median 5%-10%). Willingness to treat the infection did not differ between centers with low and high rates of CMV infection. Most centers test for CMV infection, and a considerable proportion use AVT despite the lack of evidence of its benefits. A future randomized study on treating CMV infection in BA patients is necessary and feasible.

Management of Cytomegalovirus Infections in the Era of the Novel Antiviral Players, Letermovir and Maribavir.

Cytomegalovirus (CMV) infections may increase morbidity and mortality in immunocompromised patients. Until recently, standard antiviral drugs against CMV were limited to viral DNA polymerase inhibitors (val)ganciclovir, foscarnet and cidofovir with a risk for cross-resistance. These drugs may also cause serious side effects. This narrative review provides an update on new antiviral agents that were approved for the prevention and treatment of CMV infections in transplant recipients. Letermovir was approved in 2017 for CMV prophylaxis in CMV-seropositive adults who received an allogeneic hematopoietic stem cell transplant. Maribavir followed four years later, with an indication in the treatment of adult and pediatric transplant patients with refractory/resistant CMV disease. The target of letermovir is the CMV terminase complex (constituted of pUL56, pUL89 and pUL51 subunits). Letermovir prevents the cleavage of viral DNA and its packaging into capsids. Maribavir is a pUL97 kinase inhibitor, which interferes with the assembly of capsids and the egress of virions from the nucleus. Both drugs have activity against most CMV strains resistant to standard drugs and exhibit favorable safety profiles. However, high-level resistance mutations may arise more rapidly in the UL56 gene under letermovir than low-grade resistance mutations. Some mutations emerging in the UL97 gene under maribavir can be cross-resistant with ganciclovir. Thus, letermovir and maribavir now extend the drug arsenal available for the management of CMV infections and their respective niches are currently defined.

A review on cytomegalovirus in patients with autoimmune inflammatory rheumatic diseases: Prevalence, clinical spectrum, treatment, and antiviral prophylaxis

Human cytomegalovirus (CMV) is a highly infectious virus that is prevalent among adults worldwide. In immunocompetent individuals, CMV infection rarely causes complications. Following initial infection, however, CMV remains latent in the body and can be reactivated especially in immunocompromised patients, such as those with autoimmune inflammatory rheumatic diseases (AIIRDs), leading to tissue-invasive, life-threatening diseases, such as colitis, vascular thrombosis, and pneumonitis. Although there are standard treatment recommendations for symptomatic CMV disease, there is paucity of consensus in the role of primary and secondary antiviral prophylaxis to prevent CMV reactivation, especially in AIIRDs patients undergoing immunosuppressive therapy. Therein, this review aimed to provide an overview of the prevalence, clinical disease, risk factors, and treatment for CMV infection, as well as on the role of primary and secondary antiviral prophylaxis in AIIRDs patients. The emerging novel techniques that measure CMV-specific T-cell immunity as a guide to initiate prophylaxis in high-risk patients were also discussed.

Features of cytomegalovirus infection in severely premature newborns

Cytomegalovirus infection of newborns is one of the serious medical and social problems of neonatology and is often the cause of disability and mortality of the child population.The purpose of the work was to study the incidence and clinical characteristics of cytomegalovirus infection in very premature newborns. Materials and methods. Data from 384 medical records of premature infants with a gestational age of less than 32 weeks were analyzed.Results. The variants of the clinical course of the disease are described, the results of laboratory studies are presented, as well as the methods of therapy used. Clinical cases with fatal outcome demonstrated. The results of the study showed that the postnatal form of the disease was 3 times more common than congenital and often occurred under the “mask” of another severe pathology, which made early diagnosis difficult. For timely diagnosis and treatment of cytomegalovirus infection in severely premature newborns, regular polymerase chain reaction examination is recommended.

2740. Letermovir for the Prevention and Treatment of Cytomegalovirus Infection in Solid Organ Transplant Recipients

Abstract Background Cytomegalovirus (CMV) is a common infection that can lead to end-organ damage and graft rejection in solid organ transplant (SOT) recipients. Due to the increase in drug-resistant CMV and unfavorable side effect profile of available CMV-active agents, there is a need for additional prophylactic and treatment strategies in this patient population. The goal of this study is to evaluate SOT recipients prescribed letermovir for prophylaxis and/or treatment of CMV. Methods This study was a retrospective review of adult SOT recipients in the Cleveland Clinic Health System prescribed letermovir from 11/8/2017 to 8/1/2022. The primary objective was to describe the utilization of letermovir in SOT recipients. Secondary objectives included: proportion of SOT recipients that experienced CMV breakthrough on letermovir prophylaxis, proportion of SOT recipients that experienced refractory CMV infection on letermovir treatment, prevalence of letermovir resistance, and letermovir-induced adverse effects. Results A total of 45 patients were included in the study, with 52 letermovir courses. Lung was the most commonly transplanted organ (35%), followed by kidney (22%). 78% of patients were high-risk CMV and the most common immunosuppression regimen consisted of a calcineurin inhibitor in combination with a corticosteroid (82%). 11 patients received letermovir for primary CMV prophylaxis, with only one patient experiencing new/worsening viremia while on the agent. Of the 34 patients who received letermovir for secondary CMV prophylaxis, 11 experienced new/worsening viremia. 7 patients received letermovir for CMV treatment, at a median viral load of 991 IU/mL (IQR 603-2,738) on initiation and peak viral load of 3,892 IU/mL (IQR 1,407-10,209) while on therapy. No patients in the treatment group experienced refractory infection. 7/52 (13.5%) letermovir courses were discontinued due to new/worsening viremia, with no letermovir resistance identified. No letermovir-related adverse effects were documented. Conclusion Our study shows that letermovir appears to be effective in suppressing CMV viremia. Letermovir may be an alternative option for SOT recipients who are unable to tolerate or have resistance to traditional CMV therapeutics. Disclosures All Authors: No reported disclosures

Cytomegalovirus Infection in Pregnancy Prevention and Treatment Options: A Systematic Review and Meta-Analysis.

Cytomegalovirus (CMV) infection is a significant health concern affecting numerous expectant mothers across the globe. CMV is the leading cause of health problems and developmental delays among infected infants. Notably, this study examines CMV infection in pregnancy, its management, prevention mechanisms, and treatment options. Specifically, information from the Cochrane Library, PUBMED, Wiley Online, Science Direct, and Taylor Francis databases were reviewed along with additional records identified through the register, the Google Scholar search engine. Based on the search, 21 articles were identified for systematic review. A total of six randomized controlled trials (RCTs) were utilized for a meta-analytic review. As heterogeneity was substantial, the random effects model was used for meta-analysis. Utilizing the random-effects model, the restricted maximum likelihood (REML) approach, the estimate of effect size (d = -0.479, 95% CI = -0.977 to 0.019, p = 0.060) suggests the results are not statistically significant, so it cannot be inferred that the prevention methods used were effective, despite an inverse relationship between treatment and number of infected cases. The findings indicated that several techniques are used to prevent, diagnose, and manage CMV infection during pregnancy, including proper hygiene, ultrasound examination (US), magnetic resonance imaging (MRI), amniocentesis, viremia, hyperimmunoglobulin (HIG), and valacyclovir (VACV). The current review has significant implications for addressing CMV infection in pregnancy. Specifically, it provides valuable findings on contemporary management interventions to prevent and treat CMV infection among expectant mothers. Therefore, it allows relevant stakeholders to address these critical health concerns and understand the effectiveness of the proposed prevention and treatment options.

Establishment and Evaluation of a Parametric Population Pharmacokinetic Model Repository for Ganciclovir and Valganciclovir.

Ganciclovir and valganciclovir are used for prophylaxis and treatment of cytomegalovirus infection. However, there is great interindividual variability in ganciclovir's pharmacokinetics (PK), highlighting the importance of individualized dosing. To facilitate model-informed precision dosing (MIPD), this study aimed to establish a parametric model repository of ganciclovir and valganciclovir by summarizing existing population pharmacokinetic information and analyzing the sources of variability. (2) Methods: A total of four databases were searched for published population PK models. We replicated these models, evaluated the impact of covariates on clearance, calculated the probability of target attainment for each model based on a predetermined dosing regimen, and developed an area under the concentration-time curve (AUC) calculator using maximum a posteriori Bayesian estimation. (3) Results: A total of 16 models, one- or two-compartment models, were included. The most significant covariates were body size (weight and body surface area) and renal function. The results show that 5 mg/kg/12 h of ganciclovir could make the AUC0-24h within 40-80 mg·h/L for 50.03% pediatrics but cause AUC0-24h exceeding the exposure thresholds for toxicity (120 mg·h/L) in 51.24% adults. (4) Conclusions: Dosing regimens of ganciclovir and valganciclovir should be adjusted according to body size and renal function. This model repository has a broad range of potential applications in MIPD.

Genetic Variants Associated with Drug Resistance of Cytomegalovirus in Hematopoietic Cell Transplantation Recipients.

Cytomegalovirus (CMV) infection is a serious complication in hematopoietic cell transplantation (HCT) recipients. Drug-resistant strains make it more challenging to treat CMV infection. This study aimed to identify variants associated with CMV drug resistance in HCT recipients and assess their clinical significance. A total of 123 patients with refractory CMV DNAemia out of 2271 HCT patients at the Catholic Hematology Hospital between April 2016 and November 2021 were analyzed, which accounted for 8.6% of the 1428 patients who received pre-emptive therapy. Real-time PCR was used to monitor CMV infection. Direct sequencing was performed to identify drug-resistant variants in UL97 and UL54. Resistance variants were found in 10 (8.1%) patients, and variants of uncertain significance (VUS) were found in 48 (39.0%) patients. Patients with resistance variants had a significantly higher peak CMV viral load than those without (p = 0.015). Patients with any variants had a higher risk of severe graft-versus-host disease and lower one-year survival rates than those without (p = 0.003 and p = 0.044, respectively). Interestingly, the presence of variants reduced the rate of CMV clearance, particularly in patients who did not modify their initial antiviral regimen. However, it had no apparent impact on individuals whose antiviral regimens were changed due to refractoriness. This study highlights the importance of identifying genetic variants associated with CMV drug resistance in HCT recipients for providing appropriate antiviral treatment and predicting patient outcomes.

Comparison of Three Renal Function Formulas for Ganciclovir/Valganciclovir Dose Individualization in CMV-Infected Solid Organ Transplantation Patients Using a Population Approach.

The gold standard treatment of established cytomegalovirus infection or prevention in solid organ transplantation is the intravenous administration of ganciclovir (GCV) or oral administration of valganciclovir (VGCV), both adjusted to the renal function. In both instances, there is a high interindividual pharmacokinetic variability, mainly owing to the wide range of variation of both the renal function and body weight. Therefore, accurate estimation of the renal function is crucial for GCV/VGCV dose optimization. This study aimed to compare three different formulas for estimating the renal function in solid organ transplantation patients with cytomegalovirus infection, for individualizing antiviral therapy with GCV/VGCV, using a population approach. A population pharmacokinetic analysis was performed using NONMEM 7.4. A total of 650 plasma concentrations obtained after intravenous GCV and oral VGCV administrations were analyzed, from intensive and sparse sampling designs. Three different population pharmacokinetic models were built with the renal function given by Cockcroft-Gault, Modification of Diet in Renal Disease, or Chronic Kidney Disease EPIdemiology Collaboration (CKD-EPI) formulas. Pharmacokinetic parameters were allometrically scaled to body weight. The CKD-EPI formula was identified as the best predictor of between-patient variability in GCV clearance. Internal and external validation techniques showed that the CKD-EPI model had better stability and performed better compared with the others. The model based on the more accurate estimation of the renal function with the CKD-EPI formula and body weight as a size metric most used in the clinical practice can refine initial dose recommendations and contribute to GCV and VGCV dose individualization when required in the prevention or treatment of cytomegalovirus infection in solid organ transplantation patients.

A great pediatrician and scholar devoting his whole life to pediatric infectious and digestive diseases—In memoriam of Professor Yongsui Dong

A great pediatrician and scholar devoting his whole life to pediatric infectious and digestive diseases—In memoriam of Professor Yongsui Dong

Risk Factors for Cytomegalovirus Infection and Its Impact on Survival after Living Donor Liver Transplantation in South Korea: A Nested Case-Control Study.

Cytomegalovirus (CMV), a common pathogen, causes infectious complications and affects long-term survival after transplantation. Studies examining living donor liver transplantation (LDLT) are limited. This study analyzed the risk factors for CMV infection and its impact on the survival of LDLT patients. A nested case-control design retrospectively analyzed data from 952 patients who underwent LDLT from 2005-2021. The incidence of CMV infection for the study cohort was 15.2% at 3 months for LDLT patients managed preemptively. Patients with CMV infections were matched with those without the infection at corresponding time points (index postoperative day) in a 1:2 ratio. Graft survival was significantly lower in the CMV infection group than in the control group. CMV infection was an independent risk factor for graft survival in the matched cohort (HR 1.93, p = 0.012). Independent risk factors for CMV infection were female sex (HR 2.4, p = 0.003), pretransplant MELD (HR 1.06, p = 0.004), pretransplant in-hospital stay (HR 1.83, p = 0.030), ABO incompatibility (HR 2.10, p = 0.009), donor macrovesicular steatosis ≥10% (HR 2.01, p = 0.030), and re-operation before index POD (HR 2.51, p = 0.035). CMV infection is an independent survival risk factor, and its risk factors should be included in the surveillance and treatment of CMV infections after LDLT.

Redox-based Spectrophotometric Method for the Determination of Ganciclovir in Bulk and Pharmaceutical Dosage Form

Background: Ganciclovir is a synthetic analogue of 2′-deoxy- guanosine, used in the treatment of cytomegalovirus infection. The aim of the present investigation was to develop and validate a simple, rapid and sensitive redox-based spectrophotometric method for the quantification of Ganciclovir in pure and in pharmaceutical dosage form.&#x0D; Methods: It was developed by using 0.1 M HCl as solvent and mixture of ferric chloride and 1,10-phenanthroline as chromogenic reagent. The developed method was optimized for various method conditions and then statistically validated.&#x0D; Results: The mixture containing 0.3% w/v of ferric chloride and 0.5% w/v of 1,10-phenanthroline and drug to reagent mole ratio of 0.5:0.5, were identified as optimum for the method, based on the optimization studies. Linearity of the method was found to be 5.0-30.0 μg/mL for Ganciclovir, when the measurement was done at 510.0 nm. The method was proved to be sensitive by its low limit of detection and quantification values i.e., 0.30 and 0.90 μg/mL, respectively. The results of the validation parameters comply with the ICH guidelines. The %assay value 99.2 indicated the successful adaptation of the contemplated method for the pharmaceutical formulation.&#x0D; Conclusion: The developed method was simple and could be applied in the quality control testing of Ganciclovir in formulation.

Update on treatment of cytomegalovirus infection in pregnancy: preliminary data from the regional reference center in Campania, Italy

Update on treatment of cytomegalovirus infection in pregnancy: preliminary data from the regional reference center in Campania, Italy

A quick guide to diagnosis and treatment of cytomegalovirus infection in the gut: current dilemmas

Abstract Cytomegalovirus is a ubiquitous herpesvirus, which, after often asymptomatic primary infection, establishes a life-long latency in different organs, including gut. As there is a close synergistic relationship between mucosal inflammation and viral expression, particularly in patients suffering from inflammatory bowel disease, it is often challenging to distinguish subclinical cytomegalovirus replication from cytomegalovirus-mediated colitis. The outcome for patients with cytomegalovirus reactivation appears to be worse than that for patients without reactivation, but the true role of cytomegalovirus is not entirely clear, as is the dilemma whether specific treatment with antivirals alters the course of inflammatory bowel disease. This review focuses on gastrointestinal tract cytomegalovirus disease, with special emphasis on diagnostic and treatment considerations of cytomegalovirus colitis in patients with inflammatory bowel disease.

Cytomegalovirus infection in pregnant women - threats, diagnosis and treatment

Cytomegalovirus is one of the most widespread DNA viruses, with 90% of women of childbearing age in Poland infected with it. Infection poses a risk to the mother as well as the fetus, as the virus can cross the placenta and damage the fetus. The purpose of this paper is to review scientific publications from 2017-2022, which describe the course of cytomegalovirus infection in pregnant women, the risks to the mother and fetus associated with the infection, methods of diagnosing the infection in the pregnant woman and the fetus, as well as treatment of cytomegalovirus infection and directions for vaccine research.&#x0D; The most common complications of congenital cytomegalovirus infection include hearing loss, mental developmental delays and miscarriage. The infection can be detected in the pregnant woman by immunological testing, while polymerase chain reaction is used in the fetus and newborn. Early detection of infection in a pregnant woman allows the implementation of treatment which includes ganciclovir, valganciclovir, acyclovir and valacyclovir. A vaccine against cytomegalovirus has not been developed. Particularly important in the prevention of infection is to conduct educational activities regarding the routes of transmission of the virus and the consequences of congenital infection for the fetus.&#x0D; Cytomegalovirus infections among pregnant women. It is important to monitor fetal development and possibly diagnose for congenital CMV infection in case of abnormalities, and the best diagnostic method is polymerase chain reaction testing. For the treatment of congenital CMV infection, acyclovir and valacyclovir are preferred, and therapy should be implemented for specific indications. Attention should be paid to educating women about infections caused by cytomegalovirus.

Adoptive Immunotherapy for Prophylaxis and Treatment of Cytomegalovirus Infection.

Cytomegalovirus (CMV), a member of the Herpesviridae family, is frequent among hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients in absence of antiviral prophylaxis, and is a major cause of morbidity and mortality in these vulnerable populations. Antivirals such ganciclovir, valganciclovir, and foscarnet are the backbone therapies, however drug toxicity and antiviral resistance may render these agents suboptimal in treatment. Newer therapies such as letermovir and maribavir have offered additional approaches for antiviral prophylaxis as well as treatment of drug resistant CMV infection, though may be limited by cost, drug intolerance, or toxicity. Adoptive immunotherapy, the transfer of viral specific T-cells (VSTs), offers a new approach in treatment of drug-resistant or refractory viral infections, with early clinical trials showing promise with respect to efficacy and safety. In this review, we will discuss some of the encouraging results and challenges of widespread adoption of VSTs in care of immunocompromised patients, with an emphasis on the clinical outcomes for treatment and prophylaxis of CMV infection among high-risk patient populations.

Efficacy of pp65-specific TCR-T cell therapy in treating cytomegalovirus infection after hematopoietic stem cell transplantation.

Cytomegalovirus (CMV) infection remains a major cause of mortality after hematopoietic stem cell transplantation (HSCT). Current treatments, including antiviral drugs and adoptive cell therapy with CMV-specific cytotoxic T lymphocytes (CTLs), only show limited benefits in patients. T-cell receptor (TCR)-T cell therapy offers a promising option to treat CMV infections. Here, using tetramer-based screening and single-cell TCR cloning technologies, we identified various CMV antigen-specific TCRs from healthy donors, and generated TCR-T cells targeting multiple pp65 epitopes corresponding to three major HLA-A alleles. The TCR-T cells showed efficient cytotoxicity toward epitope-expressing target cells in vitro. After transfer into immune-deficient mice bearing pp65+ HLA+ tumor cells, TCR-T cells induced dramatic tumor regression and exhibited long-term persistence. In a phase I clinical trial (NCT04153279), CMV TCR-T cells were applied to treat patients with CMV reactivation after HSCT. Except one patient who withdrew at early treatment stage, all other six patients were well-tolerated and achieved complete response (CR), no more than grade 2 cytokine release syndrome (CRS) and other adverse events were observed. CMV TCR-T cells persisted up to 3months. Among them, two patients have survived for more than 1 year. This study demonstrates the great potential in the treatment and prevention of CMV infection following HSCT or other organ transplantation.