Publications by authors named "Mengfen Wu"

8 Publications

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T-Cell Therapy for Lymphoma Using Nonengineered Multiantigen-Targeted T Cells Is Safe and Produces Durable Clinical Effects.

J Clin Oncol 2021 Jan 28:JCO2002224. Epub 2021 Jan 28.

Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX.

Purpose: Patients with relapsed lymphomas often fail salvage therapies including high-dose chemotherapy and mono-antigen-specific T-cell therapies, highlighting the need for nontoxic, novel treatments. To that end, we clinically tested an autologous T-cell product that targets multiple tumor-associated antigens (TAAs) expressed by lymphomas with the intent of treating disease and preventing immune escape.

Patients And Methods: We expanded polyclonal T cells reactive to five TAAs: PRAME, SSX2, MAGEA4, SURVIVIN, and NY-ESO-1. Products were administered to 32 patients with Hodgkin lymphomas (n = 14) or non-Hodgkin lymphomas (n = 18) in a two-part phase I clinical trial, where the objective of the first phase was to establish the safety of targeting all five TAAs (fixed dose, 0.5 × 10 cells/m) simultaneously and the second stage was to establish the maximum tolerated dose. Patients had received a median of three prior lines of therapy and either were at high risk for relapse (adjuvant arm, n = 17) or had chemorefractory disease (n = 15) at enrollment.

Results: Infusions were safe with no dose-limiting toxicities observed in either the antigen- or dose-escalation phases. Although the maximum tolerated dose was not reached, the maximum tested dose at which efficacy was observed (two infusions, 2 × 10 cells/m) was determined as the recommended phase II dose. Of the patients with chemorefractory lymphomas, two (of seven) with Hodgkin lymphomas and four (of eight) with non-Hodgkin lymphomas achieved durable complete remissions (> 3 years).

Conclusion: T cells targeting five TAAs and administered at doses of up to two infusions of 2 × 10 cells/m are well-tolerated by patients with lymphoma both as adjuvant and to treat chemorefractory lymphoma. Preliminary indicators of antilymphoma activity were seen in the chemorefractory cohort across both antigen- and dose-escalation phases.
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http://dx.doi.org/10.1200/JCO.20.02224DOI Listing
January 2021

BK Virus Epidemiology, Risk Factors, and Clinical Outcomes: An Analysis of Hematopoietic Stem Cell Transplant Patients at Texas Children's Hospital.

J Pediatric Infect Dis Soc 2021 Jan 8. Epub 2021 Jan 8.

Department of Pediatrics, Section of Infectious Diseases, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA.

Background: BK virus-associated hemorrhagic cystitis (BKV-HC) is a serious complication after hematopoietic stem cell transplantation (HSCT).

Methods: A retrospective review was performed to determine the frequency of BKV-HC and identify risk factors and renal morbidity associated with BKV-HC in pediatric HSCT recipients at our institution.

Results: A total of 314 pediatric recipients underwent allogeneic HSCT for either malignant (173, 55.1%) or nonmalignant disorders (141, 44.9%) from January 1, 2011, to December 31, 2015, with a minimum follow-up of 5 years post-HSCT. Severe BKV-HC (grades 3 and 4) was prevalent in 46 out of 67 (68.7%) recipients. Timing to presentation of severe BKV-HC (grades 3 and 4) occurred at a median of 37 days (26, 74; IQ1, IQ3) post-HSCT, with the duration of macroscopic hematuria lasting a median of 37.5 days (18, 71; IQ1, IQ3). In the first 60 days post-HSCT, peak acute kidney injury (AKI) stages 2 and 3 were seen more frequently in HSCT recipients who developed BKV-HC than those without (P = .004). Similarly, during post-HSCT days 61 to 100, peak AKI stage 3 was also more frequently seen in HSCT recipients who already developed BKV-HC prior to or during this time period than those without BKV-HC (P = .0002). Recipients who developed BKV-HC within 1 year of HSCT had more frequent mild to moderate chronic kidney disease (CKD stages 2-3) than those without BKV-HC (P = .002 and .007, respectively). On multivariate analysis, BKV-HC was associated with all-cause mortality (hazard ratio [HR]: 2.22; 95% confidence interval [CI]: 1.35-3.65). The following clinical variables were associated with time to development of HC on multivariate analysis: age (subdistribution HR [sHR] 1.11; 95% CI: 1.06-1.16) and myeloabalative conditioning regimen (sHR 4.2; 95% CI: 2.12-8.34).

Conclusions: Pediatric HSCT patients with BKV-HC experience significant morbidity and mortality. Renal morbidity, including AKI and CKD, is associated with BKV-HC.
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http://dx.doi.org/10.1093/jpids/piaa147DOI Listing
January 2021

Clinical effects of administering leukemia-specific donor T cells to patients with AML/MDS post-allogeneic transplant.

Blood 2020 Dec 3. Epub 2020 Dec 3.

Baylor College of Medicine, Houston, Texas, United States.

Relapse after allogeneic hematopoietic stem-cell transplantation (HCT) is the leading cause of death in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Infusions of unselected donor lymphocytes (DLIs) are used to enhance the graft-versus-leukemia (GVL) effect, as treatment for relapsed disease. However, as the infused lymphocytes are not selected for leukemia-specificity, the GVL effect is often accompanied by life-threatening graft-versus-host disease(GVHD) due to the concurrent transfer of allo-reactive lymphocytes. Thus, to minimize GVHD and maximize GVL we selectively activated and expanded stem-cell donor-derived T cells that were reactive to multiple antigens expressed by AML/MDS cells (PRAME, WT1, Survivin, NY-ESO-1). Products were successfully generated from 29 HCT donors, and they demonstrated multi-leukemia antigen specificity (mLSTs). In contrast to DLIs, mLSTs selectively recognized and killed leukemia-antigen-pulsed cells with no activity against recipient-derived normal cells in vitro. We have now administered escalating doses of these mLSTs (0.5-10x107 cells/m2) to 25 trial enrollees with AML/MDS after HCT, 17 of whom were at high risk for relapse and 8 of whom had relapsed disease. Infusions were well tolerated with no grade >2 acute or extensive chronic GVHD up to a dose of 10x107 cells/m2. We observed anti-leukemia effects in vivo that translated into not yet reached median LFS and OS at 1.9 years of follow-up among survivors, evidence of sustained immune pressure and objective responses in the active disease cohort (1 CR and 1 PR). In conclusion, mLSTs are safe and promising for the prevention or treatment of AML/MDS following HCT.
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http://dx.doi.org/10.1182/blood.2020009471DOI Listing
December 2020

Single-cell transcriptomics identifies multiple pathways underlying antitumor function of TCR- and CD8αβ-engineered human CD4 T cells.

Sci Adv 2020 Jul 3;6(27):eaaz7809. Epub 2020 Jul 3.

Department of Oncology UNIL-CHUV, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland.

Transgenic coexpression of a class I-restricted tumor antigen-specific T cell receptor (TCR) and CD8αβ (TCR8) redirects antigen specificity of CD4 T cells. Reinforcement of biophysical properties and early TCR signaling explain how redirected CD4 T cells recognize target cells, but the transcriptional basis for their acquired antitumor function remains elusive. We, therefore, interrogated redirected human CD4 and CD8 T cells by single-cell RNA sequencing and characterized them experimentally in bulk and single-cell assays and a mouse xenograft model. TCR8 expression enhanced CD8 T cell function and preserved less differentiated CD4 and CD8 T cells after tumor challenge. TCR8CD4 T cells were most potent by activating multiple transcriptional programs associated with enhanced antitumor function. We found sustained activation of cytotoxicity, costimulation, oxidative phosphorylation- and proliferation-related genes, and simultaneously reduced differentiation and exhaustion. Our study identifies molecular features of TCR8 expression that can guide the development of enhanced immunotherapies.
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http://dx.doi.org/10.1126/sciadv.aaz7809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455496PMC
July 2020

The safety and clinical effects of administering a multiantigen-targeted T cell therapy to patients with multiple myeloma.

Sci Transl Med 2020 07;12(554)

Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX 77030, USA.

Multiple myeloma (MM) is an almost always incurable malignancy of plasma cells. Despite the advent of new therapies, most patients eventually relapse or become treatment-refractory. Consequently, therapies with nonoverlapping mechanisms of action that are nontoxic and provide long-term benefit to patients with MM are greatly needed. To this end, we clinically tested an autologous multitumor-associated antigen (mTAA)-specific T cell product for the treatment of patients with high-risk, relapsed or refractory MM. In this study, we expanded polyclonal T cells from 23 patients with MM. T cells whose native T cell receptors were reactive toward five myeloma-expressed target TAAs (PRAME, SSX2, MAGEA4, Survivin, and NY-ESO-1) were enriched ex vivo. To date, we have administered escalating doses of these nonengineered mTAA-specific T cells (0.5 × 10 to 2 × 10 cells/m) to 21 patients with MM, 9 of whom were at high risk of relapse after a median of 3 lines of prior therapy and 12 with active, relapsed or refractory disease after a median of 3.5 prior lines. The cells were well tolerated, with only two transient, grade III infusion-related adverse events. Furthermore, patients with active relapsed or refractory myeloma enjoyed a longer than expected progression-free survival and responders included three patients who achieved objective responses concomitant with detection of functional TAA-reactive T cell clonotypes derived from the infused mTAA product.
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http://dx.doi.org/10.1126/scitranslmed.aaz3339DOI Listing
July 2020

Aggressive utilization of liver allografts: Improved outcomes over time.

Clin Transplant 2020 07 30;34(7):e13860. Epub 2020 May 30.

Division of Abdominal Transplantation and Division of Hepatobiliary Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA.

Background: Aggressive acceptance of liver allografts has driven utilization of marginal allografts. Our aim was to assess the impact of the aggressive phenotype on transplant center outcomes over time.

Methods: We used a cohort of 148 361 candidates from the Organ Procurement and Transplantation Network for liver transplantation between 2002 and 2016 in 134 centers. Using the Discard Risk Index, we designated high probability discard allografts by the top 10th percentile for likelihood of discard. Aggressive phenotype was defined by usage of high probability discard (HPD) allografts (top 10th percentile). Our analysis of survival on waitlist and graft survival after transplantation included a comprehensive list of center level covariates across three equal time periods (2002-2006, 2007-2011, and 2012-2016).

Results: After adjusting for recipient and center-level factors, aggressive centers had improving graft survival over time. Aggressive vs non-aggressive centers: 2002-2006 HR 1.12 (1.05-1.19), 2007-2011 HR 1.13 (1.05-1.22), 2012-2016 HR 0.99 (0.89-1.10). Aggressive centers had improved waitlist survival compared with non-aggressive centers after adjusting for allograft disparity.

Conclusions: Aggressive phenotype had a positive impact on waitlist survival, and graft survival in aggressive centers have improved to benchmark levels over time. These findings serve as justification for aggressive utilization of allografts.
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http://dx.doi.org/10.1111/ctr.13860DOI Listing
July 2020

Allogeneic hematopoietic stem cell transplant for relapsed and refractory non-Hodgkin lymphoma in pediatric patients.

Blood Adv 2019 09;3(18):2689-2695

Center for Cell and Gene Therapy, Texas Children's Hospital/Baylor College of Medicine/Houston Methodist Hospital, Houston, TX.

Allogeneic hematopoietic stem cell transplant (HSCT) for relapsed pediatric non-Hodgkin lymphoma (NHL) is often reserved for patients with certain NHL subtypes or high-risk disease whereas the remainder receive autologous HSCT. Given the aggressive nature of pediatric NHL, we performed allogeneic HSCTs for all patients regardless of disease risk. We report overall survival (OS) and prognostic variables in 36 pediatric patients who underwent allogeneic HSCT between 1998 and 2016. OS at 3 years was 67%. The 3-year OS varied based on NHL subtype: 100% for anaplastic large cell lymphoma (n = 14), 63% for diffuse large B-cell lymphoma (n = 8), 17% for lymphoblastic lymphoma (LL; n = 9) and 80% for other subtypes combined (n = 5). Disease status influenced outcome with 3-year OS of 100% for patients in complete remission (n = 15), 59% with partial remission (PR; n = 17), and 0% with progressive/stable disease (n = 3) ( = .004). Of the 17 patients in PR, all 6 with LL died of relapsed disease, whereas the other 11 attained remission after HSCT and remained disease-free. The cumulative incidence of relapse after HSCT for LL was 78% compared with 15% for all other NHL subtypes combined ( < .0001). Cumulative incidence of nonrelapse mortality (NRM) was low in our cohort at 6%. Hence, allogeneic HSCT is a well-tolerated and useful therapeutic option with low rates of NRM and relapse for all NHL subtypes except LL with active disease at HSCT.
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http://dx.doi.org/10.1182/bloodadvances.2018026203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759733PMC
September 2019

"Mini" bank of only 8 donors supplies CMV-directed T cells to diverse recipients.

Blood Adv 2019 09;3(17):2571-2580

Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital, Texas Children's Hospital, Houston, TX.

Cytomegalovirus (CMV) infections remain a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT), and standard antiviral therapies are associated with significant side effects and development of drug-resistant mutants. Adoptively transferred donor-derived CMV-specific T cells (CMVSTs) can provide an alternative treatment modality with few side effects but are not widely available due to their patient-specific nature. Here we report the establishment and use of a bank of CMVSTs derived from just 8 CMV-seropositive donors, with HLA types representing the diverse US population, as an "off-the-shelf" therapy to treat drug-refractory infections. To date, we have screened 29 patients for study participation and identified a suitable line, with ≥2 of 8 shared HLA antigens, for 28 (96.6%) patients with a median of 4 shared HLA antigens. Of these, 10 patients with persistent/refractory CMV infections or disease were eligible for treatment; a single infusion of cells produced 3 partial responses and 7 complete responses, for a cumulative response rate of 100% (95% confidence interval, 69.2-100) with no graft-versus-host disease, graft failure, or cytokine release syndrome. Potential wider use of the tested CMVSTs across transplant centers is made more feasible by our ability to produce sufficient material to generate cells for >2000 infusions from a single donor collection. Our data indicate that a "mini" bank of CMVSTs prepared from just 8 well-chosen third-party donors can supply the majority of patients with an appropriately matched line that produces safe and effective anti-CMV activity post-HSCT.
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http://dx.doi.org/10.1182/bloodadvances.2019000371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737421PMC
September 2019