Publications by authors named "Helen E Heslop"

229 Publications

Beyond CD19 CAR-T cells in lymphoma.

Curr Opin Immunol 2021 Nov 17;74:46-52. Epub 2021 Nov 17.

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

Adoptive transfer of CD19-specific chimeric antigen receptor T-cells (CAR-T cells) has transformed the treatment paradigm of relapsed/refractory (R/R) CD19 B-cell malignancies, dramatically improving remission rates and cures in patients with chemo-refractory disease. However, the applicability of CD19 CAR-T cells is limited to B cell malignancies and antigen loss can result in treatment failure, prompting the exploration of alternative targets to overcome tumor escape via CD19 antigen loss, as well as extend the CAR-T cell platform to treat Hodgkin and T cell lymphomas. This review highlights recent clinical trials testing CAR-T cell targets beyond CD19.
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http://dx.doi.org/10.1016/j.coi.2021.09.009DOI Listing
November 2021

High risk of relapsed disease in patients with NK/T cell chronic active Epstein-Barr virus disease outside of Asia.

Blood Adv 2021 Oct 20. Epub 2021 Oct 20.

NIH, Bethesda, Maryland, United States.

Chronic active Epstein-Barr virus (EBV) disease (CAEBV) is characterized by high levels of EBV predominantly in T and/or NK cells with lymphoproliferation, organ failure due to infiltration of tissues with virus-infected cells, hemophagocytic lymphohistiocytosis (HLH) and/or lymphoma. The disease is more common in Asia than in the United States and Europe. While allogeneic hematopoietic stem cell transplantation (HSCT) is considered the only curative therapy for CAEBV, its efficacy and the best treatment modality to reduce disease severity prior to HSCT is unknown. Here, we retrospectively assessed an international cohort of 57 patients outside of Asia. Treatment for the disease varied widely, although most patients ultimately proceeded to HSCT. Though patients undergoing HSCT had better survival than those who did not (55% v 25%, p<0.01), there was still a high rate of death in both groups. Mortality was largely not affected by age, ethnicity, cell type involvement, or disease complications, but development of lymphoma showed a trend with increased mortality (56% v 35%, p=0.1). The overwhelming majority (75%) of patients who died after HSCT succumbed to relapsed disease. CAEBV remains challenging to treat when advanced disease is present. Outcomes would likely improve with better disease control strategies, earlier referral for HSCT, and close follow-up after HSCT including aggressive management of rising EBV DNA levels in the blood.
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http://dx.doi.org/10.1182/bloodadvances.2021005291DOI Listing
October 2021

Scalable Manufacturing of CAR T cells for Cancer Immunotherapy.

Blood Cancer Discov 2021 Sep 3;2(5):408-422. Epub 2021 Aug 3.

Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.

As of April 2021, there are five commercially available chimeric antigen receptor (CAR) T cell therapies for hematological malignancies. With the current transition of CAR T cell manufacturing from academia to industry, there is a shift toward Good Manufacturing Practice (GMP)-compliant closed and automated systems to ensure reproducibility and to meet the increased demand for cancer patients. In this review we describe current CAR T cells clinical manufacturing models and discuss emerging technological advances that embrace scaling and production optimization. We summarize measures being used to shorten CAR T-cell manufacturing times and highlight regulatory challenges to scaling production for clinical use.

Statement Of Significance ∣: As the demand for CAR T cell cancer therapy increases, several closed and automated production platforms are being deployed, and others are in development.This review provides a critical appraisal of these technologies that can be leveraged to scale and optimize the production of next generation CAR T cells.
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http://dx.doi.org/10.1158/2643-3230.bcd-21-0084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462122PMC
September 2021

Blood and Marrow Transplant Clinical Trials Network State of the Science Symposium 2021: Looking Forward as the Network Celebrates its 20th Year.

Transplant Cell Ther 2021 Nov 27;27(11):885-907. Epub 2021 Aug 27.

Center for International Blood & Marrow Transplant Research, Minneapolis, Minnesota.

In 2021 the BMT CTN held the 4th State of the Science Symposium where the deliberations of 11 committees concerning major topics pertinent to a particular disease, modality, or complication of transplant, as well as two committees to consider clinical trial design and inclusion, diversity, and access as cross-cutting themes were reviewed. This article summarizes the individual committee reports and their recommendations on the highest priority questions in hematopoietic stem cell transplant and cell therapy to address in multicenter trials.
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http://dx.doi.org/10.1016/j.jtct.2021.08.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8556300PMC
November 2021

Genetic errors of immunity distinguish pediatric nonmalignant lymphoproliferative disorders.

J Allergy Clin Immunol 2021 Jul 28. Epub 2021 Jul 28.

Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Texas Children's Hospital, Houston, Tex; Division of Pediatric Hematology/Oncology, Texas Children's Hospital Cancer Center, Houston, Tex. Electronic address:

Background: Pediatric nonmalignant lymphoproliferative disorders (PLPDs) are clinically and genetically heterogeneous. Long-standing immune dysregulation and lymphoproliferation in children may be life-threatening, and a paucity of data exists to guide evaluation and treatment of children with PLPD.

Objective: The primary objective of this study was to ascertain the spectrum of genomic immunologic defects in PLPD. Secondary objectives included characterization of clinical outcomes and associations between genetic diagnoses and those outcomes.

Methods: PLPD was defined by persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant Epstein-Barr virus (EBV) infection. Fifty-one subjects from 47 different families with PLPD were analyzed using whole exome sequencing.

Results: Whole exome sequencing identified likely genetic errors of immunity in 51% to 62% of families (53% to 65% of affected children). Presence of a genetic etiology was associated with younger age and hemophagocytic lymphohistiocytosis. Ten-year survival for the cohort was 72.4%, and patients with viable genetic diagnoses had a higher survival rate (82%) compared to children without a genetic explanation (48%, P = .03). Survival outcomes for individuals with EBV-associated disease and no genetic explanation were particularly worse than outcomes for subjects with EBV-associated disease and a genetic explanation (17% vs 90%; P = .002). Ascertainment of a molecular diagnosis provided targetable treatment options for up to 18 individuals and led to active management changes for 12 patients.

Conclusions: PLPD defines children at high risk for mortality, and whole exome sequencing informs clinical risks and therapeutic opportunities for this diagnosis.
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http://dx.doi.org/10.1016/j.jaci.2021.07.015DOI Listing
July 2021

Autologous EBV-specific T cell treatment results in sustained responses in patients with advanced extranodal NK/T lymphoma: results of a multicenter study.

Ann Hematol 2021 Oct 24;100(10):2529-2539. Epub 2021 Jul 24.

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

We conducted a phase II clinical trial to develop an autologous EBV-specific T cell product (baltaleucel T) for advanced, relapsed ENKTL. Among 47 patients who provided whole blood starting material for manufacturing the product, 15 patients received a median of 4 doses of baltaleucel T. Thirty-two (68%) patients did not receive baltaleucel-T due to manufacturing failure, rapid disease progression, and death. Of the 15 patients, 10 patients had measurable disease at baseline (salvage cohort), and 5 patients had no disease at baseline assessment (adjuvant cohort). In the 15 patients, the median follow-up duration was 10.2 months (range 2.0-23.5 months), median progression-free survival (PFS) was 3.9 months, and the median overall survival (OS) was not reached. Patients in the salvage cohort achieved a 30% complete response (CR) and a 50% overall response rate (ORR). In the adjuvant cohort, disease progression was reported in three patients and two patients did not relapse during study follow-up. When we compared survival outcomes of seven responders and eight non-responders, the PFS (P = 0.001) and OS (P = 0.014) of responders proved statistically superior to that of non-responders. Baltaleucel-T was well tolerated. We have performed a phase II clinical trial of autologous EBV-specific T cell treatment (baltaleucel-T) in R/R ENKTL. Autologous EBV-specific T cells were well tolerated and demonstrated single-agent activity in R/R ENTKL.
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http://dx.doi.org/10.1007/s00277-021-04558-0DOI Listing
October 2021

Health disparities experienced by Black and Hispanic Americans with multiple myeloma in the United States: a population-based study.

Leuk Lymphoma 2021 Jul 18:1-8. Epub 2021 Jul 18.

Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Atrium Health, Charlotte, NC, USA.

Hispanics and non-Hispanic (NH)-Blacks continue to face numerous health disparities related to multiple myeloma (MM). We aimed to analyze trends of MM-related hospitalizations and incidence of in-hospital mortality with a 10-year cross-sectional analysis of inpatient hospitalizations. The prevalence of MM-related hospitalizations was higher in NH-Blacks compared to NH-Whites (476.0 vs. 305.6 per 100,000 hospitalizations,  < .001). MM-related in-hospital mortality was higher in Hispanics compared to NH-Whites and NH-Blacks (6.2 vs. 5.3%,  < .001). Using average annual percent change (AAPC), we found a statistically significant decline of in-hospital mortality among all MM patients except NH-Blacks (AAPC: -2.2, 95% confidence interval (CI) -4.7, 0.4,  = .47), who had the highest inpatient mortality in recent years. Multivariate analysis showed that NH-Blacks received fewer transplants, more blood product transfusions, fewer palliative care consults, less inpatient chemotherapy, and utilized more intensive care. Disparities in MM care for NH-Blacks and Hispanics continue to persist despite recent advancements in MM therapy.
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http://dx.doi.org/10.1080/10428194.2021.1953013DOI Listing
July 2021

Matched related hematopoietic cell transplant for sickle cell disease with alemtuzumab: the Texas Children's Hospital experience.

Bone Marrow Transplant 2021 Nov 17;56(11):2797-2803. Epub 2021 Jul 17.

Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA.

Serotherapeutic agents facilitate engraftment and prevent graft-versus-host disease (GVHD) following hematopoietic stem cell transplant. Anti-thymocyte globulin is generally added to conditioning chemotherapy for matched related donor transplant (MRD-HCT) for sickle cell disease (SCD). Alemtuzumab, however, is appealing due to its broad lymphocyte killing that may achieve very low rejection and GVHD rates. To assess the impact of alemtuzumab in MRD-HCT for SCD, we retrospectively reviewed transplant-related outcomes and markers of immunity in 38 consecutive patients at Texas Children's Hospital having received myeloablative conditioning with alemtuzumab. Median follow-up was 4.8 years (range: 0.2-17). All patients engrafted. Donor chimerism was mixed in 47.1% of patients at ≥2-years. Donor chimerism <50% was uncommon (n = 2). One patient with low myeloid chimerism (19%) had sickle-related hemolysis at 10-years. Incidence of acute GVHD grade II-IV (5.3%) and extensive chronic GVHD (2.8%) was very low. Five-year event-free survival (EFS) and composite chronic GVHD-EFS were excellent at 94.7% (95% CI: 80.3, 98.6) and 89.2% (95% CI: 73.7, 95.8), respectively. Infections did not contribute to mortality although cytomegalovirus reactivation occurred commonly in the first 3 months after transplant. Our data suggest potential for alemtuzumab in myeloablative transplant for children with SCD although further evaluation in older patients and with unrelated donors is warranted.
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http://dx.doi.org/10.1038/s41409-021-01415-6DOI Listing
November 2021

Demographic and Clinical Donor Characteristics as Predictors of Total Nucleated Cell Concentrations in Harvested Marrow Products.

Transplant Cell Ther 2021 09 31;27(9):785.e1-785.e6. Epub 2021 May 31.

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

Successful allogeneic hematopoietic stem cell transplantation (alloHSCT) relies significantly on adequate allograft cell composition to achieve sustained engraftment, and a minimum of 2 × 10 total nucleated cells (TNCs) per kilogram of recipient body weight has been identified as the prerequisite cell dose for successful engraftment of marrow-derived products. To meet this minimum requirement, marrow harvest volumes are estimated based on anticipated TNC concentrations of 18.3 × 10/mL. However, there is considerable variability in marrow TNC concentrations. Thus, an algorithm that incorporates baseline donor characteristics to predict TNC concentrations could optimize outcomes for both donors and recipients. For this study, donor baseline characteristics and corresponding unstimulated marrow products harvested between 2004 and 2017 at a single large-volume donor center were collected. Multivariable analysis was used to identify significant predictors of TNC concentration. Two models-ordinary least squares (OLS) and least absolute shrinkage and selection operator (LASSO) regression-were compared for their fitness to the data and their utility in predicting TNCs. Donors with higher body mass index, younger age, male sex, white race/ethnicity, smaller harvest volumes, lower preharvest hematocrit, higher preharvest platelet count, and higher preharvest WBC count predicted significantly higher TNC concentrations in marrow products. When comparing predictive models that incorporate these characteristics, the cross-validated LASSO and bootstrapped OLS provided the best fit. We now supply these formulas to be validated in other datasets before clinical use. TNC concentration in marrow products can be predicted using donor characteristics, most of which are readily available during the donor clinical assessment. The ability to predict marrow allograft TNC concentrations can optimize collection volumes during a harvest.
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http://dx.doi.org/10.1016/j.jtct.2021.05.021DOI Listing
September 2021

Virus-specific T cells for malignancies - then, now and where to?

Curr Stem Cell Rep 2020 Jun 7;6(2):17-29. Epub 2020 May 7.

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

Purpose Of Review: Virus-associated malignancies are a global health burden, constituting 10-12% of cancers worldwide. As these tumors express foreign viral antigens that can elicit specific T cell responses, virus-directed immunotherapies are a promising treatment strategy. Specifically, adoptive cell transfer of virus-specific T cells (VSTs) has demonstrated the potential to eradicate cancers associated with certain viruses.

Recent Findings: Initial studies in 1990s first showed that VSTs specific for the Epstein-Barr virus (EBVSTs) can induce complete remissions in patients with post-transplant lymphoproliferative disease. Since then, studies have validated the specificity and safety of VSTs in multiple lymphomas and solid malignancies. However, challenges remain to optimize this platform for widespread use, including enhancing potency and persistence, overcoming the immunosuppressive tumor microenvironment, and streamlining manufacturing processes that comply with regulatory requirements.

Summary: This review focuses on data from clinical trials evaluating VSTs directed against three viruses (EBV, HPV and MCPyV), as well as recent preclinical and clinical advances, and potential future directions.
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http://dx.doi.org/10.1007/s40778-020-00170-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963109PMC
June 2020

Taking T-Cell Oncotherapy Off-the-Shelf.

Trends Immunol 2021 03 1;42(3):261-272. Epub 2021 Feb 1.

Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA; Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA. Electronic address:

Banked allogeneic or 'off-the-shelf' (OTS) T cells from healthy human donors are being developed to address the limitations of autologous cell therapies. Potential challenges of OTS T cell therapies are associated with their allogeneic origin and the possibility of graft-versus-host disease (GvHD) and host-versus-graft immune reactions. While the risk of GvHD from OTS T cells has been proved to be manageable in clinical studies, approaches to prevent immune rejection of OTS cells are at an earlier stage of development. We provide an overview of strategies to generate OTS cell therapies and mitigate alloreactivity-associated adverse events, with a focus on recent advances for preventing immune rejection.
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http://dx.doi.org/10.1016/j.it.2021.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914205PMC
March 2021

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

J Clin Oncol 2021 05 28;39(13):1415-1425. 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274795PMC
May 2021

Adoptive T-Cell Therapy for Epstein-Barr Virus-Related Lymphomas.

J Clin Oncol 2021 02 12;39(5):514-524. Epub 2021 Jan 12.

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

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http://dx.doi.org/10.1200/JCO.20.01709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462582PMC
February 2021

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

Blood 2021 05;137(19):2585-2597

Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX; and.

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). Infusion of unselected donor lymphocytes (DLIs) enhances the graft-versus-leukemia (GVL) effect. However, because the infused lymphocytes are not selected for leukemia specificity, the GVL effect is often accompanied by life-threatening graft-versus-host disease (GVHD), related to the concurrent transfer of alloreactive lymphocytes. Thus, to minimize GVHD and maximize GVL, we selectively activated and expanded stem cell donor-derived T cells reactive to multiple antigens expressed by AML/MDS cells (PRAME, WT1, Survivin, and NY-ESO-1). Products that demonstrated leukemia antigen specificity were generated from 29 HCT donors. In contrast to DLIs, leukemia-specific T cells (mLSTs) selectively recognized and killed leukemia antigen-pulsed cells, with no activity against recipient's normal cells in vitro. We administered escalating doses of mLSTs (0.5 to 10 × 107 cells per square meter) to 25 trial enrollees, 17 with high risk of relapse and 8 with relapsed disease. Infusions were well tolerated with no grade >2 acute or extensive chronic GVHD seen. We observed antileukemia effects in vivo that translated into not-yet-reached median leukemia-free and overall survival at 1.9 years of follow-up and objective responses in the active disease cohort (1 complete response and 1 partial response). In summary, mLSTs are safe and promising for the prevention and treatment of AML/MDS after HCT. This trial is registered at www.clinicaltrials.com as #NCT02494167.
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http://dx.doi.org/10.1182/blood.2020009471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120140PMC
May 2021

Modulating TNFα activity allows transgenic IL15-Expressing CLL-1 CAR T cells to safely eliminate acute myeloid leukemia.

J Immunother Cancer 2020 09;8(2)

Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA

Background: C-type lectin-like molecule 1 (CLL-1) is highly expressed in acute myeloid leukemia (AML) but is absent in primitive hematopoietic progenitors, making it an attractive target for a chimeric antigen receptor (CAR) T-cell therapy. Here, we optimized our CLL-1 CAR for anti-leukemic activity in mouse xenograft models of aggressive AML.

Methods: First, we optimized the CLL-1 CAR using different spacer, transmembrane and costimulatory sequences. We used a second retroviral vector to coexpress transgenic IL15. We measured the effects of each construct on T cell phenotype and sequential (recursive) co culture assays with tumor cell targets to determine the durability of the anti tumor activity by flow cytometry. We administered CAR T cells to mice engrafted with patient derived xenografts (PDX) and AML cell line and determined anti tumor activity by bioluminescence imaging and weekly bleeding, measured serum cytokines by multiplex analysis. After euthanasia, we examined formalin-fixed/paraffin embedded sections. Unpaired two-tailed Student's t-tests were used and values of p<0.05 were considered significant. Survival was calculated using Mantel-Cox log-rank test.

Results: In vitro, CLL-1 CAR T cells with interleukin-15 (IL15) were less terminally differentiated (p<0.0001) and had superior expansion compared with CD28z-CD8 CAR T cells without IL15 (p<0.001). In both AML PDX and AML cell line animal models, CLL-1 CAR T coexpressing transgenic IL15 initially expanded better than CD28z-CD8 CAR T without IL15 (p<0.0001), but produced severe acute toxicity associated with high level production of human tumor necrosis factor α (TNFα), IL15 and IL2. Histopathology showed marked inflammatory changes with tissue damage in lung and liver. This acute toxicity could be managed by two strategies, individually or in combination. The excessive TNF alpha secretion could be blocked with anti-TNF alpha antibody, while excessive T cell expansion could be arrested by activation of an inducible caspase nine safety switch by administration of dimerizing drug. Both strategies successfully prolonged tumor-free survival.

Conclusion: Combinatorial treatment with a TNFα blocking antibody and subsequent activation of the caspase-9 control switch increased the expansion, survival and antileukemic potency of CLL-1 CAR T-cells expressing transgenic IL15 while avoiding the toxicities associated with excessive cytokine production and long-term accumulation of activated T-cells.
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http://dx.doi.org/10.1136/jitc-2020-001229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497527PMC
September 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

Anti-CD30 CAR-T Cell Therapy in Relapsed and Refractory Hodgkin Lymphoma.

J Clin Oncol 2020 11 23;38(32):3794-3804. Epub 2020 Jul 23.

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Purpose: Chimeric antigen receptor (CAR) T-cell therapy of B-cell malignancies has proved to be effective. We show how the same approach of CAR T cells specific for CD30 (CD30.CAR-Ts) can be used to treat Hodgkin lymphoma (HL).

Methods: We conducted 2 parallel phase I/II studies (ClinicalTrials.gov identifiers: NCT02690545 and NCT02917083) at 2 independent centers involving patients with relapsed or refractory HL and administered CD30.CAR-Ts after lymphodepletion with either bendamustine alone, bendamustine and fludarabine, or cyclophosphamide and fludarabine. The primary end point was safety.

Results: Forty-one patients received CD30.CAR-Ts. Treated patients had a median of 7 prior lines of therapy (range, 2-23), including brentuximab vedotin, checkpoint inhibitors, and autologous or allogeneic stem cell transplantation. The most common toxicities were grade 3 or higher hematologic adverse events. Cytokine release syndrome was observed in 10 patients, all of which were grade 1. No neurologic toxicity was observed. The overall response rate in the 32 patients with active disease who received fludarabine-based lymphodepletion was 72%, including 19 patients (59%) with complete response. With a median follow-up of 533 days, the 1-year progression-free survival and overall survival for all evaluable patients were 36% (95% CI, 21% to 51%) and 94% (95% CI, 79% to 99%), respectively. CAR-T cell expansion in vivo was cell dose dependent.

Conclusion: Heavily pretreated patients with relapsed or refractory HL who received fludarabine-based lymphodepletion followed by CD30.CAR-Ts had a high rate of durable responses with an excellent safety profile, highlighting the feasibility of extending CAR-T cell therapies beyond canonical B-cell malignancies.
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http://dx.doi.org/10.1200/JCO.20.01342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655020PMC
November 2020

Tumor response and endogenous immune reactivity after administration of HER2 CAR T cells in a child with metastatic rhabdomyosarcoma.

Nat Commun 2020 07 15;11(1):3549. Epub 2020 Jul 15.

Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.

Refractory metastatic rhabdomyosarcoma is largely incurable. Here we analyze the response of a child with refractory bone marrow metastatic rhabdomyosarcoma to autologous HER2 CAR T cells. Three cycles of HER2 CAR T cells given after lymphodepleting chemotherapy induces remission which is consolidated with four more CAR T-cell infusions without lymphodepletion. Longitudinal immune-monitoring reveals remodeling of the T-cell receptor repertoire with immunodominant clones and serum autoantibodies reactive to oncogenic signaling pathway proteins. The disease relapses in the bone marrow at six months off-therapy. A second remission is achieved after one cycle of lymphodepletion and HER2 CAR T cells. Response consolidation with additional CAR T-cell infusions includes pembrolizumab to improve their efficacy. The patient described here is a participant in an ongoing phase I trial (NCT00902044; active, not recruiting), and is 20 months off T-cell infusions with no detectable disease at the time of this report.
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http://dx.doi.org/10.1038/s41467-020-17175-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363864PMC
July 2020

Engineered off-the-shelf therapeutic T cells resist host immune rejection.

Nat Biotechnol 2021 01 13;39(1):56-63. Epub 2020 Jul 13.

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

Engineered T cells are effective therapies against a range of malignancies, but current approaches rely on autologous T cells, which are difficult and expensive to manufacture. Efforts to develop potent allogeneic T cells that are not rejected by the recipient's immune system require abrogating both T- and natural killer (NK)-cell responses, which eliminate foreign cells through various mechanisms. In the present study, we engineered a receptor that mediates deletion of activated host T and NK cells, preventing rejection of allogeneic T cells. Our alloimmune defense receptor (ADR) selectively recognizes 4-1BB, a cell surface receptor temporarily upregulated by activated lymphocytes. ADR-expressing T cells resist cellular rejection by targeting alloreactive lymphocytes in vitro and in vivo, while sparing resting lymphocytes. Cells co-expressing chimeric antigen receptors and ADRs persisted in mice and produced sustained tumor eradication in two mouse models of allogeneic T-cell therapy of hematopoietic and solid cancers. This approach enables generation of rejection-resistant, 'off-the-shelf', allogeneic T-cell products to produce long-term therapeutic benefit in immunocompetent recipients.
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http://dx.doi.org/10.1038/s41587-020-0601-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854790PMC
January 2021

Sensitizing Burkitt lymphoma to EBV-CTLs.

Authors:
Helen E Heslop

Blood 2020 05;135(21):1822-1823

Baylor College of Medicine.

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http://dx.doi.org/10.1182/blood.2020005492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243150PMC
May 2020

CRISPR-Edited Immune Effectors: The End of the Beginning.

Mol Ther 2020 04 22;28(4):995-996. Epub 2020 Mar 22.

Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX, USA; Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.

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http://dx.doi.org/10.1016/j.ymthe.2020.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132620PMC
April 2020

Incorporation of thiotepa in a reduced intensity conditioning regimen may improve engraftment after transplant for HLH.

Br J Haematol 2020 03 27;188(6):e84-e87. Epub 2020 Jan 27.

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

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http://dx.doi.org/10.1111/bjh.16370DOI Listing
March 2020

CAR-T cell Therapy for Non-Hodgkin Lymphomas: A New Treatment Paradigm.

Adv Cell Gene Ther 2019 Jul 28;2(3). Epub 2019 Mar 28.

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

The majority of patients with B-cell non-Hodgkin lymphoma (NHL) can be cured with standard chemoimmunotherapy. However, patients who fail first line therapy have dismal outcomes, particularly if they have disease that is resistant to salvage therapy, including chemoimmunotherapy, radiation and/or autologous stem cell transplantation. Indolent B-NHLs, such as follicular lymphoma (FL), although not generally considered curable may be treated over many years with good prognosis. However, a subset of B-NHLs can undergo histologic transformation into more aggressive subtypes with outcomes similar to aggressive B-NHLs. In recent years, T cells genetically modified with chimeric antigen receptors (CARs), have demonstrated a remarkable capacity to induce complete and durable clinical responses in patients with chemotherapy-refractory lymphomas. Indeed, two autologous CD19-directed CAR-modified T cell products have now been FDA-approved for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL) and transformed FL, while a plethora of other CAR-T cell targets are being explored in ongoing clinical trials. The purpose of this review is to summarize the clinical efficacy and unique toxicities of individually developed CAR-T cell products for the treatment of lymphomas, and their evolution from the laboratory bench to commercialization.
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http://dx.doi.org/10.1002/acg2.54DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880960PMC
July 2019

T-Cell Receptor Stimulation Enhances the Expansion and Function of CD19 Chimeric Antigen Receptor-Expressing T Cells.

Clin Cancer Res 2019 12 26;25(24):7340-7350. Epub 2019 Sep 26.

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

Purpose: Current protocols for CD19 chimeric antigen receptor-expressing T cells (CD19.CAR-T cells) require recipients to tolerate preinfusion cytoreductive chemotherapy, and the presence of sufficient target antigen on normal or malignant B cells.

Patients And Methods: We investigated whether additional stimulation of CD19.CAR-T cells through their native receptors can substitute for cytoreductive chemotherapy, inducing expansion and functional persistence of CD19.CAR-T even in patients in remission of B-cell acute lymphocytic leukemia. We infused a low dose of CD19.CAR-modified virus-specific T cells (CD19.CAR-VST) without prior cytoreductive chemotherapy into 8 patients after allogeneic stem cell transplant.

Results: Absent virus reactivation, we saw no CD19.CAR-VST expansion. In contrast, in patients with viral reactivation, up to 30,000-fold expansion of CD19.CAR-VSTs was observed, with depletion of CD19 B cells. Five patients remain in remission at 42-60+ months.

Conclusions: Dual T-cell receptor and CAR stimulation can thus potentiate effector cell expansion and CAR-target cell killing, even when infusing low numbers of effector cells without cytoreduction.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062259PMC
December 2019

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

Use of Chimeric Antigen Receptor T Cell Therapy in Clinical Practice for Relapsed/Refractory Aggressive B Cell Non-Hodgkin Lymphoma: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy.

Biol Blood Marrow Transplant 2019 12 22;25(12):2305-2321. Epub 2019 Aug 22.

Lymphoma Program, Abramson Cancer Center at University of Pennsylvania, Philadelphia, Pennsylvania.

Axicabtagene ciloleucel (YESCARTA; Kite Pharma, a Gilead Company, Los Angeles CA) and tisagenlecleucel (KYMRIAH; Novartis Pharmaceuticals Corp., Basel, Switzerland) are two CD19-directed chimeric antigen receptor (CAR) T cell products currently approved by the US Food and Drug Administration; the European Medicines Agency; Health Canada; Ministry of Health, Labor and Welfare (Japan); and Therapeutic Goods Administration (Australia) for treatment of specific subtypes of relapsed/refractory aggressive B cell non-Hodgkin lymphoma (NHL). Although this approval has been transformative in the use of cellular immunotherapy in lymphoma, there are concerns regarding appropriate use of this novel therapy and of short- and long-term toxicities. To address these issues, representatives of the American Society of Transplantation and Cellular Therapy convened to recognize and address key issues surrounding the clinical application of CD19 CAR T cell therapy in B cell lymphomas, in collaboration with worldwide experts. The aim of this article is to provide consensus opinion from experts in the fields of hematopoietic cell transplantation, cellular immunotherapy, and lymphoma regarding key clinical questions pertinent to the use of CD19 CAR T cell products for the treatment of NHL. As the clinical practice using CAR T cells grows worldwide, we anticipate that this guidance will be relevant for hematology/oncology physicians who care for patients with lymphomas.
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http://dx.doi.org/10.1016/j.bbmt.2019.08.015DOI Listing
December 2019

Survival outcomes of allogeneic hematopoietic cell transplants with EBV-positive or EBV-negative post-transplant lymphoproliferative disorder, A CIBMTR study.

Transpl Infect Dis 2019 Oct 31;21(5):e13145. Epub 2019 Jul 31.

Division of Hematology and Oncology, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.

Background: Post-transplant lymphoproliferative disorders (PTLD) are associated with significant morbidity and mortality following allogeneic hematopoietic cell transplant (alloHCT). Although most PTLD is EBV-positive (EBV ), EBV-negative (EBV ) PTLD is reported, yet its incidence and clinical impact remain largely undefined. Furthermore, factors at the time of transplant impacting survival following PTLD are not well described.

Methods: Between 2002 and 2014, 432 cases of PTLD following alloHCT were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). After exclusions, 267 cases (EBV = 222, 83%; EBV = 45, 17%) were analyzed.

Results: Two hundred and eight patients (78%) received in vivo T-cell depletion (TCD) with either anti-thymocyte globulin (ATG) or alemtuzumab. Incidence of PTLD was highest using umbilical cord donors (UCB, 1.60%) and lowest using matched related donors (MRD, 0.40%). Clinical features and histology did not significantly differ among EBV or EBV PTLD cases except that absolute lymphocyte count recovery was slower, and CMV reactivation was later in EBV PTLD [EBV 32 (5-95) days versus EBV 47 (10-70) days, P = .016]. There was no impact on survival by EBV status in multivariable analysis [EBV RR 1.42, 95% CI 0.94-2.15, P = .097].

Conclusions: There is no difference in survival outcomes for patients with EBV or EBV PTLD occurring following alloHCT and 1-year survival is poor. Features of conditioning and use of serotherapy remain important.
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http://dx.doi.org/10.1111/tid.13145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239317PMC
October 2019

T-cell receptor sequencing demonstrates persistence of virus-specific T cells after antiviral immunotherapy.

Br J Haematol 2019 10 20;187(2):206-218. Epub 2019 Jun 20.

Center for Cancer and Immunology Research, Children's National Health System, Washington, DC, USA.

Viral infections are a serious cause of morbidity and mortality following haematopoietic stem cell transplantation (HSCT). Adoptive cellular therapy with virus-specific T cells (VSTs) has been successful in preventing or treating targeted viruses in prior studies, but the composition of ex vivo expanded VST and the critical cell populations that mediate antiviral activity in vivo are not well defined. We utilized deep sequencing of the T-cell receptor beta chain (TCRB) in order to classify and track VST populations in 12 patients who received VSTs following HSCT to prevent or treat viral infections. TCRB sequencing was performed on sorted VST products and patient peripheral blood mononuclear cells samples. TCRB diversity was gauged using the Shannon entropy index, and repertoire similarity determined using the Morisita-Horn index. Similarity indices reflected an early change in TCRB diversity in eight patients, and TCRB clonotypes corresponding to targeted viral epitopes expanded in eight patients. TCRB repertoire diversity increased in nine patients, and correlated with cytomegalovirus (CMV) viral load following VST infusion (P = 0·0071). These findings demonstrate that allogeneic VSTs can be tracked via TCRB sequencing, and suggests that T-cell receptor repertoire diversity may be critical for the control of CMV reactivation after HSCT.
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http://dx.doi.org/10.1111/bjh.16053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786907PMC
October 2019
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