Publications by authors named "Paul W Eldridge"

8 Publications

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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

Special report: Summary of the first meeting of African Blood and Marrow Transplantation (AfBMT) group, Casablanca, Morocco, April 19-21, 2018 held under the auspices of the Worldwide Network for Blood and Marrow Transplantation (WBMT).

Hematol Oncol Stem Cell Ther 2020 Dec 4;13(4):202-207. Epub 2019 Jun 4.

Hematology, pediatric oncology, Ibn Rochd University Hospital, University of Hassan II, Casablanca, Morocco.

The first meeting of the African Blood and Marrow Transplantation (AfBMT) was held in Casablanca from April 19, 2018 to April 21, 2018, with the aim of fostering hematopoietic stem cell transplantation (HSCT) activity in Africa. Out of the 54 African countries, HSCT is available only in six (Algeria, Egypt, Morocco, Nigeria, South Africa, and Tunisia). During this meeting, African teams and international experts from the Worldwide Network for Blood and Marrow Transplantation (WBMT) gathered to share their experience and discussed ways to help fill the gap. Nurses and patients held their meeting in parallel. International support and collaboration can help by providing expertise adapted to local resources and regional population needs. Local engagement including government and private participants are necessary to initiate and develop local HSCT capability.
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http://dx.doi.org/10.1016/j.hemonc.2019.05.003DOI Listing
December 2020

Haploidentical stem cell transplantation augmented by CD45RA negative lymphocytes provides rapid engraftment and excellent tolerability.

Pediatr Blood Cancer 2015 Apr 5;62(4):666-73. Epub 2015 Jan 5.

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee 38105; Department of Pediatrics, University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee 38163.

Background: Haploidentical donors are being increasingly used for allogeneic hematopoietic cell transplantation (HCT). However, the requisite T-cell depletion results in a profound and often long-lasting immunocompromised state, and donor lymphocyte infusions bring a risk of graft-versus-host disease (GVHD). Naïve T-cells are believed to be among the most alloreactive T-cell subset and can be identified by CD45RA expression. Allogeneic HCT using CD45RA depletion has not been previously described for haploidentical donors.

Procedure: Eight children with relapsed or refractory solid tumors were transplanted following myeloablative conditioning. Each patient received two cell products, one created by CD3 depletion and the other through CD45RA depletion.

Results: Median CD34 recovery was 59.2% with CD45RA depletion, compared to 82.4% using CD3 depletion. Median CD3+ T-cell dose after CD45RA reduction was 99.2 × 10(6)  cells/kg, yet depletion of CD3+ CD45RA+ cells exceeded 4.5 log. CD45RA depletion also resulted in substantial depletion of B-cells (median 2.45 log). All eight patients engrafted within 14 days and rapidly achieved 100% donor chimerism. No acute GVHD or secondary graft failure was observed.

Conclusions: CD45RA depletion is a novel approach to haploidentical HCT that offers rapid engraftment with minimal risk of GVHD.
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http://dx.doi.org/10.1002/pbc.25352DOI Listing
April 2015

TGFα-PE38 enhances cytotoxic T-lymphocyte killing of breast cancer cells.

Oncol Lett 2014 Jun 12;7(6):2113-2117. Epub 2014 Mar 12.

Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA.

The aim of the present study was to determine whether the combination of two modalities of immunotherapy, targeting two different tumor antigens, may be feasible and non-toxic, yet enhance the killing of a human breast cancer cell line. The first modality was tumor growth factor α- exotoxin 38 (TGFα-PE38), which specifically targets and kills tumor cells that express the epidermal growth factor receptor. The second modality was mucin-1 (MUC1)-specific cytotoxic T lymphocytes (CTLs), generated by MUC1 stimulation of peripheral blood mononuclear cells, to target the human breast cancer cell line, MCF7. TGFα-PE38 exhibited specific lysis of the MCF7 cells in a concentration- and time-dependent manner. TGFα-PE38 did not kill the normal hematopoietic stem cells or CTLs. Furthermore, TGFα-PE38 was not inhibitory for the growth or differentiation of the normal human hematopoietic stem cells into erythroid and myeloid colonies. In addition, TGFα-PE38 did not inhibit the killing function of CTLs, either when preincubated or co-incubated with CTLs. Finally, therapeutic enhancement was observed, in that TGFα-PE38 and CTLs were additive in the specific lysis of the MCF7 cells. These two modalities of immunotherapy may be beneficial for humans with breast cancer with or without other therapies, including autologous hematopoietic stem cell transplantation, specifically for purging cancer cells from hematopoietic stem cells prior to transplantation.
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http://dx.doi.org/10.3892/ol.2014.1969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049764PMC
June 2014

Ex vivo activation of CD56(+) immune cells that eradicate neuroblastoma.

Cancer Res 2013 Apr 25;73(8):2608-18. Epub 2013 Feb 25.

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Despite the use of intensive contemporary multimodal therapy, the overall survival of patients with high-risk neuroblastoma is still less than 50%. Therefore, immunotherapy without cross-resistance and overlapping toxicity has been proposed. In this study, we report the development of a novel strategy to specifically activate and expand human CD56(+) (NCAM1) natural killer (NK) immune cells from normal donors and patients with neuroblastoma. Enriched CD56(+) cells from peripheral blood were mixed with CD56(-) fraction at 1:1 ratio and cultured in the presence of OKT3, interleukin (IL)-2, and -15 for five days and then without OKT3 for 16 more days. The final products contained more than 90% CD56(+) cells and could kill neuroblastoma cells effectively that were originally highly resistant to nonprocessed NK cells. Mechanistically, cytolysis of neuroblastoma was mediated through natural cytotoxicity receptor (NCR), DNAX accessory molecule-1 (DNAM-1; CD226), perforin, and granzyme B. Successful clinical scale-up in a good manufacturing practices (GMP)-compliant bioreactor yielded effector cells that in a neuroblastoma xenograft model slowed tumor growth and extended survival without GVHD. Investigation of CD56(+) cells from patients with neuroblastoma revealed a similar postactivation phenotype and lytic activity. Our findings establish a novel and clinically expedient strategy to generate allogeneic or autologous CD56(+) cells that are highly cytotoxic against neuroblastoma with minimal risk of GVHD.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-3322DOI Listing
April 2013

Transduction of human CD34+ repopulating cells with a self-inactivating lentiviral vector for SCID-X1 produced at clinical scale by a stable cell line.

Hum Gene Ther Methods 2012 Oct 7;23(5):297-308. Epub 2012 Nov 7.

Department of Hematology, St. Jude Children's Hospital, Memphis, TN 38105, USA.

Self-inactivating (SIN)-lentiviral vectors have safety and efficacy features that are well suited for transduction of hematopoietic stem cells (HSCs), but generation of vector at clinical scale has been challenging. Approximately 280 liters of an X-Linked Severe Combined Immunodeficiency Disorder (SCID-X1) SIN-lentiviral vector in two productions from a stable cell line were concentrated to final titers of 4.5 and 7.2×10(8) tu/ml. These two clinical preparations and three additional development-scale preparations were evaluated in human CD34(+) hematopoietic cells in vitro using colony forming cell (CFU-C) assay and in vivo using the NOD/Lt-scid/IL2Rγ(null) (NSG) mouse xenotransplant model. A 40-hour transduction protocol using a single vector exposure conferred a mean NSG repopulating cell transduction of 0.23 vector genomes/human genome with a mean myeloid vector copy number of 3.2 vector genomes/human genome. No adverse effects on engraftment were observed from vector treatment. Direct comparison between our SIN-lentiviral vector using a 40-hour protocol and an MFGγ(c) γ-retroviral vector using a five-day protocol demonstrated equivalent NSG repopulating cell transduction efficiency. Clonality survey by linear amplification-mediated polymerase chain reaction (LAM-PCR) with Illumina sequencing revealed common clones in sorted myeloid and lymphoid populations from engrafted mice demonstrating multipotent cell transduction. These vector preparations will be used in two clinical trials for SCID-X1.
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http://dx.doi.org/10.1089/hgtb.2012.150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732136PMC
October 2012

Prediction of CD34(+) cell yield in hematopoietic cell products from children by peripheral blood CD34(+) cell counts.

Cytotherapy 2012 Apr;14(4):473-82

Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

Background Aims: Peripheral blood stem cells (PBSC) are increasingly used as an alternative to bone marrow in autologous transplantations. In adult patients, the peripheral blood CD34(+) cell count is a good predictor of CD34(+) cell yield in apheresis. However, the determinants of stem cell yield in the pediatric population have not been well established.

Methods: We retrospectively studied 396 apheresis procedures in 301 pediatric patients. Receiver operating characteristic (ROC) curves based on pre-apheresis peripheral blood CD34(+) cell counts were generated to facilitate prediction of the optimal timing of PBSC collection. The associations between CD34(+) cell yield and age and mobilization regimen were analyzed.

Results: Significant differences in CD34(+) cell yield among different age groups were observed. Furthermore, higher CD34(+) cell yields were obtained in patients receiving chemotherapy as part of the mobilization regimen than those without chemotherapy. A correlation was noted between the CD34(+) cell yield and blood surrogate markers, including white blood cell count, absolute neutrophil count and pre-apheresis peripheral blood CD34(+) cell count. Cut-off values of > 35 CD34(+) cells/μL in patients < 15 years old and > 45 CD34(+) cells/μL in patients ≥ 15 years old were strong predictors of an adequate PBSC collection in one apheresis session. For clinical use, ROC curves and tables were generated to assist advance planning for PBSC collection.

Conclusions: The pre-apheresis peripheral blood CD34(+) cell count is most useful in predicting PBSC yield. Our new cut-off values have better operating characteristics for children than the conventional value of 20 CD34(+) cells/μL used for adults.
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http://dx.doi.org/10.3109/14653249.2011.652734DOI Listing
April 2012

Adoptive immunotherapy of mucin1 expressing adenocarcinomas with mucin1 stimulated human peripheral blood mononuclear cells.

Int J Mol Med 2002 Apr;9(4):401-4

Department of Veterans Affairs Medical Center, Amarillo, TX 79106, USA.

Mucin1 stimulated hematopoietic mononuclear cells (M1SHMC) from patients with breast cancer, adoptively transferred to non-obese diabetic, severe combined immunodeficient (NOD SCID) mice, extended survival in a therapy model of gross adenocarcinoma and prevented tumor growth in a model of minimal disease. M1SHMC exhibited specific lysis of a human breast adenocarcinoma cell line expressing mucin1, MCF-7 and produced interferon gamma. M1SHMC were injected intraperitoneally (IP) in NOD SCID mice after gross, palpable tumors appeared after MCF-7 were injected subcutaneously (SC). Survival was increased as compared to no M1SHMC controls. However tumors eventually regrew in all mice. To determine whether minimal disease (MD) could be controlled, NOD SCID were injected with MCF-7 cells, and on the same day, injected IP with M1SHMC. The M1SHMC injected mice were protected from tumor growth. These results imply that M1SHMC can prolong survival, but not cure NOD SCID mice bearing gross palpable adenocarcinomas. However in a minimal disease model tumor growth was prevented.
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April 2002