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Edward A Stadtmauer,
Dan T Vogl,
Eline Luning Prak,
Jean Boyer,
Nicole A Aqui,
Aaron P Rapoport,
Kenyetta R McDonald,
Xiaoling Hou,
Heather Murphy,
Rita Bhagat,
Patricia A Mangan, Anne Chew,
Elizabeth A Veloso,
Bruce L Levine,
Robert H Vonderheide,
Abbas F Jawad,
Carl H June,
Kathleen E Sullivan
[show abstract]
[hide abstract]
ABSTRACT: Severe immune deficiency follows autologous stem cell transplantation for multiple myeloma and is associated with significant infectious morbidity. This study was designed to evaluate the utility of a pretransplantation vaccine and infusion of a primed autologous T-cell product in stimulating specific immunity to influenza. Twenty-one patients with multiple myeloma were enrolled from 2007 to 2009. Patients were randomly assigned to receive an influenza-primed autologous T-cell product or a nonspecifically primed autologous T-cell product. The study endpoint was the development of hemagglutination inhibition titers to the strain-specific serotypes in the influenza vaccine. Enzyme-linked immunospot assays were performed to confirm the development of influenza-specific B-cell and T-cell immunity. Patients who received the influenza-primed autologous T-cell product were significantly more likely to seroconvert in response to the influenza vaccine (P = .001). Seroconversion was accompanied by a significant B-cell response. No differences were observed in the global quantitative recovery of T-cell and B-cell subsets or in global T-cell and B-cell function. The provision of a primed autologous T-cell product significantly improved subsequent influenza vaccine responses. This trial was registered at www.clinicaltrials.gov as #NCT00499577.
Blood 01/2011; 117(1):63-71. · 9.90 Impact Factor
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Yangbing Zhao,
Edmund Moon,
Carmine Carpenito,
Chrystal M Paulos,
Xiaojun Liu,
Andrea L Brennan, Anne Chew,
Richard G Carroll,
John Scholler,
Bruce L Levine,
Steven M Albelda,
Carl H June
[show abstract]
[hide abstract]
ABSTRACT: Redirecting T lymphocyte antigen specificity by gene transfer can provide large numbers of tumor-reactive T lymphocytes for adoptive immunotherapy. However, safety concerns associated with viral vector production have limited clinical application of T cells expressing chimeric antigen receptors (CAR). T lymphocytes can be gene modified by RNA electroporation without integration-associated safety concerns. To establish a safe platform for adoptive immunotherapy, we first optimized the vector backbone for RNA in vitro transcription to achieve high-level transgene expression. CAR expression and function of RNA-electroporated T cells could be detected up to a week after electroporation. Multiple injections of RNA CAR-electroporated T cells mediated regression of large vascularized flank mesothelioma tumors in NOD/scid/γc(-/-) mice. Dramatic tumor reduction also occurred when the preexisting intraperitoneal human-derived tumors, which had been growing in vivo for >50 days, were treated by multiple injections of autologous human T cells electroporated with anti-mesothelin CAR mRNA. This is the first report using matched patient tumor and lymphocytes showing that autologous T cells from cancer patients can be engineered to provide an effective therapy for a disseminated tumor in a robust preclinical model. Multiple injections of RNA-engineered T cells are a novel approach for adoptive cell transfer, providing flexible platform for the treatment of cancer that may complement the use of retroviral and lentiviral engineered T cells. This approach may increase the therapeutic index of T cells engineered to express powerful activation domains without the associated safety concerns of integrating viral vectors.
Cancer Research 10/2010; 70(22):9053-61. · 7.86 Impact Factor
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Aaron P Rapoport,
Nicole A Aqui,
Edward A Stadtmauer,
Dan T Vogl,
Hong-Bin Fang,
Ling Cai,
Stephen Janofsky, Anne Chew,
Jan Storek,
Gorgun Akpek, [......],
Sunita Philip,
Heather Murphy,
Rita Bhagat,
Zhaohui Zheng,
Todd Milliron,
Julio Cotte,
Andrea Cannon,
Bruce L Levine,
Robert H Vonderheide,
Carl H June
[show abstract]
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ABSTRACT: In a phase 1/2 two-arm trial, 54 patients with myeloma received autografts followed by ex vivo anti-CD3/anti-CD28 costimulated autologous T cells at day 2 after transplantation. Study patients positive for human leukocyte antigen A2 (arm A, n = 28) also received pneumococcal conjugate vaccine immunizations before and after transplantation and a multipeptide tumor antigen vaccine derived from the human telomerase reverse transcriptase and the antiapoptotic protein survivin. Patients negative for human leukocyte antigen A2 (arm B, n = 26) received the pneumococcal conjugate vaccine only. Patients exhibited robust T-cell recoveries by day 14 with supraphysiologic T-cell counts accompanied by a sustained reduction in regulatory T cells. The median event-free survival (EFS) for all patients is 20 months (95% confidence interval, 14.6-24.7 months); the projected 3-year overall survival is 83%. A subset of patients in arm A (36%) developed immune responses to the tumor antigen vaccine by tetramer assays, but this cohort did not exhibit better EFS. Higher posttransplantation CD4(+) T-cell counts and a lower percentage of FOXP3(+) T cells were associated with improved EFS. Patients exhibited accelerated polyclonal immunoglobulin recovery compared with patients without T-cell transfers. Adoptive transfer of tumor antigen vaccine-primed and costimulated T cells leads to augmented and accelerated cellular and humoral immune reconstitution, including antitumor immunity, after autologous stem cell transplantation for myeloma. This study was registered at www.clinicaltrials.gov as NCT00499577.
Blood 10/2010; 117(3):788-97. · 9.90 Impact Factor
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Aaron P Rapoport,
Edward A Stadtmauer,
Nicole Aqui,
Dan Vogl, Anne Chew,
Hong-Bin Fang,
Stephen Janofsky,
Kelly Yager,
Elizabeth Veloso,
Zhaohui Zheng, [......],
Saul Yanovich,
Gorgun Akpek,
Ming Tan,
Kristen Virts,
Kathleen Ruehle,
Carolynn Harris,
Sunita Philip,
Robert H Vonderheide,
Bruce L Levine,
Carl H June
[show abstract]
[hide abstract]
ABSTRACT: Previously, we showed that adoptive transfer of in vivo vaccine-primed and ex vivo (anti-CD3/anti-CD28) costimulated autologous T cells (ex-T) at day +12 after transplant increased CD4 and CD8 T-cell counts at day +42 and augmented vaccine-specific immune responses in patients with myeloma. Here, we investigated the safety and kinetics of T-cell recovery after infusing ex-T at day +2 after transplant.
In this phase I/II two-arm clinical trial, 50 patients with myeloma received autografts after high-dose melphalan followed by infusions of ex-T at day +2 after transplant. Patients also received pretransplant and posttransplant immunizations using a pneumococcal conjugate vaccine only (arm B; n = 24) or the pneumococcal conjugate vaccine plus an HLA-A2-restricted microltipeptide vaccine for HLA-A2(+) patients (arm A; n = 26).
The mean number of T cells infused was 4.26 x 10(10) (range, 1.59-5.0). At day 14 after transplant, the median CD3, CD4, and CD8 counts were 4,198, 1,545, and 2,858 cells/microL, respectively. Interleukin (IL)-6 and IL-15 levels increased early after transplant and IL-15 levels correlated significantly to day 14 T-cell counts. Robust vaccine-specific B- and T-cell responses were generated. T-cell infusions were well tolerated with no effect on hematopoietic recovery. Eight patients (16%) developed a T-cell "engraftment syndrome" characterized by diarrhea and fever that was clinically and histopathologically indistinguishable from grade 1 to 3 acute graft-versus-host disease (GVHD) of the gastrointestinal tract (seven patients) and/or grade 1 to 2 cutaneous GVHD (four patients).
Adoptive T-cell transfers achieve robust T-cell recovery early after transplant and induce moderate-to-severe autologous GVHD in a subset of patients.
Clinical Cancer Research 07/2009; 15(13):4499-507. · 7.74 Impact Factor
