Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias

Brentjens, Renier J.; Rivière, Isabelle; Park, Jae H.; Davila, Marco L.; Wang, Xiuyan; Stefanski, Jolanta; Taylor, Clare; Yeh, Raymond; Bartido, Shirley; Borquez-Ojeda, Orianna; Olszewska, Malgorzata; Bernal, Yvette; Pegram, Hollie J.; Przybylowski, Mark; Hollyman, Daniel; Usachenko, Yelena; Pirraglia, Domenick; Hosey, James; Santos, Elmer; Halton, Elizabeth; Maslak, Peter; Scheinberg, David A.; Jurcic, Joseph G.; Heaney, Mark L.; Heller, Glenn; Frattini, Mark G.; Sadelain, Michel

doi:10.1182/blood-2011-04-348540

Cited by 1,160 publications

(1,098 citation statements)

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“…(Brentjens et al 2011, Jensen et al 2010) In order to directly measure and compare the in vivo performance of first and second generation CD19 CAR T-cells, Savoldo et al (2011) simultaneously infused patients with refractory B-cell lymphoma with 2 autologous CD19-CAR products, one encoding both the TCRζ-endodomain and a CD28 costimulatory domain, and the other encoding only the TCRζ-endodomain. CD28ζ CAR T-cells showed enhanced expansion and persistence up to 6 months following infusion versus 2 weeks with first generation cells.…”

Section: Chimeric Antigen Receptor-modified T-cellsmentioning

confidence: 99%

Recent advances in T‐cell immunotherapy for haematological malignancies

et al. 2016

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In vitro discoveries have paved the way for bench-to-bedside translation in adoptive T cell immunotherapy, resulting in remarkable clinical responses in a variety of haematological malignancies. Adoptively transferred T cells genetically modified to express CD19 CARs have shown great promise, although many unanswered questions regarding how to optimize T-cell therapies for both safety and efficacy remain. Similarly, T cells that recognize viral or tumour antigens though their native receptors have produced encouraging clinical responses. Honing manufacturing processes will increase the availability of T-cell products, while combining T-cell therapies has the ability to increase complete response rates. Lastly, innovative mechanisms to control these therapies may improve safety profiles while genome editing offers the prospect of modulating T-cell function. This review will focus on recent advances in T-cell immunotherapy, highlighting both clinical and pre-clinical advances, as well as exploring what the future holds.

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Section: Chimeric Antigen Receptor-modified T-cellsmentioning

confidence: 99%

Recent advances in T‐cell immunotherapy for haematological malignancies

et al. 2016

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“…While children are initially more responsive to traditional salvage chemotherapy approaches than adults, these remissions are often not sustained and relapsed ALL remains a leading cause of cancer deaths in children [29,30]. It is this dismal prognosis and lack of conventional treatment options, which underscores the impact of the dramatic responses observed with CD19-CAR T-cell therapy in patients with relapsed and refractory ALL [1,3,4,31,32].…”

Section: Clinical Outcomes Of Cd19-car T-cell Therapymentioning

confidence: 99%

“…Despite a wide array of available treatment options, CLL remains incurable without an allogeneic SCT and prognosis is quite poor for patients with multiply relapsed disease and short progression free intervals between treatments [34]. CD19-CAR T-cells have been used by several programs to treat patients with relapsed and high risk CLL [2,6,31]. We recently reported long-term follow up of the first 14 patients with CLL treated at PENN using CTL019 cells [6].…”

Section: Clinical Outcomes Of Cd19-car T-cell Therapymentioning

confidence: 99%

“…MSKCC's initial experience using CD19-CAR T cells with CD28 domain were more disappointing with 0 of 7 evaluable CLL patients responding. Reasons for this differential response compared with the NCI and PENN experience are not clear but may be due to differences in the protocol design (a Phase I design with 3 of the 7 subject not receiving lymphodepletion) or patient selection [31]. …”

Section: Clinical Outcomes Of Cd19-car T-cell Therapymentioning

confidence: 99%

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CART‐cells merge into the fast lane of cancer care

Frey

Porter

2015

American J Hematol

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Chimeric antigen receptors (CARs) can be introduced into T-cells redirecting them to target specific tumor antigens. CAR-modified T cells targeting CD19 have shown remarkable activity against CD191 malignancies including B cell acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphomas (NHL). Complete remission rates as high as 90% have been observed for patients with relapsed and refractory ALL and greater than 50% response rates have been seen in heavily pre-treated CLL and NHL. Excitingly, some remissions have been durable without any additional therapy, a finding which correlates with in-vivo T-cell persistence and B-cell aplasia. The major treatment related toxicities include Bcell aplasia, neurologic toxicities, and a potentially severe cytokine release syndrome. This review summarizes outcomes for patients treated with CD19-CAR T-cells while exploring the field's challenges and future directions.

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“…The induction of lasting remissions makes the CD19 targeting CAR T cell trial [3] a milestone in the CAR field, although the trial at University of Pennsylvania is not the first or the only CAR T cell study to be launched in humans. Other centers including Sloan Kettering Memorial Institute successfully treated chronic lymphatic leukemia patients with anti-CD19 CAR T cells as well [4,5]. Of even stronger public perception was one of the follow-up trials targeting pediatric acute lymphoblastic leukemia (ALL) with CTL019 in 2012, when the first treated patient went into complete and lasting remission, and which was rewarded as 'Breakthrough Therapy' for relapsed and refractory ALL in adults and children by the US FDA in 2014.…”

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confidence: 99%