Treatment of Advanced Leukemia in Mice with mRNA Engineered T Cells

Barrett, David M.; Zhao, Yangbing; Liu, Xiaojun; Jiang, Shuguang; Carpenito, Carmine; Kalos, Michael; Carroll, Richard G.; June, Carl H.; Grupp, Stephan A.

doi:10.1089/hum.2011.070

Cited by 195 publications

(201 citation statements)

References 54 publications

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“…Such approaches would include the use of "biodegradable" CART-engineered cells such as T cells electroporated with CAR messenger RNA developed by our group and others, which transiently express the CAR transgenes and thus have a finite and short lifespan; the use of "biodegradable" CAR-engineered T cells modified with messenger RNA; the use of inducible suicide systems to ablate engineered cells when desired; the use of costimulatory molecules less potent than CD137; or the use of T-cell-depleting antibodies such as antithymocyte globulin or alemtuzuzmab. [45][46][47] A subsequent infusion of healthy hematopoietic stem cells may be then needed to reconstitute normal hematopoiesis.…”

Section: Discussionmentioning

confidence: 99%

Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor–modified T cells

Gill¹,

Tasian

Ruella

et al. 2014

Blood

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407

381

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Key Points• Targeting of CD123 via CAR-engineered T cells results in rejection of human AML and myeloablation in mouse models.Many patients with acute myeloid leukemia (AML) are incurable with chemotherapy and may benefit from novel approaches. One such approach involves the transfer of T cells engineered to express chimeric antigen receptors (CARs) for a specific cell-surface antigen. This strategy depends upon preferential expression of the target on tumor cells. To date, the lack of AML-specific surface markers has impeded development of such CARbased approaches. CD123, the transmembrane a chain of the interleukin-3 receptor, is expressed in the majority of AML cells but is also expressed in many normal hematopoietic cells. Here, we show that CD123 is a good target for AML-directed CAR therapy, because its expression increases over time in vivo even in initially CD123 dim populations, and that human CD123-redirected T cells (CART123) eradicate primary AML in immunodeficient mice. CART123 also eradicated normal human myelopoiesis, a surprising finding because anti-CD123 antibody-based strategies have been reportedly well tolerated. Because AML is likely preceded by clonal evolution in "preleukemic" hematopoietic stem cells, our observations support CART123 as a viable AML therapy, suggest that CART123-based myeloablation may be used as a novel conditioning regimen for hematopoietic cell transplantation, and raise concerns for the use of CART123 without such a rescue strategy. (Blood. 2014;123(15):2343-2354

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Section: Discussionmentioning

confidence: 99%

Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor–modified T cells

Gill¹,

Tasian

Ruella

et al. 2014

Blood

Self Cite

407

381

View full text Add to dashboard Cite

show abstract

“…These could include hematopoietic stem cell transplantation, incorporation of a suicide gene within the CAR construct, or transiently transfecting T cells with the CAR construct. 49,50 Indeed, in preliminary studies we have demonstrated the feasibility of using RNA transfection to express anti-CD33-41BB-ζ CAR on T cells (data not shown).…”

mentioning

confidence: 94%

Anti-CD33 chimeric antigen receptor targeting of acute myeloid leukemia

et al. 2014

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“…Furthermore, treatment of human ALL cell line-xenografted mice with retrovirus-or lentivirus-transduced CD19 CAR T cells (second generation) resulted in systemic trafficking of T cells to sites of CD19+ disease and in successful eradication of leukemia [Brentjens et al 2007;Milone et al 2009;Barrett et al 2011].…”

Section: Cd19-redirected Car T Cells: Optimal Designmentioning

confidence: 99%

CD19-redirected chimeric antigen receptor-modified T cells: a promising immunotherapy for children and adults with B-cell acute lymphoblastic leukemia (ALL)

Tasian

Gardner

2015

Therapeutic Advances in Hematology

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Relapsed and chemotherapy-refractory B-cell acute lymphoblastic leukemia (B-ALL) remain significant causes of cancer-associated morbidity and mortality for children and adults. Development of new molecularly targeted treatment strategies for patients with high-risk B-ALL is thus a major preclinical and clinical priority. Adoptive cellular therapy with patient-derived human T cells genetically engineered to express CD19 redirected chimeric antigen receptors (CD19 CAR T cells) is one immunotherapeutic modality that has recently demonstrated remarkable efficacy in re-inducing remission in patients with multiply relapsed B-ALL. Investigative teams at several major cancer centers are currently conducting phase I clinical trials in children and/or adults with relapsed/refractory B-ALL to assess the safety and to identify the maximally tolerated dose of each group’s CD19 CAR T-cell product. All groups have reported major clinical toxicities associated with CD19 CAR T-cell treatment, including cytokine release syndrome (CRS) and macrophage activation syndrome, neurologic dysfunction and aplasia of normal B lymphocytes, while CD19 CAR T cells persist in vivo. Toxicities have generally been transient or manageable with supportive care measures. Some patients with life-threatening CD19 CAR T-cell induced sequelae have received anti-cytokine receptor antibody treatment to diminish CRS symptoms and/or corticosteroids to terminate CAR T-cell proliferation. Remarkably, 67–90% of children and adults with B-ALL treated with CD19 CAR T cells in these trials have achieved morphologic leukemia remission with many patients also in molecular remission. The duration of CD19 CAR T cell persistence in vivo has varied appreciably among treated patients and likely reflects differences in the CD19 CAR constructs utilized at each institution. CD19-positive and CD19-negative B-ALL relapses after CD19 CAR T-cell treatment have occurred in some patients. Phase II trials to assess the efficacy of CD19 CAR T-cell immunotherapy in larger cohorts of patients with relapsed/refractory B-ALL are ongoing or planned.

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Treatment of Advanced Leukemia in Mice with mRNA Engineered T Cells

Cited by 195 publications

References 54 publications

Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor–modified T cells

Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor–modified T cells

Anti-CD33 chimeric antigen receptor targeting of acute myeloid leukemia

CD19-redirected chimeric antigen receptor-modified T cells: a promising immunotherapy for children and adults with B-cell acute lymphoblastic leukemia (ALL)

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