Anti-CD19 chimeric antigen receptor targeting of CD19 + acute myeloid leukemia

Ma, Gina; Wang, Yi; Ahmed, Tahmeena; Zaslav, Ann Leslie; Hogan, Laura; Avila, Cecilia; Wada, M.; Salman, Huda

doi:10.1016/j.lrr.2018.03.002

Cited by 9 publications

(10 citation statements)

References 8 publications

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“…Several efforts have been made to demonstrate the utility of targeting CD19 in these subgroup, including preclinical work and clinical case work with a CD19-targeting CAR (34,35), and clinical case work using the CD3 x CD19 bispecific antibody blinatumomab (36). A very recent finding that CD19 is even more widely expressed in AML highlights the potential broad applicability of this dual-antigen targeting strategy (37).…”

Section: Discussionmentioning

confidence: 99%

Anti-CD19 CAR T Cells That Secrete a Biparatopic Anti-CLEC12A Bridging Protein Have Potent Activity Against Highly Aggressive Acute Myeloid Leukemia In Vitro and In Vivo

Rennert¹,

Dufort²,

Su³

et al. 2021

Molecular Cancer Therapeutics

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Refractory Acute Myeloid Leukemia (AML) remains an incurable malignancy despite the clinical use of novel targeted therapies, new antibody-based therapies and cellular therapeutics.Here we describe the preclinical development of a novel cell therapy that targets the antigen CLEC12A with a biparatopic bridging protein. Bridging proteins are designed as "CAR-T cell engagers", with a CAR-targeted protein fused to antigen binding domains derived from antibodies. Here, we created a CD19-anti-CLEC12A bridging protein that binds to CAR19 T cells and to the antigen CLEC12A. Biparatopic targeting increases the potency of bridging protein-mediated cytotoxicity by CAR19 T cells. Using CAR19 T cells that secrete the bridging protein we demonstrate potent activity against aggressive leukemic cell lines in vivo. This CARengager platform is facile and modular, as illustrated by activity of a dual-antigen bridging protein targeting CLEC12A and CD33, designed to counter tumor heterogeneity and antigen escape, and created without the need for extensive CAR T cell genetic engineering. CAR19 T cells provide an optimal cell therapy platform with well understood inherent persistence and fitness characteristics.

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Section: Discussionmentioning

confidence: 99%

Anti-CD19 CAR T Cells That Secrete a Biparatopic Anti-CLEC12A Bridging Protein Have Potent Activity Against Highly Aggressive Acute Myeloid Leukemia In Vitro and In Vivo

Rennert¹,

Dufort²,

Su³

et al. 2021

Molecular Cancer Therapeutics

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“…Following the failure of the last treatment, and since P2 had CD19 positive blasts, she was able to receive CD19targeted chimeric antigen receptor (CAR) T cell therapy [134,135], which resulted in a short remission of three months. Recent reports on the challenges of CAR T cell therapy in general [136], and specifically in AML due to its immunosuppressive microenvironment [137,138], might explain the short duration of remission following the last treatment.…”

Section: Patientmentioning

confidence: 99%

Deciphering molecular mechanisms underlying chemoresistance in relapsed AML patients: towards precision medicine overcoming drug resistance

et al. 2021

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Background Acute myeloid leukemia (AML) remains a devastating disease with a 5-year survival rate of less than 30%. AML treatment has undergone significant changes in recent years, incorporating novel targeted therapies along with improvements in allogeneic bone marrow transplantation techniques. However, the standard of care remains cytarabine and anthracyclines, and the primary hindrance towards curative treatment is the frequent emergence of intrinsic and acquired anticancer drug resistance. In this respect, patients presenting with chemoresistant AML face dismal prognosis even with most advanced therapies. Herein, we aimed to explore the potential implementation of the characterization of chemoresistance mechanisms in individual AML patients towards efficacious personalized medicine. Methods Towards the identification of tailored treatments for individual patients, we herein present the cases of relapsed AML patients, and compare them to patients displaying durable remissions following the same chemotherapeutic induction treatment. We quantified the expression levels of specific genes mediating drug transport and metabolism, nucleotide biosynthesis, and apoptosis, in order to decipher the molecular mechanisms underlying intrinsic and/or acquired chemoresistance modalities in relapsed patients. This was achieved by real-time PCR using patient cDNA, and could be readily implemented in the clinical setting. Results This analysis revealed pre-existing differences in gene expression levels between the relapsed patients and patients with lasting remissions, as well as drug-induced alterations at different relapse stages compared to diagnosis. Each of the relapsed patients displayed unique chemoresistance mechanisms following similar treatment protocols, which could have been missed in a large study aimed at identifying common drug resistance determinants. Conclusions Our findings emphasize the need for standardized evaluation of key drug transport and metabolism genes as an integral component of routine AML management, thereby allowing for the selection of treatments of choice for individual patients. This approach could facilitate the design of efficacious personalized treatment regimens, thereby reducing relapse rates of therapy refractory disease.

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“…CD19 is a B-cell marker associated with B-ALL, that is also expressed in a small subset of patients with AML and mixed-phenotype acute leukemia, associated with t(8;21), who may benefit from CD19-directed therapies [57].…”

Section: Antigens Present In Distinct Aml Subsetsmentioning

confidence: 99%

Harnessing T Cells to Target Pediatric Acute Myeloid Leukemia: CARs, BiTEs, and Beyond

Epperly

Velasquez

2020

Children

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Outcomes for pediatric patients with acute myeloid leukemia (AML) remain poor, highlighting the need for improved targeted therapies. Building on the success of CD19-directed immune therapy for acute lymphocytic leukemia (ALL), efforts are ongoing to develop similar strategies for AML. Identifying target antigens for AML is challenging because of the high expression overlap in hematopoietic cells and normal tissues. Despite this, CD123 and CD33 antigen targeted therapies, among others, have emerged as promising candidates. In this review we focus on AML-specific T cell engaging bispecific antibodies and chimeric antigen receptor (CAR) T cells. We review antigens being explored for T cell-based immunotherapy in AML, describe the landscape of clinical trials upcoming for bispecific antibodies and CAR T cells, and highlight strategies to overcome additional challenges facing translation of T cell-based immunotherapy for AML.

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Anti-CD19 chimeric antigen receptor targeting of CD19 + acute myeloid leukemia

Cited by 9 publications

References 8 publications

Anti-CD19 CAR T Cells That Secrete a Biparatopic Anti-CLEC12A Bridging Protein Have Potent Activity Against Highly Aggressive Acute Myeloid Leukemia In Vitro and In Vivo

Anti-CD19 CAR T Cells That Secrete a Biparatopic Anti-CLEC12A Bridging Protein Have Potent Activity Against Highly Aggressive Acute Myeloid Leukemia In Vitro and In Vivo

Deciphering molecular mechanisms underlying chemoresistance in relapsed AML patients: towards precision medicine overcoming drug resistance

Harnessing T Cells to Target Pediatric Acute Myeloid Leukemia: CARs, BiTEs, and Beyond

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Anti-CD19 chimeric antigen receptor targeting of CD19 + acute myeloid leukemia

Cited by 9 publications

References 8 publications

Anti-CD19 CAR T Cells That Secrete a Biparatopic Anti-CLEC12A Bridging Protein Have Potent Activity Against Highly Aggressive Acute Myeloid Leukemia In Vitro and In Vivo

Anti-CD19 CAR T Cells That Secrete a Biparatopic Anti-CLEC12A Bridging Protein Have Potent Activity Against Highly Aggressive Acute Myeloid Leukemia In Vitro and In Vivo

Deciphering molecular mechanisms underlying chemoresistance in relapsed AML patients: towards precision medicine overcoming drug resistance

Harnessing T Cells to Target Pediatric Acute Myeloid Leukemia: CARs, BiTEs, and Beyond

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Anti-CD19 chimeric antigen receptor targeting of CD19 + acute myeloid leukemia