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Modulation of Target Antigen Density Improves CAR T-cell Functionality and Persistence.

Sneha Ramakrishna1, Steven L Highfill2, Zachary Walsh1,3,4

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Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|May 22, 2019
PubMed
Summary
This summary is machine-generated.

Low CD22 expression limits chimeric antigen receptor T-cell (CART) therapy for acute lymphoblastic leukemia (ALL). Upregulating CD22 with Bryostatin1 enhances CART efficacy and prolongs remission duration in patients with leukemia and lymphoma.

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Area of Science:

  • Immunotherapy
  • Oncology
  • Cellular Therapy

Background:

  • Chimeric antigen receptor T-cell (CART) therapy targeting CD22 shows promise for relapsed/refractory acute lymphoblastic leukemia (ALL), inducing remission in 70% of patients.
  • However, short remission durations are common, often linked to decreased CD22 expression on cancer cells, leading to antigen escape.

Purpose of the Study:

  • To investigate the impact of low CD22 expression on CD22 CART therapy effectiveness.
  • To explore strategies, including high-affinity CARs and target antigen modulation, to overcome antigen escape and improve therapeutic outcomes.

Main Methods:

  • Evaluated CD22 CART functionality (cytokine profile, cytotoxicity, in vivo activity) using ALL cell lines with varying CD22 expression.
  • Developed a high-affinity CD22 CAR and assessed the effect of Bryostatin1 to upregulate CD22 expression.

Main Results:

  • Low CD22 expression significantly impaired in vitro and in vivo CD22 CART function and persistence.
  • Increased CAR affinity did not overcome low-antigen leukemia.
  • Bryostatin1 upregulated CD22 expression, enhancing CART functionality and in vivo persistence, leading to longer-lasting responses.
  • Bryostatin1 did not adversely affect overall CART cytotoxicity despite attenuating IFNγ production.

Conclusions:

  • Target antigen modulation, specifically upregulating CD22 with Bryostatin1, is a viable strategy to enhance CD22 CART efficacy.
  • This approach holds promise for improving remission durability in patients with CD22-expressing leukemias and lymphomas.