All‐trans retinoic acid enhances cytotoxic effect of T cells with an anti‐CD38 chimeric antigen receptor in acute myeloid leukemia

Abstract

We reported that T cells with anti-CD38-chimeric antigen receptors (CAR) eliminated B-cell lymphoma cells expressing CD38. To employ anti-CD38-CAR against acute myeloid leukemia (AML) blasts not expressing CD38, it is necessary to induce or increase the intensity of CD38 expression. A lactate dehydrogenase (LDH)-releasing assay and flow cytometry showed that anti-CD38-CAR T cells were cytotoxic against AML lines (THP-1 and CMK) expressing high CD38 levels (>99%), in time- and number of effector-dependent manners. In other AML lines (KG1, U937 and HL60) partially expressing CD38, CD38+ AML cells were killed by CD38-specific T cells, but CD38− AML cells remained survived. Intriguingly, 10 nM all-trans retinoic acid (ATRA) augmented CD38 expression in KG1, U937 and HL60 cells and primary leukemic cells from AML patients. Moreover, the withdrawal of ATRA from the medium decreased CD38 expression in AML cells. Killing effects of anti-CD38-CAR T cells against AML lines and AML cells were limited without ATRA, whereas CD38-specific T cells enhanced cytotoxicity on AML cells by ATRA in association with enhanced CD38 expression. These results indicate that anti-CD38-CAR T cells eliminate AML cells through CD38 expression induced by ATRA.

Finding new lanes: Chimeric antigen receptor (CAR) T‐cells for myeloid leukemia

“…CLL‐1 based ACT, therefore, has the potential to be used against AML either in combination with conventional chemotherapy or as standalone treatment. Similarly, expression of CD38 on a subset of AML cell population and relative absence of healthy mature HSCs has been shown in several studies . AntiCD38‐41BB‐CD3ζ CAR T‐cell was found to be cytotoxic against AML cell lines expressing high CD38 levels in a dose‐dependent manner .…”

AML—is it time to drive a CAR(-T)?

“…In this study the investigators could reveal another example of ATRA-enhanced cytotoxicity by using CD38-41-BB-CD3zeta CARs. Those results highlighted that ATRA may be an interesting combinatorial partner for CAR-T cells in AML [17]. ATRA is widely used for the treatment of acute promyelocytic leukemia (APL).…”

Immunobiology of chimeric antigen receptor T cells and novel designs

“…Strategies have evolved to immediately overcome the problem of insensitivity to low levels of antigen by modulating the level of antigen expression on the malignant cells. A recent study demonstrated the ability of all‐trans retinoic acid (ATRA) to upregulate CD38 expression on AML cell lines and subsequently improved the cytotoxic response of CD38 CAR T cells . Furthermore, the PKC‐modulating drug, Bryostatin 1, was shown to upregulate CD22 expression on B‐ALL and improve the cytokine production, cytotoxicity, and in vivo durability of CD22 CAR T cells .…”

“…A recent study demonstrated the ability of all-trans retinoic acid (ATRA) to upregulate CD38 expression on AML cell lines and subsequently improved the cytotoxic response of CD38 CAR T cells. 77 Furthermore, the PKC-modulating drug, Bryostatin 1, was shown to upregulate CD22 expression on B-ALL and improve the cytokine production, cytotoxicity, and in vivo durability of CD22 CAR T cells. 78 Such observations not only offer strategies for improving CAR T cell efficacy, but also illustrate the importance of antigen sensitivity to the success of CAR T cell therapy.…”