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. 2023 Aug 22;7(16):4418-4430.
doi: 10.1182/bloodadvances.2022007059.

CD38 as a pan-hematologic target for chimeric antigen receptor T cells

Tina Glisovic-Aplenc  1 , Caroline Diorio  1   2 , John A Chukinas  1 , Kimberly Veliz  3   4 , Olga Shestova  3   4 , Feng Shen  3   4 , Selene Nunez-Cruz  3 , Tiffaney L Vincent  1 , Fei Miao  3 , Michael C Milone  3 , Carl H June  3 , David T Teachey  1   2 , Sarah K Tasian  1   2 , Richard Aplenc  1   2 , Saar Gill  3   4
Affiliations

CD38 as a pan-hematologic target for chimeric antigen receptor T cells

Tina Glisovic-Aplenc et al. Blood Adv. .

Abstract

Many hematologic malignancies are not curable with chemotherapy and require novel therapeutic approaches. Chimeric antigen receptor (CAR) T-cell therapy is 1 such approach that involves the transfer of T cells engineered to express CARs for a specific cell-surface antigen. CD38 is a validated tumor antigen in multiple myeloma (MM) and T-cell acute lymphoblastic leukemia (T-ALL) and is also overexpressed in acute myeloid leukemia (AML). Here, we developed human CD38-redirected T cells (CART-38) as a unified approach to treat 3 different hematologic malignancies that occur across the pediatric-to-adult age spectrum. Importantly, CD38 expression on activated T cells did not impair CART-38 cells expansion or in vitro function. In xenografted mice, CART-38 mediated the rejection of AML, T-ALL, and MM cell lines and primary samples and prolonged survival. In a xenograft model of normal human hematopoiesis, CART-38 resulted in the expected reduction of hematopoietic progenitors, which warrants caution and careful monitoring of this potential toxicity when translating this new immunotherapy into the clinic. Deploying CART-38 against multiple CD38-expressing malignancies is significant because it expands the potential for this novel therapy to affect diverse patient populations.

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Conflict of interest statement

Conflict-of-interest disclosure: M.C.M. declares multiple patents related to CAR-Ts. C.H.J. is a scientific founder and has equity in Tmunity Therapeutics and Capstan Therapeutics and reports grants from Tmunity Therapeutics and is on the scientific advisory boards of BlueSphereBio, Cabaletta, Carisma, Cellares, Celldex, ImmuneSensor, Poseida, Verismo, Viracta Therapeutics, WIRB Copernicus Group, and Ziopharm Oncology. D.T.T. serves on advisory boards for Sobi, Beam Therapeutics, and Janssen; receives research funding from Beam Therapeutics and NeoImmune Tech; and has patents related to CAR-Ts. S.K.T. receives research funding from Beam Therapeutics, Gilead Sciences, Incyte Corporation, and Kura Oncology for unrelated studies; has consulted for bluebird bio; and is on the scientific advisory boards of Aleta Biotherapeutics, Kura Oncology, and Syndax Pharmaceuticals. S.G. declares multiple patents related to CAR-Ts; is a scientific founder and has equity in Carisma Therapeutics and Interius Biotherapeutics; and reports grants from Carisma Therapeutics and Interius Biotherapeutics. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
CART-38 expansion and protection from self-lysis.
Figure 2.
Figure 2.
CART-38 effector functions in vitro.
Figure 3.
Figure 3.
In vivo activity of CART-38 in AML.
Figure 4.
Figure 4.
In vivo activity of CART-38 in AML patient-derived xenograft models.
Figure 4.
Figure 4.
In vivo activity of CART-38 in AML patient-derived xenograft models.
Figure 5.
Figure 5.
In vivo activity of CART-38 in T-ALL.
Figure 6.
Figure 6.
Activity of CART-38 in myeloma.
Figure 7.
Figure 7.
Hematopoietic toxicity of CART-38.
See this image and copyright information in PMC

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