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CD38-CAR NK Cell Therapy Has Antitumor Potential for Treating CD38-Expressing Hematologic Malignancies

CD38-CAR NK Cell Therapy Has Antitumor Potential for Treating CD38-Expressing Hematologic Malignancies 1024 649 Jessica Nye, PhD

Investigators from Nationwide Children’s Hospital created fratricide-resistant and metabolically-enhanced chimeric antigen receptor (CAR) natural killer (NK) and T cells that have cytotoxic effects on many hematologic tumors.

“One of the problems that we usually have with blood cancers is making effective therapies using immune cells, because the immune cells then recognize themselves as a threat and start killing each other,” says Meisam Naeimi Kararoudi, DVM, PhD, principal investigator in the Center for Childhood Cancer Research at Nationwide Children’s Hospital.

In a study published in Blood Neoplasia lead by first author Ella Troy, who was a research assistant in the Center for Childhood Cancer Research at the time of the study, and co-senior authors Dean A. Lee, MD, PhD, and Dr. Naeimi Kararoudi, the team used the CRISPR-Cas9 platform to edit the genome of NK and T cells from matched pair donors. The cells underwent simultaneous CD38 knock out (KO) and knock-in using isatuximab-based CD38 fragments. The antitumor activity of the resulting CD38KO/CD38-CAR NK cells was tested using cell lines generated from samples obtained from pediatric patients with acute myeloid leukemia (AML), multiple myeloma (MM) and Burkitt lymphoma (BL).

Compared with wild type (WT) NK cells, the CD38KO/CD38-CAR NK cells had similar levels of cell expansion over 12 days, suggesting a lack of NK cell fratricide.

“We saw that the CAR itself provides some sort of protection, by kind of covering the gene that we were going after. We still don’t know why it happened, but we think that covering, we call it the mocking effect, is the reason that the CAR NK and T cells that we generated ¾ and are supposed to kill each other ¾ didn’t kill each other,” says Dr. Kararoudi.

In addition, the CD38KO/CD38-CAR NK cells demonstrated more pronounced antitumor effects against AML (P =.001), MM (P =.001) and BL (P =.001) than WT NK cells.

The antitumor effects of the CD38KO/CD38-CAR NK cells against AML were enhanced with all-trans retinoic acid (ATRA) combinatorial therapy. Treatment with CD38KO/CD38-CAR NK cells alone resulted in 12% live AML cells whereas when combined with ATRA resulted in 4.8% live AML cells compared with 31.4% and 32.0% after treatment with WT NK cells alone or combined with ATRA, respectively.

Similar to the CD38KO/CD38-CAR NK cells, the matched donor pair CD38KO/CD38-CAR T cells were found expand in a similar manner as WT T cells, indicating a lack of fratricide.

The results of this study directly led to the startup company CARTx Theraputics.

“I use the same target, CD38, and put it into an off-the-shelf CAR T-cell therapy and a different type of CAR T, called Gamma Delta T cells. They are different from the Alpha Beta T cells and NK cells reported in this paper. Gamma Delta T cells are something in between those two and they are a very small population of the immune cells, 1% to 5%. Based on this research, we founded a company called CARTx therapeutics where we generate CD38 CAR Gamma Delta T cells,” says Dr. Kararoudi.

 

 

Reference:

Troy E, Caporale J, Sezgin Y, Pereira MSF, Behbehani G, Lyberger J, Lee DA, Kararoudi MN. CD38-CAR human NK cells in combination with ATRA enhance cytotoxicity against CD38-expressing hematologic malignancies. Blood Neoplasia. 2024;1(4):100032.

About the author

Jessica Nye, PhD, is a freelance science and medical writer based in Barcelona, Spain. She completed her BS in biology and chemistry and MS in evolutionary biology at Florida State University. Dr. Nye studied population genetics for her doctorate in biomedicine at University of Pompeu Fabra. She conducted her postdoctoral research on the inheritance of complex traits at the Autonomous University of Barcelona.

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