Researchers Highlight Delivery of CAR T-Cell Therapy Through Modified AAV

In a preclinical study, researchers were able to show that their modified adeno-associated virus (AAV) vector safely delivered the chimeric antigen receptor (CAR) gene into the host cells and produced enough CAR T cells to cause effective tumor regression and elicit antitumor immunological characteristics in a mouse model of human T-cell leukemia.

Recently published findings are documenting a novel approach that researchers say may make chimeric antigen receptor (CAR) T-cell therapy for leukemia simpler and less expensive because it doesn’t require patient lymphodepletion or the β processes of current CAR T-cell production. The approach allows the patient to generate CAR T cells by injecting an adeno-associated virus (AAV) vector that supplies the CAR gene.

In the current study, researchers were able to show that their modified AAV vector safely delivered the CAR gene into the host cells and produced enough CAR T cells to cause effective tumor regression and elicit antitumor immunological characteristics in a mouse model of human T-cell leukemia. Notably, this response was observed after a single infusion and the generated CAR T cells circulated the host body for weeks, able to detect and attack the target cells.

“To the best of our knowledge, this is the first report describing that an AAV carrying a CAR gene can reprogram immune cells in vivo to generate enough CAR T cells to induce tumor regression,” reflected the researchers. “Our current CAR gene-carrying AAV strategy contrasts with the costly and time-consuming method of conventional manufacturing CAR T therapy, which requires primary T-cell isolation and transgene introduction and expansion via lentiviral vectors or retroviral vectors ex vivo.”

According to the researchers, AAV has been a popular method and is being extensively studied for therapeutic gene delivery, often being leveraged to carry genetic material into the target cells to cure or treat a disease.

For the study, the researchers chose CD4-targeting CAR due to the aggressive nature of CD4+ leukemia and lymphoma, which often don’t respond to chemotherapy.

“Initial preclinical studies of CAR T cells for targeting CD4+ tumors are encouraging, but to date, no standard care has been developed,” explained the group. “Furthermore, CD4 + cells are the major latent reservoir of HIV, posing a challenge for HIV eradication; therapies targeting CD4+ cells can also be translated into HIV treatment and treatments for other infectious diseases, including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and psoriasis.”

The researchers noted that there was a complete CD4+ depletion in the mice, which raises concerns about the possible effects in the long term or clinical setting, as long-term CD4 helper T-cell depletion can cause “on-target, off-tumor” toxicities and immunodeficiency.

Reference

Nawaz W, Huang B, Xu S, et al. AAV-mediated in vivo CAR gene therapy for targeting human T-cell leukemia. Blood Cancer J. 2021;11(6):119. doi:10.1038/s41408-021-00508-1