Novel OX40 and 4-1BB derived spacers enhance CD30 CAR activity and safety in CD30 positive lymphoma models.
Mol Ther
; 32(10): 3504-3521, 2024 Oct 02.
Article
in En
| MEDLINE
| ID: mdl-38946142
ABSTRACT
The chimeric antigen receptor (CAR) derived from the CD30 specific murine antibody, HRS-3, has produced promising clinical efficacy with a favorable safety profile in the treatment of relapsed or refractory CD30-positive lymphomas. However, persistence of the autologous CAR-T cells was brief, and many patients relapsed a year after treatment. The lack of persistence may be attributed to the use of a wild-type immunoglobulin (Ig)G1 spacer that can associate with Fc receptors. We first identified the cysteine-rich domain (CRD) 5 of CD30 as the primary binding epitope of HRS-3 and armed with this insight, attempted to improve the HRS-3 CAR functionality with a panel of novel spacer designs. We demonstrate that HRS-3 CARs with OX40 and 4-1BB derived spacers exhibited similar anti-tumor efficacy, circumvented interactions with Fc receptors, and secreted lower levels of cytokines in vitro than a CAR employing the IgG1 spacer. Humanization of the HRS-3 scFv coupled with the 4-1BB spacer preserved potent on-target, on-tumor efficacy, and on-target, off-tumor safety. In a lymphoma mouse model of high tumor burden, T cells expressing humanized HRS-3 CD30.CARs with the 4-1BB spacer potently killed tumors with low levels of circulating inflammatory cytokines, providing a promising candidate for future clinical development in the treatment of CD30-positive malignancies.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Immunotherapy, Adoptive
/
Ki-1 Antigen
/
Xenograft Model Antitumor Assays
/
Receptors, OX40
/
Receptors, Chimeric Antigen
/
Lymphoma
Limits:
Animals
/
Humans
Language:
En
Journal:
Mol Ther
/
Mol. ther
/
Molecular therapy
Journal subject:
BIOLOGIA MOLECULAR
/
TERAPEUTICA
Year:
2024
Type:
Article
Affiliation country:
Singapore