Language
English
Publication Date
10-2-2024
Journal
Molecular Therapy
DOI
10.1016/j.ymthe.2024.06.037
PMID
38946142
PMCID
PMC11489532
PubMedCentral® Posted Date
6-29-2024
PubMedCentral® Full Text Version
Post-print
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.
Keywords
Animals, Humans, Mice, Cell Line, Tumor, Disease Models, Animal, Immunotherapy, Adoptive, Ki-1 Antigen, Lymphoma, Receptors, Chimeric Antigen, Receptors, OX40, T-Lymphocytes, Tumor Necrosis Factor Receptor Superfamily, Member 9, Xenograft Model Antitumor Assays, CAR design, spacer domain, CD30, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, immunotherapy
Published Open-Access
yes
Recommended Citation
Kua, Lindsay; Ng, Chee Hoe; Tan, Jin Wei; et al., "Novel OX40 and 4–1BB Derived Spacers Enhance CD30 Car Activity and Safety in CD30 Positive Lymphoma Models" (2024). Faculty, Staff and Students Publications. 6353.
https://digitalcommons.library.tmc.edu/baylor_docs/6353