Novel OX40 and 4-1BB Derived Spacers Enhance CD30 CAR Activity and Safety in CD30 Positive Lymphoma Models.

in Molecular therapy : the journal of the American Society of Gene Therapy by Lindsay Kua, Chee Hoe Ng, Jin Wei Tan, Hwee Ching Tan, Cheah Chen Seh, Fiona Wong, Richard Ong, Cliona M Rooney, Joel Tan, Qingfeng Chen, Ivan D Horak, Kar Wai Tan, Lionel Low

TLDR

  • The study aims to improve the effectiveness of a treatment for a type of cancer called CD30-positive lymphomas. The treatment is called CAR-T cell therapy, which involves using genetically modified cells called T cells to attack and destroy cancer cells. The study focuses on a specific type of CAR-T cell therapy called HRS-3, which is derived from a mouse antibody. The study finds that a specific type of spacer called 4-1BB is more effective than a different type of spacer called IgG1 in improving the effectiveness of HRS-3. The study uses a mouse model of cancer to test the effectiveness of HRS-3 with the 4-1BB spacer. The study's findings suggest that the 4-1BB spacer is a promising candidate for future clinical development in the treatment of CD30-positive lymphomas.

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 wildtype IgG1 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 a 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.

Overview

  • The study aims to improve the functionality of a chimeric antigen receptor (CAR) derived from the CD30 specific murine antibody, HRS-3, in the treatment of relapsed or refractory CD30-positive lymphomas. The study focuses on the cysteine rich domain (CRD) 5 of CD30 as the primary binding epitope of HRS-3 and attempts to improve the HRS-3 CAR functionality with a panel of novel spacer designs. The study uses a lymphoma mouse model of high tumor burden to evaluate the efficacy and safety of the HRS-3 CD30.CARs with the 4-1BB spacer. The primary objective of the study is to identify a CAR design that exhibits potent on-target, on-tumor efficacy and on-target, off-tumor safety in the treatment of CD30-positive malignancies.

Comparative Analysis & Findings

  • The study compares the anti-tumor efficacy of HRS-3 CARs with OX40 and 4-1BB derived spacers to a CAR employing the IgG1 spacer. The results show 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. The study also demonstrates that 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. The findings suggest that the 4-1BB spacer design is a promising candidate for future clinical development in the treatment of CD30-positive malignancies.

Implications and Future Directions

  • The study's findings suggest that the 4-1BB spacer design is a promising candidate for future clinical development in the treatment of CD30-positive malignancies. The study identifies the cysteine rich domain (CRD) 5 of CD30 as the primary binding epitope of HRS-3 and attempts to improve the HRS-3 CAR functionality with a panel of novel spacer designs. The study uses a lymphoma mouse model of high tumor burden to evaluate the efficacy and safety of the HRS-3 CD30.CARs with the 4-1BB spacer. The study's limitations include the use of a murine model, which may not fully capture the complexity of human disease. Future research should focus on translating the findings of this study to human clinical trials to evaluate the safety and efficacy of the 4-1BB spacer design in the treatment of CD30-positive malignancies.
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