IL-12-engineered human PSMA-CAR T cells for the treatment of advanced prostate cancer
Lupita S Lopez1,2,3, Ziyou Cui4, Yukiko Yamaguchi1
1Division of Medical Oncology, Department of Medicine, Keck School of Medicine (KSOM) of USC, Los Angeles, CA 90033, USA.
Abstract:
Adoptive cell therapies used to treat advanced prostate cancer are being developed to target several tumor-associated antigens, including prostate-specific membrane antigen (PSMA). Chimeric antigen receptor (CAR) T cell therapy using the single-chain variable fragment (scFv) derived from the humanized murine mAb clone J591 as the antigen-binding domain has shown promising anti-tumor activity. However, it has also been associated with macrophage activation syndrome and other unwanted toxicities, highlighting the need for more specific and human-derived antigen-binders with optimized construct designs for improved safety and efficacy. Here, we optimize a human scFv-based PSMA-targeted CAR (hPSMA-CAR) with highly selective PSMA targeting. We further introduce a membrane-bound IL-12 (mbIL12) molecule, which enhances potency with increased T cell expansion, IFN-γ production, and anti-tumor cell activity in vitro. Using two clinically relevant bone-metastatic prostate cancer models, we show that mbIL12-engineered hPSMA-CAR T cells drive potent in vivo anti-tumor responses. In summary, we have developed a promising therapeutic that has potential to promote safe and effective treatment of advanced PSMA+ prostate cancer.
Insights
Researchers developed an improved chimeric antigen receptor (CAR) T cell therapy targeting prostate-specific membrane antigen (PSMA) for advanced prostate cancer. This new therapy enhances T cell activity and shows potent anti-tumor responses in preclinical models.
Area of Science:
- Immunotherapy
- Oncology
- Cellular Therapy
Background:
- Advanced prostate cancer treatment faces challenges with existing adoptive cell therapies targeting tumor antigens like prostate-specific membrane antigen (PSMA).
- Current chimeric antigen receptor (CAR) T cell therapies, while promising, have shown toxicities, necessitating safer and more effective antigen binders.
- There is a need for optimized CAR T cell constructs with improved specificity and reduced adverse effects for prostate cancer.
Purpose of the Study:
- To develop and optimize a human single-chain variable fragment (scFv)-based PSMA-targeted CAR (hPSMA-CAR) for enhanced specificity and safety.
- To engineer hPSMA-CAR T cells with membrane-bound IL-12 (mbIL12) to improve potency and anti-tumor activity.
- To evaluate the therapeutic efficacy of mbIL12-engineered hPSMA-CAR T cells in preclinical models of advanced prostate cancer.
Main Methods:
- Optimization of a human scFv-based CAR construct targeting PSMA.
- Introduction of a membrane-bound IL-12 (mbIL12) molecule into the CAR T cell design.
- In vitro assessment of T cell expansion, IFN-γ production, and anti-tumor activity.
- In vivo evaluation of therapeutic efficacy in two clinically relevant bone-metastatic prostate cancer models.
Main Results:
- The engineered hPSMA-CAR demonstrated highly selective PSMA targeting.
- Incorporation of mbIL12 led to enhanced T cell expansion, increased IFN-γ production, and improved in vitro anti-tumor cell activity.
- mbIL12-engineered hPSMA-CAR T cells exhibited potent in vivo anti-tumor responses in bone-metastatic prostate cancer models.
Conclusions:
- A novel, optimized hPSMA-CAR T cell therapy has been developed with enhanced potency and specificity.
- The addition of mbIL12 significantly boosts the anti-tumor efficacy of PSMA-targeted CAR T cells.
- This mbIL12-engineered hPSMA-CAR T cell therapy holds potential for safe and effective treatment of advanced PSMA+ prostate cancer.
