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IL12-engineered human PSMA-CAR T cells for the treatment of advanced prostate cancer
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, IFNy 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 enhanced chimeric antigen receptor (CAR) T cell therapy targeting prostate-specific membrane antigen (PSMA) for advanced prostate cancer. This new therapy shows potent anti-tumor activity with improved safety and efficacy.
Area of Science:
- Oncology
- Immunotherapy
- Cellular Therapy
Background:
- Advanced prostate cancer treatment faces challenges with existing adoptive cell therapies targeting prostate-specific membrane antigen (PSMA).
- Current therapies, like J591-derived CAR T cells, show efficacy but are linked to toxicities, necessitating safer, human-derived binders and optimized designs.
- There is a critical need for improved CAR T cell constructs with enhanced specificity and reduced adverse effects for prostate cancer.
Purpose of the Study:
- To optimize a human single chain variable fragment (scFv)-based CAR T cell therapy targeting PSMA (hPSMA-CAR) for enhanced safety and efficacy.
- To engineer the hPSMA-CAR T cells with membrane-bound IL-12 (mbIL12) to augment anti-tumor potency and T cell responses.
- To evaluate the therapeutic potential of mbIL12-engineered hPSMA-CAR T cells in preclinical models of metastatic prostate cancer.
Main Methods:
- Development and optimization of a human scFv-based CAR targeting PSMA (hPSMA-CAR).
- Engineering of hPSMA-CAR T cells with membrane-bound IL-12 (mbIL12) to enhance immune cell functions.
- In vitro assessment of T cell expansion, IFN-gamma production, and anti-tumor activity.
- In vivo evaluation of mbIL12-engineered hPSMA-CAR T cells in clinically relevant bone-metastatic prostate cancer models.
Main Results:
- The optimized hPSMA-CAR demonstrated highly selective PSMA targeting.
- Incorporation of mbIL12 significantly enhanced T cell expansion, IFN-gamma production, and 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:
- Engineered hPSMA-CAR T cells with mbIL12 represent a promising therapeutic strategy for advanced prostate cancer.
- This approach has the potential to improve the safety and efficacy of adoptive cell therapy for PSMA+ prostate cancer.
- The developed therapeutic offers a potential advancement in treating advanced, metastatic prostate cancer targeting PSMA.
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