This invention includes ten novel PSMA-targeted CAR-T therapies to treat castration-resistant prostate cancer. The CAR-T constructs were generated using scFvs from five different mouse hybridomas. We have further enhanced the lead PSMA-targeted CAR-T therapy by co-expressing IRF4 to regulate effector T cell activity and tissue infiltration. The co-expression of these two biological components facilitates more selective and potent therapeutic effects.
Stage of Development
In vitro data: 8 out of 10 of the PSMA-specific CAR-T therapies displayed higher toxicity to PSMA-expressing cells compared to activated T-cells alone and a J591-derived CAR-T therapies. Additionally, our PSMA-IRF4 enhanced CAR-T therapy demonstrated more cytotoxicity of PSMA-expressing cells compared to both the PSMA CAR-T therapy without any enhancement and a PSMA-c-Jun enhanced CAR-T therapy.
In vivo data: Intravenous injection of our lead PSMA-targeted CAR-T therapy led to complete metastatic tumor regression after 3 weeks. Furthermore, unlike the J591-derived CAR-T therapy, no tumor recurrence was observed from our lead construct within the 7 week monitoring period.
Competitive Landscape
There are several reports of PSMA-specific CAR-T therapies which have shown anti-prostate cancer activity, however, majority of these therapies have suffered from immunosuppression and subsequent T cell exhaustion. Studies by the University of Pennsylvania have shown that co-expression of dominant-negative TGFβRII in a J591-derived CAR T therapy can successfully prevent these immunosuppressive mechanisms and improve anti-cancer activity. Our invention builds upon this strategy but differs in that it utilizes a more potent PSMA-specific CAR and co-expresses a different enhancement strategy to control T cell function.
Competitive Advantages
• Increased cell targeting and killing
• Minimized off-target affects
• Reduced incidence of recurrence
• Enhanced tissue infiltration
• Synergistic effects with traditional anti-androgen therapy
