This innovative immunotherapy platform leverages p32-specific antibodies to create Chimeric Antigen Receptor (CAR) T cells, specifically targeting p32—a tumor-associated antigen expressed in glioblastomas and other aggressive cancers. The approach combines tumor elimination with antiangiogenic effects, paving the way for enhanced therapeutic outcomes in solid tumors.

Unmet Need
Glioblastoma, a highly aggressive brain cancer, has limited effective treatment options due to its heterogeneous nature and resistance to current therapies. Similarly, other solid tumors expressing p32, including breast, lung, ovarian, and pancreatic cancers, lack targeted immunotherapy solutions. Current therapies are often unable to address tumor vasculature-associated mechanisms critical to cancer progression.

Our Solution
Our technology employs p32-specific antibodies incorporated into CAR T cells. These engineered T cells:
• Recognize and destroy p32-expressing cancer cells.
• Target tumor-derived endothelial cells (TDECs), inhibiting tumor angiogenesis and circumventing resistance mechanisms like VEGF-independent vasculature formation.
• Extend survival in preclinical glioblastoma models, demonstrating both safety and efficacy.

Unique Advantages
1. Dual Action: Combines direct tumor cell killing with antiangiogenic activity to inhibit tumor progression and recurrence.
2. Specificity and Safety: Minimal off-target toxicity due to precise targeting of p32, which is overexpressed on cancer cells and TDECs but absent in healthy tissues.
3. Versatility: Applicable to a range of solid tumors beyond glioblastoma, including pancreatic, breast, and ovarian cancers.

Potential Applications
• Cancer Treatment: Glioblastoma, breast, lung, ovarian, pancreatic cancers, and other p32-expressing solid tumors.
• Combination Therapies: Enhancing the efficacy of existing treatments, such as checkpoint inhibitors.
• Antiangiogenic Therapy: Addressing VEGF-independent tumor vasculature for resistant tumors.

Current Status
Preclinical Validation The efficacy of p32-specific CAR T cells has been rigorously demonstrated in preclinical studies using multiple glioblastoma models. Key findings include:
• Prolonged Survival: In syngeneic mouse models of glioblastoma, treatment with p32 CAR T cells significantly extended survival compared to control groups, highlighting both tumor clearance and prevention of recurrence.
• Antiangiogenic Activity: The CAR T cells effectively targeted tumor-derived endothelial cells (TDECs), leading to a marked reduction in tumor vascularization. This unique mechanism of action addresses VEGF-independent angiogenesis, a common resistance pathway in glioblastomas and other cancers.
• Efficacy Across Models: Validation was conducted in both syngeneic mouse models (immune-competent) and human-derived xenograft models (immune-compromised), demonstrating broad applicability and therapeutic potential across different tumor microenvironments.
• Low Toxicity: Comprehensive analysis revealed no significant off-target effects in normal tissues, affirming the safety profile of the therapy.
• Histological Evidence: Tumor sections analyzed post-treatment showed a marked reduction in p32 expression, confirming effective targeting and elimination of cancerous cells and TDECs.

Patent
P32-SPECIFIC ANTIBODIES AND CAR T CELLS FOR THE TREATMENT OF P32 EXPRESSING TUMORS, PCT/IL2024/051167

Reference:
Rousso-Noori, L., Mastandrea, I., Talmor, S. et al. P32-specific CAR T cells with dual antitumor and antiangiogenic therapeutic potential in gliomas. Nat Commun 12, 3615 (2021)