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Vascular targeted photodynamic therapy with TOOKAD-from local ablation to systemic cancer treatment
Background:
Local therapies that allow for safe ablation of primary lesions and trigger anti-tumor immunity with minimal side effects, may be particularly effective in management of early-stage cancer. Vascular-targeted photodynamic therapy (VTP) with TOOKAD®, recently granted EMA approval as a first-line treatment for localized prostate cancer, has been shown by us to also trigger anti-tumor immunity. Our recent preclinical and current clinical studies aim to test the hypothesis that synchronizing TOOKAD®VTP with immune-modulation that attenuates the pro-tumor immunity, will result in systemic micrometastases annihilation and a high cure rate.
Methods:
4T1-Luc, adenosquamous JA and Met-Lu cells were orthotopically grafted in the mammary pad, esophagus and prostate of immune-competent mice and rats, respectively. Seven days postgrafting, tumors were treated with TOOKAD®VTP, with or without immune-modulators. Immune profiles were examined by 10-X genomics, FACS analysis and immunohistochemistry. Animal survival and lung and lower abdomen metastases counts were followed up for 3 months. Clinical protocols were composed based on the preclinical data and utilized in the clinical studies that will be described in other lectures of this session.
Results:
TOOKAD®VTP triggered anti-tumor immunity sufficient to achieve 60-90% cure in various cancer models. However, primary lesion annihilation did not prevent disease progression in the more aggressive cancers such as 4T1-Luc breast cancer. TOOKAD®VTP synchronized with metronomic administration of immune-modulators was associated with a 60-90% disease-free animals and resistance to re-challenge. The rate of success was highly pending on the exact synchronization of the immune modulating agents with the VTP timing. The required modulators match the deciphered immune profiles. This combined immuno-VTP therapy concept has been translated to clinical trials currently ongoing at Memorial Sloan Kettering Cancer Center.
Conclusion:
Application of TOOKAD®VTP to localized tumors combined with immune modulation appears to provide novel means to treat early disseminated cancers.
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