Georgetown University Medical Center,
Keywords: SGT-53, tumor targeting nano-medicine, clinical studies, immunotherapy, glioblastoma
Summary:The clinical potential immune checkpoint inhibitors targeting PD-1 has been demonstrated in a number of tumor types, and anti-PD-1 antibodies are now approved for several indications. However, results from immunotherapy trials with patients having recurrent glioblastoma multiforme (GBM) have been disappointing thus far. To overcome the unresponsiveness of GBM and other brain tumors, strategies combining checkpoint inhibitors with other treatment modalities are being explored that aim to alter the immunosuppressive microenvironment that appears to characterize these tumors. We have demonstrated that introducing functional p53 gene via a tumor-targeting nanocomplex can improve tumor response and overcome resistance to anti-PD-1 by converting immunologically ‘cold’ tumors into ‘hot’ tumors. We have employed this investigational nanomedicine (termed SGT-53) in a number of syngeneic mouse tumor models. In addition to subcutaneous and intracranial GBM, we have studied syngeneic models for breast, lung, kidney and head & neck tumors. All of these tumors are relatively unresponsive to immune checkpoint inhibitors as monotherapy. Transcriptome analysis revealed modulation of a number of genes linked to either cancer progression (e.g., proliferation and invasion) or immune activation, (e.g., antigen presentation and T cell activation) in animals receiving SGT-53 plus an anti-PD-1 antibody. We have also observed a significant increase of GzmB-positive staining in tumors indicating increased infiltration of the tumors by cytotoxic T cells following the combination treatment. SGT-53 plus an anti-PD-1 antibody is more effective than either agent individually in inhibiting tumor growth, inducing tumor cell apoptosis, and recruiting T cells into the tumors. SGT-53 plus anti-PD-1 significantly lengthens the lifespan of mice bearing intracranial GBM. SGT-53 are currently being evaluated in several clinical Phase II studies. Collectively, our data provide a strong mechanistic rationale for combining SGT-53 and immune checkpoint blockade in a clinical trial involving GBM patients.