Oncolytic virotherapy, an innovative approach, explores using modified viruses to selectively target and destroy cancer cells while sparing healthy tissues. This article updates the progress of using a modified polio virus in cancer treatment.
Polio Virus as a Cancer Fighter
The modified polio virus used in this therapy, known as PVSRIPO (now called lerapolturev), is a genetically altered version of the Sabin type 1 live-attenuated poliovirus vaccine. Its genetic modification involves replacing a part of the poliovirus genome with a segment from human rhinovirus type 2, making it non-pathogenic to normal nerve cells.
This engineered virus is designed to specifically target cancer cells, primarily by recognizing a protein called CD155, which is often overexpressed on the surface of many tumor cells. Upon entering a cancer cell, PVSRIPO replicates extensively, causing the cell to burst and release new virus particles. This direct destruction of cancer cells is a key mechanism of its action.
Beyond direct cell killing, the virus also stimulates the patient’s immune system to recognize and attack the tumor. As infected cancer cells die, they release tumor-associated antigens and other signals that alert the immune system. This process can lead to a robust anti-tumor immune response, where the body’s own defenses are mobilized against the cancer. The virus is engineered to be “neuron-incompetent,” meaning it does not effectively replicate in or harm normal nerve cells, which is crucial for its safety profile.
Current Status and Clinical Progress
The modified poliovirus therapy, lerapolturev, has advanced through various stages of clinical trials. Over 200 patients have received this investigational immunotherapy across multiple solid tumor types. Current research includes several ongoing Phase 2 trials to evaluate its safety and efficacy in different cancers.
Recurrent glioblastoma (rGBM), an aggressive brain tumor, has been a primary focus of these trials. Lerapolturev is administered directly into the tumor through a process called convection-enhanced delivery (CED). Phase 2 studies are actively recruiting patients with rGBM, often combining lerapolturev with an immune checkpoint inhibitor called pembrolizumab to potentially enhance the anti-tumor response.
Beyond brain tumors, the therapy is also being investigated in advanced melanoma and muscle-invasive bladder cancer (MIBC). A Phase 1 study in unresectable melanoma showed promising results, leading to a Phase 2 trial that is also exploring combination with pembrolizumab. Additionally, permission has been granted by the FDA to initiate a clinical protocol for MIBC, where lerapolturev will be administered with or without pembrolizumab.
The therapy has received several designations from the U.S. Food and Drug Administration (FDA), including Breakthrough Therapy Designation and Orphan Drug status for recurrent glioblastoma and advanced melanoma. [1, 2, 4_search_results] It also received Fast Track status for advanced melanoma patients who have progressed after anti-PD-1/L1 therapy. [1, 4_search_results] These designations expedite the development and review process for promising new treatments. [1_search_results]
Patient Experiences and Outcomes
In a Phase 1 trial involving 61 adult patients with recurrent glioblastoma, the overall survival rate at 24 and 36 months was 21%, which compares favorably to historical control groups that showed 14% at 24 months and 4% at 36 months. [4_search_results, 1_search_results] Some patients in this trial achieved remarkable long-term survival, with three individuals surviving beyond 60 months. [4_search_results]
In a Phase 1 study for recurrent, non-resectable melanoma, four out of twelve patients achieved either a partial or complete response. These responses were durable, with cancer control extending beyond 19 months after the last dose of the therapy. These outcomes indicate that the treatment can lead to sustained control of the disease in some individuals.
Regarding side effects, events were generally mild to moderate and attributed to localized inflammation within the tumor. For glioblastoma patients, common side effects included headaches (52%), pyramidal tract syndrome (50%), seizures (45%), dysphasia (28%), and cognitive disturbance (25%). [4_search_results, 3_search_results] Low-dose bevacizumab was sometimes used to help manage the inflammation and associated side effects. [1_search_results] One notable patient, Stephanie Hopper, who was the first to receive the poliovirus therapy for glioblastoma, survived for eight years after her treatment. [2_search_results]
Availability and Future Directions
Lerapolturev is not widely available outside of clinical trials and has not received full marketing approval from the U.S. Food and Drug Administration. The FDA designations, such as Breakthrough Therapy and Orphan Drug status, facilitate an accelerated development and review pathway but do not signify approval for commercial availability. [5_search_results]
Ongoing Phase 2 trials are expanding to include more patients and investigate the therapy in additional cancer types, such as pediatric brain tumors and breast cancer. [1_search_results, 4_search_results] A significant area of future research involves combining lerapolturev with other existing cancer treatments, particularly immune checkpoint inhibitors. [1, 2, 3_search_results]
Further studies will aim to understand optimal dosing, treatment schedules, and patient selection to maximize its efficacy and safety across a broader spectrum of solid tumors.