In this conversation, we engage with Dr. Thomas Heineman, Chief Medical Officer of Oncolytics Biotech, to explore the innovative cancer treatment, pelareorep (pela). This proprietary oncolytic virus is making waves in the field of immuno-oncology, particularly in breast and pancreatic cancers. Dr. Heineman shares insights into pela’s unique mechanisms, administration, and potential to redefine therapeutic strategies and improve patient outcomes.
Moe: Pela reshapes tumors from cold to hot. Can you explain the biological mechanism and how it compares to other immunotherapy approaches?
Thomas Heineman: Pela is a non-genetically modified reovirus that selectively infects cancer cells, sparing normal tissue. Unlike most oncolytic viruses requiring direct tumor inoculation, pela is administered intravenously, enhancing its reach to both primary and metastatic sites. This method simplifies dosing and broadens its therapeutic impact. The double-stranded RNA of pela is recognized by pattern recognition receptors in cancer cells, leading to an upregulation of interferon expression and pro-inflammatory cytokines. This cascade recruits T, natural killer, and dendritic cells, fostering innate and adaptive immune responses. Additionally, pela stimulates the expansion of
tumor-infiltrating lymphocyte clones in the blood, enhancing their ability to attack the tumor. This dual action of modifying the tumor microenvironment and expanding immune cell populations sets pela apart from other immunotherapies, offering a comprehensive approach to tumor eradication.
Moe: How does IV administration of pela affect biodistribution and tumor selectivity, and what are its efficacy and safety implications?
Thomas Heineman: The intravenous administration of pela is a significant advancement, allowing for safe, convenient dosing without the need for special biohazard precautions. This method enhances effectiveness by delivering pela to primary and metastatic tumor sites and lymph nodes, stimulating antiviral T-cell responses. This capability supports the expansion and proliferation of anti-tumor T cells, which is crucial for its anti-tumor effect. The ability to reach lymph nodes is critical, as it facilitates the generation of new antiviral T-cell responses that bolster the anti-tumor immune response. This aspect of pela’s administration broadens its therapeutic reach and enhances its safety profile, making it a versatile option for various cancer types.
Moe: In the BRACELET-1 study, how does pela enhance paclitaxel’s effectiveness in HR-positive HER2-negative metastatic breast cancer?
Thomas Heineman: The BRACELET-1 study, which combined pela with paclitaxel, revealed a strong clinical signal, underscoring pela’s potential in enhancing chemotherapy efficacy. Pela stimulated the expansion of T cell populations and indirectly expanded tumor-infiltrating lymphocyte clones, a key element of its immunologic effect. This expansion is crucial, as it directly correlates with improved clinical outcomes. In the study, patients receiving paclitaxel alone performed as expected, but those receiving the combination with pela showed significant T-cell expansion and a robust clinical efficacy signal, almost doubling median PFS, from 6.4 to 12.1 months and increasing median OS by almost 80%, from 18.2 months to an estimated 32.1 months. This direct link between immunologic effects and clinical response highlights pela’s potential to transform standard chemotherapy regimens, offering a more effective treatment strategy for patients with advanced breast cancer.
Moe: What potential biomarkers could predict response to pela in combination with checkpoint inhibitors, as seen in the GOBLET study?
Thomas Heineman: Pela’s ability to increase PDL1 expression forms the basis for its synergy with checkpoint inhibitors, as demonstrated in the GOBLET study. While no specific biomarkers are required for patient selection, potential biomarkers like tumor-infiltrating lymphocyte clonal expansion could serve as on-treatment indicators. This approach is speculative but consistent with existing data, suggesting it might be valuable in future studies. The ability to predict response through biomarkers would enhance patient selection and treatment personalization, maximizing therapeutic outcomes and minimizing unnecessary exposure to ineffective treatments.
Moe: What are the key considerations in designing registration-enabling studies for pela, especially in patient selection and study endpoints?
Thomas Heineman: In HR-positive HER2-negative breast cancer, pela has shown pronounced benefits, particularly in patients with advanced or metastatic disease who have progressed on prior therapies. The treatment path for these patients is complex, with a need for better options for post-antibody drug conjugate therapy. Pela’s broad mechanism of action allows it to treat a range of patients without requiring specific genetic markers, making it a versatile option in the evolving immuno-oncology landscape. The challenge lies in designing studies capturing this broad applicability while ensuring robust endpoints demonstrating clinical benefit. The ability to address unmet needs in this patient population positions pela as a promising candidate for registration-enabling studies.
Moe: How does pela’s mechanism compare to other oncolytic viruses, and what unique advantages or limitations does it present?
Thomas Heineman: Pela’s intravenous delivery and non-genetically modified nature set it apart from other oncolytic viruses. It naturally targets cancer cells and stimulates immune responses without genetic manipulation. Pela’s ability to expand tumor-infiltrating lymphocyte populations is a powerful differentiator, enabling it to make the tumor accessible to the immune system and attack it effectively. This dual capability offers a unique advantage in combination immunotherapy strategies, as it enhances the overall immune response while maintaining a broad applicability across different cancer types. The absence of genetic modification also simplifies its clinical use, reducing regulatory hurdles and expanding its potential reach in oncology.
Moe: Is there anything else you want to add about pela’s potential and future directions?
Thomas Heineman: We focus on breast and pancreatic cancer programs, but pela has broad potential applicability. We’re exploring its use in earlier stages of breast cancer and combination with CAR T therapy for solid tumors. Pela’s potential extends beyond current applications, and we look forward to expanding our development in these directions. The versatility and efficacy of pela position it as a promising candidate for future cancer therapies, with the potential to significantly impact patient outcomes across a range of malignancies.
Moe Alsumidaie is Chief Editor of The Clinical Trial Vanguard. Moe holds decades of experience in the clinical trials industry. Moe also serves as Head of Research at CliniBiz and Chief Data Scientist at Annex Clinical Corporation.
