In this discussion with Bobby Reddy, Chief Medical Officer of ImmunityBio, we delve into the innovative immunotherapy strategies targeting non-small cell lung cancer (NSCLC). Reddy discusses the promising combination of ANKTIVA’s IL-15 super agonist with tislelizumab PD-1 inhibition, aimed at reactivating immune responses in patients resistant to prior therapies. This conversation explores the mechanisms, clinical trials, and future directions of this groundbreaking approach, offering a glimpse into the potential transformation of cancer treatment.
Moe: How does ANKTIVA’s IL-15 super agonist with tislelizumab PD-1 inhibition synergize to reactivate immune responses in resistant NSCLC patients?
The combination addresses T cell exhaustion, a common issue in patients who have lost response to checkpoint inhibitors. ANKTIVA’s IL-15 super agonist activates and proliferates NK cells, CD8 positive T cells, and memory T cells, reinvigorating the immune response. This is crucial because, in cancer, T cells can become exhausted, similar to what we see in infectious diseases. By activating these cells, we can potentially restore the immune response, vital for patients with developed resistance. In our trials, we’ve seen that this approach can lead to meaningful extensions in survival, as evidenced by our 14.1-month overall survival data in NSCLC patients. This is particularly significant given the recent high-profile failures in similar trials targeting other pathways, such as TIGIT and LAG-3, highlighting our focus on enhancing the host’s immune response.
Moe: What biomarkers or clinical characteristics identify NSCLC patients who might benefit most from this combination therapy?
Interestingly, we focus not on specific tumor phenotypes but on the patient’s immune response. For instance, PDL1 status doesn’t significantly impact outcomes in our trials. We’re exploring other biomarkers, such as MHC loss, a known immune escape mechanism. Enriching NK cells could be a critical factor, and we’re collecting blood samples in our trials to investigate these aspects further. Our approach is to look at the host’s immune system holistically, which could lead to a more universal therapy applicable to a broader range of patients, regardless of their tumor’s genetic makeup. This strategy aligns with our goal of developing treatments that are not only effective but also widely applicable, addressing the diverse needs of the cancer patient population.
Moe: How does the efficacy of this combination compare to existing second and third-line NSCLC treatments in terms of survival and quality of life?
Our data shows a 14.1-month overall survival, which is promising compared to the 7-8 months typically seen with standard treatments like docetaxel. Importantly, our therapy doesn’t carry the severe side effects associated with chemotherapy, such as neutropenia and hair loss. This makes it a potentially more attractive option for patients, offering a better quality of life while extending survival. In recent trials, other therapies have struggled to demonstrate significant improvements, often due to targeting “passenger” alterations rather than enhancing the immune system’s capacity. Our approach, which avoids the severe toxicities of chemotherapy, could redefine the standard of care for patients who have exhausted other options.
Moe: What are the potential risks and adverse events with ANKTIVA and tislelizumab, and how will the trial design address these safety concerns?
We’ve observed mild, self-limiting local cutaneous reactions and low-grade flu-like symptoms but no severe cytokine release syndrome. Importantly, we haven’t seen an increased rate of immune-related adverse events compared to checkpoint inhibitors alone. Our trial design includes rigorous monitoring to ensure patient safety and effectively manage adverse effects. This safety profile is particularly encouraging because it suggests we can enhance the immune response without significantly increasing the risk of adverse events, a common concern with combination therapies. By focusing on the host’s immune system, we aim to provide a treatment that is effective and well-tolerated, improving the overall patient experience.
Moe: What regulatory challenges do you anticipate for the BLA submission in 2025, and how might the Rescue 21201A trial outcomes influence approval?
We’ve had positive discussions with the FDA, who encouraged us to file based on our promising data. The ongoing confirmatory trial will provide additional support, potentially facilitating an accelerated approval. The regulatory agencies recognize the unmet need in NSCLC, especially for patients progressing after checkpoint inhibitors, and our trial aims to address this gap. By demonstrating safety and efficacy, we hope to meet the regulatory requirements and bring this innovative therapy to patients desperately needing new options. Our collaboration with regulatory bodies ensures we can navigate the approval process efficiently and effectively.
Moe: If successful, how might this combination therapy influence future research and development of immunotherapies for other resistant cancers?
Success with this combination could pave the way for more personalized and multi-faceted treatment approaches. Understanding the biology of resistance and leveraging combination therapies, including cell therapies and targeted agents, could lead to significant advancements in treating various cancers. We aim to achieve long-term disease control and potential cures by enhancing the host’s immune response. This approach could revolutionize how we think about cancer treatment, moving beyond a one-size-fits-all model to more tailored therapies that address each patient’s unique needs. By focusing on the host’s immune system, we can develop strategies that are effective and adaptable to a wide range of cancers, offering hope to patients who have exhausted other options.
Moe: Is there anything else you’d like to add?
We’re excited about our partnership with BeiGene and the potential of tislelizumab. Our holistic approach focuses on the host’s immune response rather than excluding patients with driver mutations. This inclusivity could lead to broader applicability and better outcomes for patients who have exhausted other treatment options. By considering the host’s immune system as a whole, we aim to develop therapies that are effective and widely applicable, addressing the diverse needs of the cancer patient population. This strategy aligns with our goal of providing innovative solutions that can make a real difference in patients’ lives.
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.
