The field of oncology is experiencing a paradigm shift through the integration of liquid biopsies, which are non-invasive diagnostic methods that analyze circulating tumor DNA (ctDNA) in blood samples. These advanced technologies are transforming lung cancer care by allowing clinicians to detect genetic mutations, monitor disease progression, and assess treatment responses with molecular precision.
In a recent episode of “Lung Cancer Considered,” a podcast hosted by the International Association for the Study of Lung Cancer (IASLC), Dr. Stephen Liu interviewed liquid biopsy experts Dr. Valsamo (Elsa) Anagnostou and Dr. Umberto Malapelle about the evolving role of liquid biopsy in clinical practice. The discussion highlighted how this innovative approach is especially valuable for identifying actionable mutations that can guide the selection of targeted therapies. Compared to traditional tissue biopsies, liquid biopsy reduces procedural risks and allows for more frequent monitoring, enabling oncologists to detect treatment resistance in real time. Furthermore, the cost-effectiveness and accessibility of liquid biopsy render it a practical solution for ongoing patient care, minimizing the need for invasive procedures while delivering timely molecular insights. As we continue to refine these technologies, their integration into routine clinical workflows can improve outcomes for lung cancer patients worldwide.
Follow the [link] for the podcast episode to listen to the full conversation and gain deeper insights into the future of lung cancer diagnostics.
In this study, our group at the Johns Hopkins Kimmel Cancer Center demonstrated that a minimally invasive blood test effectively captures early responses to immunotherapy in patients with advanced lung cancer. By measuring circulating tumor DNA (ctDNA) levels, this liquid biopsy approach provides monitoring of therapy response with molecular precision and predicts survival. This advancement holds great potential for molecular response-adaptive treatment decision-making.
To gain a deeper insight, view the following video, “Capturing Immunotherapy Response in a Blood Drop”.
In a webinar hosted by Labroots, Dr. Anagnostou discussed cutting-edge advancements in diagnostics that enable precision oncology, focusing on the integration of circulating cell-free DNA (cfDNA) and matched white blood cell (WBC) analyses. This approach represents a significant advancement in the evaluation of circulating tumor DNA (ctDNA), providing improved sensitivity and specificity for assessing tumor dynamics and therapeutic responses.
The combined analysis of cfDNA and WBCs addresses a key challenge in liquid biopsy applications: distinguishing tumor-derived mutations from clonal hematopoiesis and other non-tumor genetic alterations. This method enhances the reliability of ctDNA assays by cross-referencing genomic alterations in plasma and matched WBCs, thereby reducing false-positive results. Using this method, clinicians can track molecular responses more accurately and identify new resistance mutations. With the ongoing advancements in liquid biopsy, this detailed analytical framework shows significant potential in providing non-invasive and real-time insights into tumor biology and its evolution under the selective pressure of treatment.
Listen to the full presentation and gain deeper insights into this innovative approach, by visiting this [link]
Significant advancements have been made in the therapeutic landscape of cancer, driven by the imperative to develop treatments for patients that are both effective and less toxic. Traditional therapeutic strategies like surgery, chemotherapy, and radiation therapy are generally effective but inherently limited by their lack of specificity regarding the molecular profile of tumors and collateral damage to healthy tissues. These constraints have spurred the pursuit of innovative approaches that leverage the body’s intrinsic defense mechanisms, collectively called immunotherapies. Immunotherapy activates the immune system to recognize and eradicate cancer cells and signifies a paradigm shift in oncology. By enhancing the body’s anti-tumor immune defense, immunotherapy has broadened the therapeutic arsenal and redefined the trajectory of cancer care, offering the potential for durable responses and improved patient outcomes.
The conceptual foundation of immunotherapy dates back over a century, with pioneering observations made by Dr. William Coley in the late 1800s. Coley noted tumor regression in patients with concurrent bacterial infections, suggesting that immune system activation could combat malignancies. Despite the initial promise, his methods, which involved administering bacterial toxins, lacked the mechanistic insights that modern science provides. Advances in immunology throughout the 20th century elucidated key components of the immune response, including T-cells and cytokines, and laid the groundwork for contemporary immunotherapeutic strategies. Checkpoint inhibitors emerged in the early 21st century; these block inhibitory pathways on T-cells that are a safety mechanism to prevent autoimmunity. Ipilimumab (which targets CTLA-4) and nivolumab/pembrolizumab (which target PD-1) showed that blocking immune checkpoints can reinvigorate anti-tumor immunity.
Immunotherapy encompasses several distinct modalities operating through different mechanisms. As mentioned above, checkpoint inhibitors disrupt inhibitory signals that cancer cells exploit to evade immune detection, thereby reinvigorating T-cell activity. Chimeric antigen receptor (CAR) T-cell therapy involves genetically engineering T-cells to express synthetic receptors that recognize tumor-specific antigens, enabling tumor clearance. Monoclonal antibodies bind to surface proteins on cancer cells, tagging them for destruction or blocking proliferative signaling. Cancer vaccines prime the immune system to recognize tumor-specific antigens, while cytokine therapies such as interleukin-2 and interferons amplify immune responses, enhancing tumor eradication.
Non-small cell lung cancer (NSCLC), the most common subtype of lung cancer, has experienced significant advancements due to immunotherapy. Drugs like pembrolizumab and nivolumab have become the standard of care, particularly for tumors with high PD-L1 expression. These therapies promote T-cell activation by disrupting the PD-1/PD-L1 axis, fostering more robust and sustained anti-tumor immune responses. Clinical trials have demonstrated that immunotherapy often surpasses chemotherapy in both efficacy and tolerability, representing a paradigm shift in the management of NSCLC.
Although immunotherapy has achieved notable successes, its effectiveness is inconsistent across all cases, making real-time monitoring of therapeutic responses essential for optimizing clinical outcomes. Traditional imaging techniques may fall short in promptly and accurately portraying therapeutic responses, especially in patients with heterogeneous responses or stable disease. Liquid biopsies have emerged as a minimally invasive alternative, analyzing circulating tumor DNA (ctDNA) molecules shed by tumor cells into the bloodstream. Longitudinal tracking of fluctuations in ctDNA levels enables clinicians to assess systemic tumor burden and treatment efficacy precisely. These approaches can elucidate the heterogeneity of immunotherapy responses and facilitate timely therapy modifications. Concurrently, monitoring T-cell activation and differentiation patterns provides insights into the immune system’s engagement, revealing proliferation, exhaustion, and memory formation markers correlating with differential therapeutic outcomes or the emergence of immune-related toxicities.
In conclusion, immunotherapy has redefined the field of oncology, harnessing the immune system to achieve targeted and durable anti-tumor responses. Its success is exemplified by breakthroughs in NSCLC treatment, where checkpoint inhibitors have improved clinical outcomes compared to traditional chemotherapy for many patients. However, timely and accurate capture of therapeutic response remains a challenge. Liquid biopsies and immune cell population profiling represent pivotal advancements in combating this challenge. Ongoing research is honing these technologies, enabling synergies between immunotherapy and real-time molecular monitoring of treatment response, ultimately leading to improved outcomes with precision immuno-oncology.
References:
Pardoll, D.M. (2012). The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews Cancer, 12(4), 252-264.
Topalian, S.L., et al. (2012). Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. New England Journal of Medicine, 366(26), 2443-2454.
Ribas, A., & Wolchok, J.D. (2018). Cancer immunotherapy using checkpoint blockade. Science, 359(6382), 1350-1355.
June, C.H., O’Connor, R.S., Kawalekar, O.U., Ghassemi, S., & Milone, M.C. (2018). CAR T cell immunotherapy for human cancer. Science, 359(6382), 1361-1365.
Aredo J.V. et al. Liquid Biopsy Approaches for Cancer Characterization, Residual Disease Detection, and Therapy Monitoring. Am Soc Clin Oncol Educ Book 45, e481114 (2025). DOI:10.1200/EDBK-25-481114
Anagnostou, V., Ho, C., Nicholas, G. et al. ctDNA response after pembrolizumab in non-small cell lung cancer: phase 2 adaptive trial results. Nat Med 29, 2559–2569 (2023). https://doi.org/10.1038/s41591-023-02598-9
