Over the last two decades, cancer treatment has dramatically changed. Much of this change has been driven by a molecular understanding of cancer and an increasing ability to apply this knowledge in a clinical setting. So, in addition to the tried and tested methods of treating cancer by surgery, chemotherapy, radiation therapy and targeted therapies, increasingly there are growing numbers of tumors for which treatment by Immuno-Oncology is becoming an option.
Among the novel cancer therapies that have recently entered into clinical practice, the class of so-called pd-1 inhibitors has become particularly noteworthy. These agents, which are used for the treatment of a variety of tumors, including selected cases of non-small cell lung cancer, act by releasing the brakes on T cells and thereby allowing them to carry out their function of killing tumor cells. The therapeutic use of these drugs underscores the importance of biomarker-driven treatment decisions, of a multidisciplinary team of oncologists and of an individualized therapeutic strategy.
This article explains how PD-1 inhibitor are revolutionizing the cancer treatment in modern oncology, how they work, where they are used right now and where they are expected to be used in the near future.
The Evolution of Cancer Treatment
The historic approach to treating cancer has typically focused on local control of the tumor using surgery and/or radiation, followed by systemic therapy with chemotherapy, when the cancer has become widespread. Since the late 1990s, advances in our understanding of the molecular and immune-based mechanisms by which tumors grow and metastasize have enabled new approaches to the treatment of cancer.
Immunotherapy such as immune checkpoint inhibitors has brought a new perspective to cancer treatment. Instead of directly attacking cancer cells, immunotherapy modifies the activity of the immune system. To induce an antitumor immune response, cancer cells are attacked by restoring function of T cells, which are suppressed by immune checkpoint pathways.
In summary, the model of cancer treatment that is currently evolving influences clinical decision making by several oncology specialties and allows for treatment of individual patients with cancer.
Understanding the PD-1 Pathway
Programmed Death-1 (PD-1) is an inhibitory receptor that is expressed on activated T cells. The interaction between PD-1 and its ligands, PD-L1 and PD-L2, plays a role in the down-regulation of immune responses and the maintenance of self-tolerance under normal homeostasis. Tumors exploit this immune checkpoint pathway and express PD-L1, in some cases even inducing expression in tumor cells themselves. This allows tumors to evade immune destruction.
Tumors can use this pathway to suppress anti-tumor immune responses. Many tumors express PD-L1 and, in some instances, tumors can also induce expression of PD-L1 in cells of the tumor microenvironment. The interactions between PD-1 and PD-L1 suppress T-cell activation, thus allowing tumors to evade immune destruction. A pd-1 inhibitor prevents the PD-1/PD-L1 interaction thereby enabling T cells to recognize and attack tumor cells. This mode of action is fundamentally different from that of most other cancer therapies including conventional cytotoxic chemotherapies and most molecularly targeted cancer therapies.
Clinical Applications Across Multiple Malignancies
PD-1 inhibitors are becoming an integral component in the treatment of various cancers based on clinical trial data and approval from regulatory health authorities.
Current clinical applications include selected patients with:
Use of immunotherapy in specific tumor types, stages, prior therapy, biomarker status and clinical guideline recommendations.
Biomarker-Driven Patient Selection
The treatment of cancer is increasingly based on a set of characteristics of individual tumors, which are often referred to as biomarkers.
Evaluation before initiating immunotherapy may include:
Biomarker assessment should be integrated with clinical information including histological assessment, imaging, clinical assessment of extent of disease, performance status and other relevant clinical information. Appropriate patient selection may help in benefit-risk assessments.
Integration Into Multimodal Cancer Care
In addition to advanced, metastatic disease, the role of PD-1 inhibitors is expanding into other clinical settings. Current treatment strategies may incorporate immunotherapy:
Multidisciplinary cancer management is increasingly being optimized by the addition of immunotherapy to treatment strategies.
Immune-Related Adverse Events
Treatment with immune checkpoint inhibitors may lead to immune-related adverse events due to immune system activation, which are different from the side effects associated with conventional chemotherapy.
Potential immune-related adverse events may involve:
Early recognition and evaluation of potential toxicity with appropriate management is key to minimizing the severity of potential immune-related adverse events occurring during treatment and after completion of therapy for patients receiving immunotherapy. Patient and family education, ongoing monitoring, and a multidisciplinary team approach can ensure proper management of patients with cancer.
The Importance of Multidisciplinary Collaboration
Immunotherapy is a treatment approach that is increasingly becoming a focus for several specialties. Comprehensive care may involve:
Effective communication among team members allows for the coordinated treatment of patients with cancer and allows for the management of treatment-related toxicity as well as long-term follow-up of patients.
Ongoing Research and Emerging Directions
Research involving PD-1 inhibitors is rapidly expanding into many other areas in Oncology.
Current investigations include:
However, clinical trials are ongoing and will hopefully in the future lead to further treatment options of different types of cancers at different stages of the disease.
Future Implications for Oncology Practice
Immunotherapy, specifically with the use of cancer treatments with immunological properties, has also significantly affected other areas of oncology. These include the diagnostic work-up of cancer patients, multidisciplinary cancer treatment, follow-up care of long-term cancer survivors and the supportive care of patients with cancer.
Future developments in molecular and translational research will be needed to better understand tumor immunology and allow for more accurate selection of patients for treatment with immunotherapies. These are expected to become more individualized and be based on the clinical, molecular and pathological features of the cancer in question.
Healthcare professionals will need to become familiar with emerging evidence, changing clinical guidelines and ongoing clinical trials to make appropriate patient-centered treatment decisions.
Closing Perspective
The introduction of the pd-1 inhibitor has impacted modern cancer treatment by broadening the spectrum of options offered by cancer immunotherapy to be applied to a variety of human cancers. The modulating of immune-checkpoint pathways by these compounds enables the development of novel approaches for the systemic treatment of human cancers. In addition, these compounds are intended for the treatment of patients selected on the basis of biomarkers for enduring clinical benefit in the context of concomitant treatment by multidisciplinary teams of healthcare professionals.
In the meantime, healthcare professionals can make sense of and apply the growing evidence base of PD-1 inhibitors. Understanding their biological basis and corresponding clinical applications including the key criteria for patient selection, as well as the typical toxicities and other current evidence will make up the core of modern oncology practice and evolving corresponding research.