Colorectal cancer (CRC) is a leading cause of cancer deaths globally. Advances in early detection have improved survival rates, but patients diagnosed with metastatic CRC still have stubbornly poor 5-year survival rates. Standard treatments for CRC include surgery, chemotherapy, and radiotherapy, but alternative immuno-oncology therapies are showing promising results in CRC patients. Here we highlight advances in immuno-oncology therapies that are being used to treat CRC patients or are being pursued in preclinical and clinical studies.
The management and treatment of patients with chronic lymphocytic leukemia (CLL) has improved greatly in recent years due to new insights in genetic and molecular factors that contribute to disease progression. Clinical staging systems were first developed more than 40 years ago and include the Rai system, which is based on the presence of lymphocytosis (at least 5,000 mm3 monoclonal lymphocytes), enlargement of lymph nodes, spleen or liver, and changes in red blood cells and platelets. The Binet staging system is an alternative method based on the number of affect lymphoid tissue groups and the occurrence of thrombocytopenia and anemia. The Rai system is more common used in the United States, whereas the Binet system is used more frequently in Europe.
A wide range of mouse models are currently available to researchers working on the preclinical development of oncology therapeutics. Syngeneic mouse models, also known as allograft mouse tumor models, are mice engrafted with mouse-derived cancer cell lines. These mice have an intact murine immune system and thus are appealing for proof-of-concept immuno-oncology studies. However, one limitation of traditional syngeneic models is that they are not suitable for human-specific therapies. To overcome this, scientists have developed genetically engineered mice that express human immune targets, such as PD-1, PD-L1, CTLA4 and OX40, in an otherwise immunocompetent model. Tumor cell lines have been developed that also express immune checkpoint molecules, which can have a significant effect on the efficacy of potential immune checkpoint inhibitors being evaluated.
Chronic lymphocytic leukemia (CLL) is one of the most common forms of adult leukemia, and its chronic nature has made it a challenging blood cancer to completely cure. CLL affects B cells and is typically classified into two categories: little or no somatic hypermutation in the immunoglobulin heavy chain variable region (IGHV), called unmutated CLL, or high mutation levels in the IGHV gene, called mutated CLL. Unmutated CLL is associated with more aggressive disease than mutated CLL, and the presence of these abnormal IGHV sequences, which is a part of the B cell receptor (BCR), leads to abnormal BCR signaling and the uncontrolled proliferation of these leukemic cells.
Clinical flow cytometry is now a standard tool used by clinical researchers in numerous fields, especially immuno-oncology. Consider these “Do’s & Don’ts” of clinical flow cytometry as you decide to use this tool for clinical research.
Advances in oncology research have led to the development of personalized treatments based on specific knowledge of a patient’s tumor. New therapies have been customized to target signaling pathways that are hyperactivated or block specific variants of cell surface molecules, thus leading to better anti-tumor responses. Next generation sequencing (NGS) technology has been at the forefront of these breakthroughs by enabling researchers to rapidly sequence RNA transcripts (RNA-seq) or exons (whole exome sequencing; WES) within tumor tissue and translate these findings into novel therapies.
DNA damage is one of the primary triggers of cancer development and has been linked to many types of cancers, including prostate, stomach, liver and skin cancers as well as leukemia. Within cells, the DNA sequence encodes all the instructions required for building proteins that are needed for cellular functions such as metabolism, replication, tissue and organ maintenance. The fidelity of the DNA sequence in a cell is maintained by multiple mechanisms but errors and mutations can occur, which sets off a chain of events that lead to tumor growth.
Advances in precision medicine have transformed treatments for many types of solid tumors, but similar treatment options have been more limited for hematologic oncology. Now, new ex vivo models are being developed that use patient-derived lymphoma or leukemia cells for screening experimental drugs or biologics. Therapeutic antibody screening is well-suited to these platforms and can inform preclinical research decisions as well as clinical care.
In vivo models for numerous diseases and conditions have endpoints that have involved animals being gravely ill or dying. As researchers have sought to utilize animal models in more humane and practical ways, surrogate endpoints have been developed that prevent animals from suffering and provide critical research data. Flow cytometry has been instrumental to these advances. Consider these aspects of preclinical flow cytometry endpoint analysis as you develop new protocols.