Cancer-Lucky Dip Flashcards
Describe the process of generating a TCR specific to a tumor-associated antigen.
The process involves isolating T cells from a patient’s blood, screening them for reactivity against tumor-associated antigens, and then cloning the TCR genes from the reactive T cells. These genes can then be engineered into other T cells to generate a population of tumor-specific T cells.
What are the advantages of using non-viral CRISPR gene editing for CAR T cell manufacturing?
Non-viral CRISPR editing offers several advantages, including reduced risk of insertional mutagenesis, increased efficiency of gene knockout and knock-in, and simplified manufacturing processes. This allows for more precise and scalable production of CAR T cells with desired genetic modifications.
Explain the concept of tumor heterogeneity and its relevance to cancer therapy.
Tumor heterogeneity refers to the genetic and phenotypic diversity within a tumor. This diversity can lead to resistance to therapies as subclones with advantageous mutations may survive treatment and drive relapse.
How does dN/dS analysis contribute to understanding the selective pressures on cancer genes?
dN/dS analysis compares the rate of non-synonymous (amino acid-changing) to synonymous mutations in a gene. A high dN/dS ratio suggests positive selection, indicating the gene is under selective pressure to evolve and may be involved in tumor development or progression.
What role does IL-4 play in the exhaustion of CAR T cells?
IL-4, a cytokine associated with Th2 immune responses, can contribute to CAR T cell exhaustion by inducing the expression of inhibitory receptors and promoting a less effective anti-tumor response. This highlights the importance of understanding the tumor microenvironment and its impact on CAR T cell functionality.
What are the potential benefits of combining neoantigen-specific TCR T cell therapy with IL-2 administration?
IL-2 can enhance the proliferation and survival of neoantigen-specific TCR T cells, potentially improving their persistence and anti-tumor activity. This combination therapy aims to boost the immune response against tumor cells expressing specific neoantigens.
Explain the significance of phylogenetic signal analysis in studying tumor evolution.
Phylogenetic signal analysis investigates whether closely related tumor cells in a phylogenetic tree tend to have similar gene expression patterns. A strong phylogenetic signal suggests that gene expression is influenced by the evolutionary history of the tumor, providing insights into tumor evolution and potential therapeutic targets.
What are some of the limitations of current dN/dS analysis methods in characterizing cancer gene evolution?
Limitations include difficulties in accounting for subclonal mutations and variations in mutation rates across different regions of the genome. These challenges can lead to inaccurate dN/dS estimates and hinder the identification of truly significant evolutionary events in cancer genes.
Describe the role of HLA typing in personalized TCR T cell therapy.
HLA typing determines the specific HLA alleles expressed by an individual. This information is crucial for selecting TCRs that can bind to the patient’s HLA molecules presenting tumor-associated antigens. HLA matching ensures that the engineered T cells can effectively recognize and target tumor cells.
Discuss the ethical considerations associated with using CRISPR technology for human gene editing.
Ethical considerations include potential off-target effects, unintended consequences of germline editing, and equitable access to these therapies. Public discourse and robust ethical guidelines are necessary to ensure responsible development and application of CRISPR
What is adoptive T cell transfer and how is it used in cancer treatment?
Adoptive T cell transfer is a type of immunotherapy that involves collecting and modifying a patient’s own T cells to enhance their ability to recognize and attack cancer cells. These modified T cells are then expanded in the lab and infused back into the patient to boost their immune response against the tumor.
How can T cells be engineered to target specific cancer mutations?
T cells can be engineered to recognize specific cancer mutations through the use of T cell receptors (TCRs). TCRs are proteins on the surface of T cells that bind to specific antigens, such as mutated proteins expressed by cancer cells. Researchers can identify TCRs that recognize these cancer-specific antigens and then use gene editing techniques, like CRISPR, to introduce these TCR genes into a patient’s T cells. This allows the engineered T cells to specifically target and destroy cancer cells expressing those mutations.
What are some challenges associated with developing T cell therapies for cancer?
Identifying suitable targets: Not all cancer mutations produce antigens that are effectively recognized by T cells.
Off-target effects: Engineered T cells may attack healthy tissues that express similar antigens to the targeted cancer cells.
T cell exhaustion: T cells can become exhausted and lose their ability to kill cancer cells over time, especially in the presence of immunosuppressive factors within the tumor microenvironment.
Manufacturing complexity: The process of collecting, modifying, expanding, and infusing T cells is complex and expensive.
What is the role of IL-4 in T cell exhaustion?
IL-4, a cytokine associated with allergic responses and Th2 differentiation, has been shown to contribute to T cell exhaustion in the context of cancer immunotherapy. Chronic exposure to IL-4 can induce phenotypic and functional changes in engineered T cells, including reduced cytokine production, decreased killing capacity, and altered gene expression profiles, leading to diminished anti-tumor activity.
How does the spatial distribution of tumor cells and their mutations impact metastasis?
The spatial distribution of tumor cells and their mutations within the primary tumor plays a crucial role in metastasis. Studies have shown that subclones with specific mutations may be localized to certain regions of the tumor. Subclones in regions that readily shed cells into the circulation are more likely to metastasize. The genetic makeup of these seeding clusters may confer advantages in survival and growth at distant sites.
How can we study the evolutionary dynamics of cancer cells and their spread?
Multi-region sequencing: Sequencing DNA from different areas of a tumor to identify subclones and track their mutations over time.
Phylogenetic analysis: Reconstructing the evolutionary relationships between subclones to understand how they have diversified and spread.
Spatial modeling: Using computational models to simulate tumor growth and predict patterns of metastasis based on factors like mutation rates and selective pressures.
What is the significance of dN/dS ratios in understanding cancer evolution?
dN/dS is the ratio of non-synonymous (amino-acid changing) to synonymous (silent) mutations in a gene. Elevated dN/dS ratios indicate positive selection pressure, meaning mutations in those genes provide a survival advantage to the cancer cell. Analyzing dN/dS ratios in different subclones can reveal genes important for metastasis or therapy resistance.
What are the potential benefits of personalizing T cell therapies based on a patient’s tumor mutations?
Increased specificity: Targeting patient-specific mutations minimizes the risk of off-target effects on healthy tissues.
Enhanced efficacy: T cells engineered to recognize unique tumor antigens may be more effective at eliminating cancer cells.
Potential for long-lasting immunity: By targeting multiple mutations, personalized therapies could prevent tumor relapse by eliminating subclones that may have developed resistance to previous treatments.
