Gene Therapy in Oncology
Summary of Key Points
Recent Advances in Gene Therapy
Ideal Vector Attributes
• Can be targeted either physically or via promoter expression and is nontoxic, noninflammatory, and nonimmunogenic
• Should have the potential to incorporate a large transgene and result in high levels of both transduction and transgene expression
• Duration of transgene expression and/or genomic integration ought to be regulatable
1. What toxicity issue has been observed with retroviral vectors?
A Integration into the host genome and development of leukemia
B Development of inflammatory responses to the vector
C Recombination and formation of a replication-competent virus
2. Which of the following can be considered a positive attribute of retroviral vectors?
A Permanent integration of the transgene into the cellular genome
B Induction of an inflammatory response
3. What can be considered a positive attribute for adenoviral vectors?
A Transient expression of the transgene
B High levels of transduction and transgene transcription
4. Which clinical studies have shown curative therapeutic activity in the majority of patients treated?
A Intratumoral administration of adenoviral vectors with the p53 transgene in patients with head and neck cancer
B Vaccinia vectors with antigenic transgenes as a vaccine for the treatment of colon cancer
C Retroviral vectors delivering the Il-2Rγ transgene to the cellular genome in the treatment of severe combined immunodeficiency
5. Which of the following attributes can be considered a positive aspect for gene therapies using naked DNA?
A Permanent integration of the transgene into the genome
B Minimal to no inflammatory response to the vector
6. Which of the following could be considered a positive attribute for lentiviral vectors?
1. Answer: A. When 10 individuals with x-linked severe combined immunodeficiency were treated by gene transfer to restore the missing IL-2Rγ gene to hematopoietic stem cells using retroviral vectors, treatment was successful in 9 of the 10 patients. However, leukemia developed in four of the nine successfully treated patients several years after gene therapy.
2. Answer: A. Transgenes delivered by retroviral vectors to proliferating cells will integrate the transgene into the cellular genome. This attribute contrasts with other vectors, which have a transient transgene expression.
3. Answer: D. Adenoviral vectors introduce a transient transgene expression typically with high levels of transduction and transgene transcription. In addition, adenoviruses have a broad range of cellular targets. Thus the most appropriate answer would be all of the above.
4. Answer: C. Retroviral vector delivery of the IL-2Rγ or adenosine deaminase has shown a curative response in the majority of patients treated. Intratumoral administration of adenoviral vectors with the p53 transgene, although approved for clinical use in China, has not shown curative activity in the majority of patients. Vaccinia vectors with antigenic transgenes, such as carcinoembryonic antigen, which have been used as a vaccine in the treatment of colon cancer, have provided encouraging results but not curative activity.
5. Answer: B. Naked DNA, or plasmid DNA, whether given alone or with a carrier formulation, rarely results in permanent integration of the transgene, and relative to most viral vectors, do not introduce high levels of transduction or transcription. However, in contrast to many of the viral vectors, which induce a high level of inflammatory response, the naked DNA vectors introduce minimal to no inflammatory response.
6. Answer: D. Lentiviral vectors integrate the transgene into the host genome, and unlike other vectors, can integrate the transgene in the absence of cellular proliferation, making them the vector of choice for transgene delivery to hematopoietic stem cells. In addition, inflammatory response to lentiviral vectors, compared with adenoviral or vaccinia vectors, is relatively minimal. Thus the correct answer would be all of the above.
