ABSTRACT

Cancer treatment entered a new era in 1990 when the first approved gene therapy was administered. Over 100 gene therapy or gene transfer trials had been approved in North America since 1994. Most of these trials utilize disabled retroviral vectors to permanently integrate genetic material into germ cell lines. In contrast adenoviral vectors transiently introduce foreign DNA to target cells. Adenoviral vectors offer several advantages over other gene delivery systems.
The Toronto Hospital received approval from Bureau of Biologics Health Protection Branch, Ottawa, Canada and the U of T Research Administration to commence clinical trials of adenoviral mediated gene transfer of interlukin-2 for metastatic breast cancer and melanoma in 1996. The Infection Control Unit was asked to assist in the development of guidelines to prevent transmission of wild type adenovirus to the patient and to prevent spread of inadvertently generated replication in competent ADCAIL-2 to staff and visitors. A review of the protocol indicated that the adenoviral vector, ADCAIL-2 is injected directly to a single tumor nodule by a trial physician. Multiple injection sites may also be administered to a single tumor using small volumes of ADCAIL-2 at each site. The presence of adenovirus is monitored by direct viral cultures and by PCR assay for viral sequences from the tumor, blood, stool, urine, and throat.
Given this background we developed the following guidelines: 1) Hospital staff who provide direct patient care are required to be screened for adenovirus antibodies, 2) antibody negative hospital staff are excluded from patient care, 3) the patient is isolated in a negative pressure room for 3 days prior to infection of ADCAIL-2, 4) staff and visitors suffering from an upper respiratory tract infection or known adenoviral conjunctivitis or undiagnosed conjunctivitis are not allowed to enter the isolation room, 5) barrier precautions include the use of masks, gloves, gowns and good handwashing, 6) the patient is required to wear a mask when out of the room.
Gene therapy is new and rapidly evolving. Benefits of gene therapy in the treatment of incurable malignancies are not known. As clinical trials with gene therapy increases and experience is gained with respect to the risk of transfer of replication incompetent adenovirus to staff, the infection control guidelines will be updated to reflect progress in this area.


INTRODUCTION

TheToronto Hospital, a 1200 bed tertiary care medical school affiliated health care facility, was given approval from the U of T Research Administration and the Bureau of Biologics, Health Protection Branch, Ottawa, Canada to proceed with clinical trials of a phase 1/11 study of adenoviral mediated gene transfer of interlukin-2 in metastatic breast cancer melanoma in 1996. Gene therapy is the process of insertion of one or more genes into a cell genome for specific therapeutic purposes. Most of these trials utilize disabled retroviral vectors to permanently integrate genetic material into germ line cells. In contrast adenoviral vectors transiently introduce foreign DNA to a target cell.

OBJECTIVES
The use of gene therapy transfer in clinical trials raises considerable concern about patient and health care workers safety. For this reason the Infection Control Unit was asked to assist in the development of infection control guidelines for gene therapy. The objectives of these guidelines are:

1. To prevent transmission of wild type adenovirus to patients
   
2. To prevent spread of inadvertently generatedreplication competent ADCAIL-2 to staff and visitors
   

Reusable equipment placed in blue box and sent to CPD for decontamination

MONITORING PROCEDURES
- Clinical & Microbiologic

Patients with advanced incurable metastatic malignant melanoma and metastatic breast cancer are enrolled in clinical trials. Adenoviral vector, ADCAIL-2, is injected into a single tumor nodule by a research physician. Multiple injection sites can be administered to a single tumor using small volumes at each site. Inflammation and tissue damage at the injection site is closely monitored. Patient remains in hospital for 48 hours after injection and precautions at home for at least 10 days after ADCAIL-2 injection. Cultures for adenovirus are performed on the tumor, blood, stool urine and throat swab samples, if cultures are negative precautions are discontinued. Tumor response and evidence of resolution/regression are also monitored.

CLINICAL TRIALS

Over a period of 2 years, 30 patients with breast cancer or melanoma will be injected with escalating doses of adenoviral vector ADCAIL-2. A small sample of the tumor is obtained so that comparison can be made after treatment to prove that the adenovirus did indeed infect cancer cells.

DISCUSSION

Gene therapy may not be the answer to cancer treatment but may provide a basis to develop more effective therapies for the future. As clinical trial data increases, experience is gained with respect to the risks of spread of replication incompetent adenovirus and guidelines may have to be modified/updated to reflect new data related to gene therapy. It is important to realize that very little information is available about this new form of therapy and the infection control guidelines developed were based on underlying principles.

REFERENCES

1. Rosenberg SA. Gene therapy for cancer. JAMA 1992;268:2418-19.
   
2. Rosenberg SA, Aebersold PM, Cornetta K, Kasid A, Morgan RA, Moen R, et al. Gene transfer into humans: Immunotherapy of patients with advanced melanoma using tumor-infiltrating lymphocytes modified by retroviral gene transduction. New Eng J Med 1990;323:570-78.
   
3. Wheeler, VS. Preparing nurses for clinical trials: The cancer centre approach. Seminars in Oncology Nursing 1991;7:275-9.
   
4. Kozarsky K, Wilson JM. Gene therapy: Adenovirus vectors. Current Opinion in Genetics & Development 1993;3:499-503.
   
   

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