David Kirn

An Adenovirus Mutant That Replicates Selectively in p53- Deficient Human Tumor Cells

The human adenovirus E1B gene encodes a 55-kilodalton protein that inactivates the cellular tumor suppressor protein p53. Here it is shown that a mutant adenovirus that does not express this viral protein can replicate in and lyse p53-deficient human tumor cells but not cells with functional p53. Ectopic expression of the 55-kilodalton EIB protein in the latter cells rendered them sensitive to infection with the mutant virus. Injection of the mutant virus into p53-deficient human cervical carcinomas grown in nude mice caused a significant reduction in tumor size and caused complete regression of 60 percent of the tumors. These data raise the possibility that mutant adenoviruses can be used to treat certain human tumors.

Replicating viruses as selective cancer therapeutics

Replication-competent viruses are used as selective cancer therapeutics and the mechanisms leading to tumor-specific replication and antitumoral efficacy are now becoming apparent. The specific viruses in development include tumor-targeting herpes simplex viruses, autonomous parvoviruses, Newcastle disease viruses and adenovirus. Information is also available on antiviral immunology and viral defenses against host-mediated immunity. This approach has many potential attributes, in addition to potential hurdles that must be overcome.

Efficient induction of apoptosis by ONYX-015 adenovirus in human colon cancer cell lines regardless of p53 status.

The ONYX-015 virus is a mutated adenovirus that in theory selectively replicates and induces cytolysis in tumor cells lacking functional p53. The present study investigated whether ONYX-015 viral infection alone or in combination with conventional chemotherapeutic agents could significantly increase apoptosis in human colon cancer cell lines, regardless of p53 status, compared to untreated cells. A pair of colon cancer cell lines that differ only in their p53 status (RKO with wild-type p53 and RKOp53 with deficient p53) was tested. Two chemotherapeutic agents, 5-fluorouracil (5-FU) and CPT-11, were tested in combination with ONYX-015. Final concentrations of these agents corresponded to peak plasma levels achievable in patients. ONYX-015 concentration was 10 p.f.u./cell. In RKO and RKOp53 cell lines, ONYX-015 viral infection alone or in combination with 5-FU or CPT-11 induced a significant increase in apoptosis compared to chemotherapeutic agents alone, regardless of p53 status. Moreover, the combination of ONYX-015 and chemotherapeutics induced more apoptosis than chemotherapeutics alone in the two colon cancer cell lines independently of their p53 status. We conclude that ONYX-015 virus infection alone or in combination with 5-FU or CPT-11 induced apoptosis in human colon cancer cell lines, independently of p53 status.

Induction of an oncogenic fusion protein by a viral gene--a new chapter in an old story.

A combination of 19th century cytology and 20th century molecular biology has uncovered a previously unknown mechanism by which viruses may contribute to carcinogenesis (pages 1076–1079).

A Phase II Trial of Intratumoral Injection with a Selectively Replicating Adenovirus (ONYX-015) in Patients with Recurrent, Refractory Squamous Cell Carcinoma of the Head and Neck.

Selectively replicating viruses may offer a new approach to cancer treatment. If successful in clinical trials, these agents will constitute a new category in the antitumoral armamentarium. Many viruses are currently being studied, and an adenovirus (ONYX-015) first entered clinical trials in 1996; herpesvirus agents are scheduled to enter clinical trials in 1998. Critical issues need to be addressed if the utility of these agents is to be optimized. For each virus, the effect of antiviral immunity on antitumoral efficacy must be better understood. For all viruses, physical barriers to spread within tumors (e.g., fibrosis, pressure gradients) must be overcome. Although proof-of-concept experiments with chemotherapy and ONYX-015 have been encouraging, further studies are required to determine optimal treatment-regimen sequencing. Combination studies with radiation therapy are also underway with ONYX-015. Finally, these agents may require modification (e.g., coat modification) in order to maximize effectiveness against systemic metastases following intravenous administration.

The Candidates Speak: At the invitation of Science, President Bill Clinton and Senator Bob Dole have responded to a series of questions regarding science policy

An Adenovirus Mutant That Replicates Selectively in p53- Deficient Human Tumor Cells The human adenovirus E1B gene encodes a 55-kilodalton protein that inactivates the cellular tumor suppressor protein p53. Here it is shown that a mutant adenovirus that does not express this viral protein can replicate in and lyse p53-deficient human tumor cells but not cells with functional p53. Ectopic expression of the 55-kilodalton EIB protein in the latter cells rendered them sensitive to infection with the mutant virus. Injection of the mutant virus into p53-deficient human cervical carcinomas grown in nude mice caused a significant reduction in tumor size and caused complete regression of 60 percent of the tumors. These data raise the possibility that mutant adenoviruses can be used to treat certain human tumors.

Pulmonary aspergillosis masquerading as progressive post-transplant lymphoma.

We report a patient with post-transplant lymphoma who was treated by renal allograft nephrectomy, discontinuation of immunosuppressive therapy, and initiation of acyclovir administration. Despite these measures he appeared to have progressive lymphoma. Had a biopsy and cultures not been done, the diagnosis of aspergillosis would have been missed and the patient might have been treated with chemotherapy, with a potentially lethal outcome. Data from the Cincinnati Transplant Tumor Registry indicate that of 662 patients treated for post-transplant lymphoma, 277 patients died of cancer and 137 died of other causes, of which infection was a major factor. This case emphasizes the importance of proper work-up of patients with apparently progressive lymphomas.