Multicenter Phase I Study of Repeated Intratumoral Delivery of Adenoviral p53 in Patients With Advanced Non–Small-Cell Lung Cancer

Abstract

Multiple courses of intratumoral Ad5CMV-p53 injection alone or in combination with intravenous administration of cisplatin were feasible and well tolerated in advanced NSCLC patients, and appeared to provide clinical benefit.

WTp53 induction does not override MTp53 chemoresistance and radioresistance due to gain-of-function in lung cancer cells

“…When taken together, these results suggest that a therapeutic maneuver that solely reintroduces WTp53 expression (e.g., adenoviral WTp53 therapies) on a MTp53 background may not necessarily overcome MTp53-mediated resistance. This could explain suboptimal responses in some patients using adenoviral WTp53 therapy in clinical trials (31,33). Clinical trials are awaited for compounds, such as PRIMA-1 (34), which can revert MTp53 back into a WTp53 conformation (as monotherapy or an adjunct to radiotherapy and chemotherapy) to determine their relative efficacy as p53-targeting agents.…”

“…These therapies have been suggested as novel monotherapies or as relative sensitizers when used in combination with chemotherapy and radiotherapy in several cancers (31,33,34). Whether this maneuver is successful may depend on whether WTp53 function can override independent MTp53 effects [e.g., gain-of-function (GOF)] with respect to the cellular sensitivity to DNAdamaging agents (35).…”

Characterization of the adaptive and innate immune response to intravenous oncolytic reovirus (Dearing type 3) during a phase I clinical trial

“…For example, intracranial and intralesional delivery (sites of relative immune privilege) may result in a different response to systemic intravenous administration. 17,18 However, for oncolytic agents to find a meaningful role in the treatment of advanced cancers, it is likely that they will need to be used in a systemic setting.…”

Molecular mediators of cell death in multistep carcinogenesis: a path to targeted therapy

“…The results of these and ongoing clinical trials will ultimately determine the optimal clinical context of p53 replacement gene therapy. 97 One of the limitations in the use of replication-defective viral delivery systems is that the virus must infect individual tumor cells to induce an effect. The use of replication-competent viral vectors can solve this problem, but, to spare normal cells, the importance of tumor selectivity becomes even more critical.…”