A Phase I Study of the Combination of Intravenous Reovirus Type 3 Dearing and Gemcitabine in Patients with Advanced Cancer

Abstract

Purpose: This study combined systemic administration of the oncolytic reovirus type 3 Dearing (reovirus) with chemotherapy in human subjects. We aimed to determine the safety and feasibility of combining reovirus administration with gemcitabine and to describe the effects of gemcitabine on the antireoviral immune response.Experimental Design: Patients received reovirus in various doses, initially we dosed for five consecutive days but this was poorly tolerated. We amended the protocol to administer a single dose and administered up to 3 Â 10 10 TCID 50 . Toxicity was assessed by monitoring of clinical and laboratory measurements. We assessed antibody response by cytotoxicity neutralization assay.Results: Sixteen patients received 47 cycles of reovirus. The two initial patients and one patient in the final cohort experienced dose limiting toxicity (DLT). The DLTs consisted of two asymptomatic grade 3 liver enzyme rises and one asymptomatic grade 3 troponin I rise. Common toxicities consisted of known reovirus and gemcitabine associated side effects. Further analysis showed a potential interaction between reovirus and gemcitabine in causing liver enzyme rises. Grade 3 rises in liver enzymes were associated with concomitant aminocetophen use. Importantly, the duration of the liver enzyme rise was short and reversible. Neutralizing antibody responses to reovirus were attenuated both in time-to-occurrence and peak height of the response.Conclusions: Reovirus at the dose of 1 Â 10 10 TCID 50 can be safely combined with full dose gemcitabine.Combination of reovirus with gemcitabine affects the neutralizing antibody response and this could impact both safety and efficacy of this treatment schedule.

Reduction of Virion-Associated σ1 Fibers on Oncolytic Reovirus Variants Promotes Adaptation toward Tumorigenic Cells

“…During studies on basic reovirus biology, reovirus was discovered to possess an intrinsic specificity toward cancer cells over normal cells (11)(12)(13)(14)(15)(16)(17). Reovirus shows potent antitumor activity in a wide assortment of in vivo cancer models (18)(19)(20)(21)(22) and is being examined in numerous phase I/II and III human clinical trials (23)(24)(25)(26)(27)(28)(29)(30). All trials currently use the reovirus serotype 3 (T3) Dearing strain in its wild-type form (here referred to as T3wt).…”

Evolution of Reovirus in Cancer Therapy

“…[73] Through this study, the concluding recommended dose for this particular combination was as follows: reovirus 1×10 10 TCID 50 on day 1 and gemcitabine at 1,000 mg/m 2 on day 1 and day 8 of a 21-day cycle. Of the ten evaluable patients, one had a PR and a minor decrease in tumor size after just four cycles of therapy.…”

“…[69,71,78] However, the known toxicities of gemcitabine and reovirus were observed in one trial. [73] Lolkema et al concluded that since gemcitabine appears to have an inhibitory effect on the development of neutralizing antireoviral antibodies (NARAs), a chemotherapeutic regimen in combination with reovirusmay exacerbate reovirus toxicity in the liver and further elevate liver enzyme levels. [73] Key obstacles to reovirus oncotherapy With a total of 32 clinical trials (completed or ongoing) and continued progress in preclinical studies, reovirus therapy is well set to transition from "bench" to "bedside" for the treatment of a multitude of cancers.…”

Strategic Combinations: The Future of Oncolytic Virotherapy with Reovirus

“…Building off of preclinical work testing gemcitabine, the first combination reovirus chemotherapeutic clinical trial tested gemcitabine and REOLYSIN in 16 patients with advanced malignancies including head and neck, breast, cervical, and colorectal cancers (51). Of the 10 evaluable patients, 1 patient with metastatic nasopharyngeal carcinoma had a partial response whereas 6 other patients had stable disease for 4 to 8 treatment cycles.…”