Safety and efficacy of an oncolytic viral strategy using bortezomib with ICE/R in relapsed/refractory HIV-positive lymphomas

Abstract

HIV-associated lymphomas (HALs) have high rates of latent infection by gammaherpesviruses (GHVs). We hypothesized that proteasome inhibition would induce lytic activation of GHVs and inhibit HIV infectivity via preservation of cytidine deaminase APOBEC3G, improving lymphoma control. We tested this oncolytic and antiviral strategy by using bortezomib combined with ifosfamide, carboplatin, and etoposide (ICE) alone or with rituximab (ICE/R) in relapsed/refractory HAL. A 3+3 dose-escalation design was used with a 7-day lead-in period of single-agent bortezomib. Bortezomib was administered intravenously on days 1 and 8 of each cycle at 1 of 4 dose levels: 0.7, 1.0, 1.3, or 1.5 mg/m2 ICE began day 8 of cycle 1 and day 1 of subsequent cycles. Rituximab was included on day 1 of cycles 2 to 6 for CD20+ lymphomas. Twenty-three patients were enrolled. The maximum tolerated dose of bortezomib was not reached. Grade 4 toxicities attributable to bortezomib were limited to myelosuppression. Responses occurred in 17 (77%) of 22 patients receiving any protocol therapy. The 1-year overall survival was 57%. After bortezomib alone, both patients with Kaposi sarcoma herpesvirus (KSHV)-positive lymphoma had more than a 1-log increase in KSHV viral load. In 12 patients with Epstein-Barr virus (EBV)-positive lymphoma, median values of EBV viral load increased. Undetectable HIV viremia at baseline in the majority of patients limited evaluation of HIV inhibition. APOBEC3G levels increased in 75% of evaluable patients. Bortezomib combined with ICE/R in patients with relapsed/refractory HAL is feasible with response and survival comparing favorably against previously reported second-line therapies. Changes in GHV viral loads and APOBEC3G levels trended as hypothesized. This trial was registered at www.clinicaltrials.gov as #NCT00598169.

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Figures

Graphical abstract

Figure 1.

PBMC KSHV viral load change in patients with PEL. More than 1 log-increase occurred in PBMC KSHV viral load after bortezomib administration in the 2 patients with KSHV-positive PEL, both of whom achieved a response to protocol therapy (1 CR, 1 PR).

Figure 2.

Plasma HIV viral load change in patients not receiving ART. Three patients not already undergoing ART at enrollment did not start ART until completion of protocol therapy. Plasma HIV viral load data during cycle 1 are plotted here for each patient, demonstrating a downward trend as hypothesized in 2 of the 3 patients throughout the first week of protocol therapy, during which patients received single-agent bortezomib.

Figure 3.

APOBEC3G levels increased in 75% of evaluable patients after bortezomib administration. APOBEC3G was measured by using western blot on PBMC from 12 patients. (A) PBMCs from both baseline and day 8 were lysed, and proteins were separated by using sodium dodecyl sulfate/polyacrylamide gel electrophoresis. Gel lanes were reordered in the figure to group according to bortezomib dose level. (B) APOBEC3G level was quantified by using ImageJ software (National Institutes of Health, Bethesda, MD), and the results are presented as a fold change in the level of APOBEC3G normalized to actin.