Direct and indirect antitumor effects by human peripheral blood lymphocytes expressing both chimeric immune receptor and interleukin-2 in ovarian cancer xenograft model

Abstract

Human peripheral blood lymphocytes (PBLs) electroporated with RNA encoding anti-Her-2/neu-specific chimeric immune receptor (CIR) have been reported to elicit potent immune responses against SKOV3 tumors in a nude mouse model. However, CIRelectroporated PBL (CIR-PBL) did not proliferate, and the cell number rapidly decreased in the absence of exogenous interleukin-2 (IL-2). In this study, PBLs electroporated with both CIR and IL-2 RNA (CIR/IL-2-PBL) were studied to determine whether antitumor effects could be improved by adoptive immunotherapy. CIR and IL-2 were expressed in CIR/IL-2-PBL at levels similar to PBLs electroporated, with IL-2 RNA (IL-2-PBL) or CIR-PBL. Transfer of IL-2 RNA induced proliferation and prolonged survival of PBLs in vitro. In a xenograft model, both IL-2-PBL and CIR/IL-2-PBL showed significantly higher antitumor effects than CIR-PBL. The number of tumor-infiltrating natural killer (NK) cells was significantly increased in IL-2-PBL and CIR/IL-2-PBL. After NK cell depletion, IL-2-PBL showed significantly lower antitumor effects than CIR/IL-2-PBL. These results suggest that transfer of IL-2 RNA to CIR-PBL can promote NK cell infiltration of tumors and prolong survival of infused PBLs in vivo. RNA electroporated PBLs may represent efficient tools for delivery of functional molecules to tumors by multiple gene transfer.

Immune Therapy for Ovarian Cancer: Promise and Pitfalls

“…At 35 months median follow-up survival was potentially better than historical controls, suggesting possible efficacy, which was corroborated by a longer-term survival analysis in 2000 [49]. More recent trials of intraperitoneal 90 yttrium-labeled HMFG1 suggest that, whereas it can control local (intraperitoneal) disease, distant relapses could offset any overall survival benefits. Nonetheless, the potential to control intraperitoneal disease could be exploited further [27].…”

“…Follow-up studies testing additional antibodies continued to establish the relative safety of this approach and continued to identify occasional long-term clinical responses [46]. A phase II trial using 90 yttrium-labeled HMFG1 failed to demonstrate significant clinical benefits in 25 patients, and dose-escalation was eventually limited by myelosuppression [47].…”

“…A later phase I/II trial using 90 yttrium-labeled HMFG1 in 52 patients tested efficacy in standard-of-care surgery plus chemotherapy at initial OC diagnosis, followed by intraperitoneal antibody installation [48]. The treatment was well tolerated and 21 of these patients had no detectable disease at the end of therapy.…”

“…[90]. Interleukin-2 production attracting or activating natural killer cells that help reject tumor is a potential mechanism of action.…”

Recombinant messenger RNA technology and its application in cancer immunotherapy, transcript replacement therapies, pluripotent stem cell induction, and beyond

“…Most importantly, the mRNA‐transfected T cells show antigen‐specific effector functions including secretion of cytokines and selective lysis of antigen‐expressing target cells. Furthermore, potent antitumor responses have been reported in animal models for leukemia, mesothelioma, and ovarian cancer . Accordingly, a first phase I clinical trial for the treatment of patients with malignant pleural mesothelioma has been reported .…”