First-in-Human Phase 1 Trial of Agarose Beads Containing Murine RENCA Cells in Advanced Solid Tumors

Abstract

PURPOSEAgarose macrobeads containing mouse renal adenocarcinoma cells (RMBs) release factors, suppressing the growth of cancer cells and prolonging survival in spontaneous or induced tumor animals, mediated, in part, by increased levels of myocyte-enhancing factor (MEF2D) via EGFR-and AKT-signaling pathways. The primary objective of this study was to determine the safety of RMBs in advanced, treatment-resistant metastatic cancers, and then its efficacy (survival), which is the secondary objective.METHODSThirty-one patients underwent up to four intraperitoneal implantations of RMBs (8 or 16 macrobeads/kg) via laparoscopy in this single-arm trial (FDA BB-IND 10091; NCT 00283075). Serial physical examinations, laboratory testing, and PET-CT imaging were performed before and three months after each implant.RESULTSRMBs were well tolerated at both dose levels (mean 660.9 per implant). AEs were (Grade 1/2) with no treatment-related SAEs.CONCLUSIONThe data support the safety of RMB therapy in advanced-malignancy patients, and the preliminary evidence for their potential efficacy is encouraging. A Phase 2 efficacy trial is ongoing.

A comprehensive microbiological safety approach for agarose encapsulated porcine islets intended for clinical trials

“…The procedural risks are well known and, although real, are modest. We have been implanting cancer macrobeads (encapsulated mouse renal adenocarcinoma cells) to treat patients with various malignancies for 10 years without adverse events attributable to the macrobeads either as an intraperitoneal irritant or as a microbiological hazard . See also ClinicalTrials.gov Identifiers NCT00283075, NCT01053013, and NCT02046174.…”

A model for determining an effective in vivo dose of transplanted islets based on in vitro insulin secretion

“…It is important to note, however, that porcine insulin has been reported to have 20 to 40 times lower efficacy for restoring euglycaemia in rodents relative to humans. While our experience in clinical trials with similarly‐sized agarose macrobeads for cancer therapy indicates that a 4× or larger macrobead dose could be easily accommodated in the human abdomen, porcine islet macrobeads may be more efficacious in human recipients than in the BBDP rat, thus requiring a lower dosage ratio.…”

“…Error bars (standard deviation) have been omitted to avoid obscuring the means: 3× Females: ±18 (n = 6), ±30 (n = 4), ±103 (n = 6) for the 1st, 2nd and 3rd month, respectively; 3× Males: ±18 (n = 5), ±88 (n = 3), ±78 (n = 6). BBDP, BioBreeding diabetes-prone rat agarose macrobeads for cancer therapy indicates that a 4× or larger macrobead dose could be easily accommodated in the human abdomen 14 , porcine islet macrobeads may be more efficacious in human recipients than in the BBDP rat, thus requiring a lower dosage ratio.…”

MEF2 plays a significant role in the tumor inhibitory mechanism of encapsulated RENCA cells via EGF receptor signaling in target tumor cells

“…It remains possible that the EGF receptor does not play a role in the inhibition of RENCA cells, but this appears unlikely given the definitive phosphorylation of the receptor in the presence of the macrobeads. The role of EGF receptor and the MEF2 family of transcription factors in the RENCA macrobead-induced growth inhibitory effect could also apply to in situ tumors of varying origins and genetic profiles; we have observed tumor marker changes, decreases in 18F-fluorodeoxyglucose uptake by the tumors, and tumor necrosis during Phase I clinical trials using RENCA macrobeads as a treatment for numerous tumors, including prostate, colorectal, and hepatocellular carcinoma, among others [ 33 ].…”

“…An understanding of the mechanisms of action of the cancer growth inhibition produced by the RENCA macrobeads is critical to optimizing the therapeutic potential of this novel treatment. Phase 1 and 2 trials have recently been completed for treatment-resistant metastatic colorectal cancer [ 33 – 35 ]. Patients in these trials received RENCA macrobeads via outpatient laparoscopic implantation into the abdominal cavity.…”