Elucidation of Pelareorep Pharmacodynamics in A Phase I Trial in Patients with KRAS-Mutated Colorectal Cancer

Abstract

◥KRAS mutation is a negative predictive biomarker of anti-EGFR agents in patients with metastatic colorectal cancer (mCRC), and remains an elusive target. Pelareorep, a doublestranded RNA virus selectively replicates in KRAS-mutated cells, and is synergistic with irinotecan. A dose escalation trial of FOLFIRI/bevacizumab [irinotecan (150-180 mg/m 2 ) and pelareorep (1 Â 10 10 TCID 50 -3 Â 10 10 TCID 50 )] was implemented in adult patients with oxaliplatin refractory/intolerant, KRASmutant mCRC. Pelareorep was administered intravenously over 1 hour on days 1-5 every 4 weeks. Additional studies included pharmacokinetics, tumor morphology, and immune responses. Among FOLFIRI-na€ ve patients, the highest dose of FOLFIRI/ bevacizumab (180 mg/m 2 irinotecan) and pelareorep (3 Â 10 10 TCID 50 ) was well tolerated, without a dose-limiting toxicity. At the recommended phase II dose, 3 of 6 patients (50%) had a partial response; the median progression-free and overall survival (PFS, OS) were 65.6 weeks and 25.1 months, respectively. Toxicities included myelosuppression, fatigue, and diarrhea. Transmission electron microscopy revealed viral factories (viral collections forming vesicular structures), at various stages of development. Immunogold staining against viral capsid s-1 protein demonstrated viral "homing" in the tumor cells. The nucleus displayed sufficient euchromatin regions suggestive of active transcription. Flow cytometry revealed rapid dendritic cell maturation (48 hours) with subsequent activation of cytotoxic T cells (7 days). The combination of pelareorep with FOLFIRI/ bevacizumab is safe. The PFS and OS data are encouraging and deserve further exploration. Pelareorep leads to a clear recurrent immune stimulatory response with cytotoxic T-cell activation, and homes and replicates in the tumor.

Immune Characterization of Metastatic Colorectal Cancer Patients Post Reovirus Administration

“…By highlighting the ndings above, we encourage the further investigation of reovirus as a therapeutic adjuvant to standard of care therapy, in larger studies which can be appropriately powered to ultimately make de nitive statements regarding e cacy and safety. As of the writing of this paper, three out of six patients (50%) who received reovirus had a partial response and the median progression free survival (PFS) and overall survival (OS) were 65.5 weeks and 107.5 weeks, respectively [11]. The PFS and OS results are superior to historic data and the combination treatment was also safe and well tolerated [11].…”

“…As of the writing of this paper, three out of six patients (50%) who received reovirus had a partial response and the median progression free survival (PFS) and overall survival (OS) were 65.5 weeks and 107.5 weeks, respectively [11]. The PFS and OS results are superior to historic data and the combination treatment was also safe and well tolerated [11]. Thus, administration of reovirus in mCRC patients with KRAS positive mutations represents an important step forward in treatment.…”

“…After rinsing in distilled water and TBS successively, sections were incubated with rabbit polyclonal Granzyme B (Thermo sher Scienti c # PA5-13518) at 4°C for 2 hours [11]. Finally, the sections were covered with streptavidin peroxidase (Dako, Santa Barbara, CA) diluted 1:100 in PBS, incubated for 30 min at 37°C, washed three times in PBS and stained with 3,3'-diaminobenzidine as a substrate for the peroxidase for approximately 30 min at 37°C.…”

“…Reovirus (a naturally occurring, ubiquitous double stranded (ds) RNA virus) has been shown to preferentially replicate in and be cytopathic to transformed cells possessing an activated KRAS-signaling pathway [7], demonstrate in vivo activity in CRC cell-line models [8], and have synergistic activity with irinotecan in KRAS-mutated CRC cell lines and xenograft models [9,10,11]. In the current paper, we examined the immunomodulatory effects of reovirus across genomic, protein and immune cell distribution levels, as part of a phase 1 clinical study of mCRC patients with KRAS mutations receiving FOLFIRI and bevacizumab treatment.…”

Immune characterization of metastatic colorectal cancer patients post reovirus administration

“…Reovirus (a naturally occurring, ubiquitous double stranded (ds) RNA virus) has been shown to preferentially replicate in and be cytopathic to transformed cells possessing an activated KRAS-signaling pathway [7], demonstrate in vivo activity in CRC cell-line models [8], and have synergistic activity with irinotecan in KRASmutated CRC cell lines and xenograft models [9][10][11]. In the current paper, we examined the immunomodulatory effects of reovirus across genomic, protein and immune cell distribution levels, as part of a phase 1 clinical study of mCRC patients with KRAS mutations receiving FOL-FIRI and bevacizumab treatment.…”