Oncolytic reovirus preferentially induces apoptosis in <i>KRAS</i> mutant colorectal cancer cells, and synergizes with irinotecan

Maitra, Radhashree; Seetharam, Raviraja N.; Tesfa, Lydia; Augustine, Titto; Klampfer, Lidija; Coffey, Matthew; Mariadason, John M.; Goel, Sanjay

doi:10.18632/oncotarget.1921

Cited by 46 publications

(51 citation statements)

References 29 publications

(43 reference statements)

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“…Irinotecan has been shown to inhibit HSV-1 viral replication and lytic oncolysis in colon cancer cell lines 164. In contrast, other groups show synergy with OVs/irinotecan, including HSV-1 encoding CYP2B1,127 reovirus,128 and Sindbis virus 126. However, only the study on Sindbis virus looked at immune components in irinotecan synergy, concluding that natural killer cells are essential for the process 126…”

Section: Combining Chemotherapeutic Drugs With Ov Therapymentioning

confidence: 99%

Cancer immunotherapy via combining oncolytic virotherapy with chemotherapy: recent advances

Simpson¹,

Relph²,

Harrington³

et al. 2016

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Oncolytic viruses are multifunctional anticancer agents with huge clinical potential, and have recently passed the randomized Phase III clinical trial hurdle. Both wild-type and engineered viruses have been selected for targeting of specific cancers, to elicit cytotoxicity, and also to generate antitumor immunity. Single-agent oncolytic virotherapy treatments have resulted in modest effects in the clinic. There is increasing interest in their combination with cytotoxic agents, radiotherapy and immune-checkpoint inhibitors. Similarly to oncolytic viruses, the benefits of chemotherapeutic agents may be that they induce systemic antitumor immunity through the induction of immunogenic cell death of cancer cells. Combining these two treatment modalities has to date resulted in significant potential in vitro and in vivo synergies through various mechanisms without any apparent additional toxicities. Chemotherapy has been and will continue to be integral to the management of advanced cancers. This review therefore focuses on the potential for a number of common cytotoxic agents to be combined with clinically relevant oncolytic viruses. In many cases, this combined approach has already advanced to the clinical trial arena.

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Section: Combining Chemotherapeutic Drugs With Ov Therapymentioning

confidence: 99%

Cancer immunotherapy via combining oncolytic virotherapy with chemotherapy: recent advances

Simpson¹,

Relph²,

Harrington³

et al. 2016

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“…In EGFR‐, Sos‐, or ras ‐transformed cells, PKR is held in a nonphosphorylated state, and the replication of the reovirus proceeds uninhibited . The dependence of reovirus activity on activation or mutation of the Ras pathway may be indication‐specific …”

Section: Introductionmentioning

confidence: 99%

“…6 The dependence of reovirus activity on activation or mutation of the Ras pathway may be indicationspecific. 7,8 A reovirus administered with paclitaxel was synergistic in all NSCLC cell lines examined, including those with high-level resistance to paclitaxel or the reovirus. 9 Phase 1 clinical trials involving Reolysin dispensed as a monotherapy or in combination with gemcitabine, cyclophosphamide, docetaxel, or paclitaxel and carboplatin demonstrated its good tolerability as monotherapy (mild to moderate flulike symptoms and gastrointestinal symptoms were the major side effects) and a lack of exacerbation of the toxicities of the chemotherapeutic agents when it was given in combination.…”

Section: Introductionmentioning

confidence: 99%

Oncolytic reovirus in combination with chemotherapy in metastatic or recurrent non–small cell lung cancer patients with KRAS‐activated tumors

Villalona‐Calero

Lam

Otterson

et al. 2015

Cancer

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BACKGROUND The type 3 Dearing reovirus (Reolysin) is a naturally occurring virus that preferentially infects and causes oncolysis in tumor cells with a Ras-activated pathway. It induces host immunity and cell cycle arrest and acts synergistically with cytotoxic agents. METHODS This study evaluated Reolysin combined with paclitaxel and carboplatin in patients with metastatic/recurrent KRAS-mutated or epidermal growth factor receptor (EGFR)–mutated/amplified non–small cell lung cancer. RESULTS Thirty-seven patients were treated. Molecular alterations included 20 KRAS mutations, 10 EGFR amplifications, 3 EGFR mutations, and 4 BRAF-V600E mutations. In total, 242 cycles (median, 4; range, 1-47) were completed. The initial doses were area under the curve (AUC) 6 mg/mL/min for carboplatin, 200 mg/m2 for paclitaxel on day 1, and 3×1010 50% tissue culture infective dose for Reolysin on days 1 to 5 of each 21-day cycle. Because of diarrhea and febrile neutropenia (in the first 2 patients), subsequent doses were reduced to 175 mg/m2 for paclitaxel and AUC 5 mg/mL/min for carboplatin. Toxicities included fatigue, diarrhea, nausea/vomiting, neutropenia, arthralgia/myalgia, anorexia, and electrolyte abnormalities. Response Evaluation Criteria in Solid Tumors 1.0 responses included the following: partial response for 11 patients, stable disease (SD) for 20 patients, progressive disease for 4 patients, and not evaluable for 2 patients (objective response rate, 31%; 90% 1-sided lower confidence interval, 21%). Four SD patients had >40% positron emission tomography standardized uptake value reductions. The median progression-free survival, median overall survival, and 12-month overall survival rate were 4 months, 13.1 months, and 57%, respectively. Seven patients were alive after a median follow-up of 34.2 months; they included 2 patients without disease progression at 37 and 50 months. CONCLUSIONS Reolysin in combination with paclitaxel and carboplatin was well tolerated. The observed response rate suggests a benefit of the reovirus for chemotherapy. A follow-up randomized study is recommended. The proportion of patients surviving longer than 2 years (30%) suggests a second/third-line treatment effect or possibly the triggering of an immune response after tumor reovirus infiltration.

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“…As with the vast majority of cancer therapies, OVs are unlikely to be delivered alone but rather as part of a rationally designed, combination therapy regimen (Ottolino‐Perry et al., 2010). OVs have been combined with surgical resection (Acuna et al., 2014; Gholami et al., 2013; Nakano et al., 2005; Tai et al., 2013), radiation (Advani et al., 2012; Mansfield et al., 2013), and numerous chemotherapy drugs (Cherubini et al., 2011; Gutermann et al., 2006; Heinemann et al., 2011; Huang et al., 2011; Maitra et al., 2014; Takakura et al., 2010; Zaoui et al., 2012; Ziauddin et al., 2010) in preclinical models. Combination OV and chemotherapy studies have demonstrated that particular combinations can be highly synergistic in specific tumour models.…”

Section: Introductionmentioning

confidence: 99%

“…Other platinum‐based agents have also been shown to synergize with VV primarily through enhanced anti‐tumour immune responses (Song et al., 2007; Yu et al., 2009). While CPT‐11 has been demonstrated to interact synergistically with oncolytic herpes simplex virus (Gutermann et al., 2006), adenovirus (Cherubini et al., 2011) and reovirus (Maitra et al., 2014) its effect when combined with oncolytic VV is unknown.…”

Section: Introductionmentioning

confidence: 99%

Oncolytic vaccinia virus synergizes with irinotecan in colorectal cancer

et al. 2015

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Metastatic colorectal cancer (CRC) is complex clinical challenge for which there are limited treatment options. Chemotherapy with or without surgery provides moderate improvements in overall survival and quality of life; nevertheless the 5-year survival remains below 30%. Oncolytic vaccinia virus (VV) shows strong anti-tumour activity in models of CRC, however transient delays in disease progression are insufficient to lead to long-term survival. Here we examined the efficacy of VV with oxaliplatin or SN-38 (active metabolite of irinotecan) in CRC cell lines in vitro and VV with irinotecan in an orthotopic model of metastatic CRC. Synergistic improvements in in vitro cell killing were observed in multiple cell lines. Combination therapy was well tolerated in tumour-bearing mice and the median survival was significantly increased relative to monotherapy despite a drug-dependent decrease in the mean tumour titer. Increased apoptosis following in vitro and in vivo combination therapy was observed. In vitro cell cycle analysis showed increases in S-phase cells following infection occurred in both infected and uninfected cell populations. This corresponded to a 4-fold greater increase in apoptosis in the uninfected compared to infected cells following combination therapy. Combination treatment strategies are among the best options for patients with advanced cancers. VV is currently under clinical investigation in patients with CRC and the data presented here suggest that its combination with irinotecan may provide benefit to a subset of CRC patients. Further, investigation of this combination is necessary to determine the tumour characteristics responsible for mediating synergy.

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Oncolytic reovirus preferentially induces apoptosis in KRAS mutant colorectal cancer cells, and synergizes with irinotecan

Cited by 46 publications

References 29 publications

Cancer immunotherapy via combining oncolytic virotherapy with chemotherapy: recent advances

Cancer immunotherapy via combining oncolytic virotherapy with chemotherapy: recent advances

Oncolytic reovirus in combination with chemotherapy in metastatic or recurrent non–small cell lung cancer patients with KRAS‐activated tumors

Oncolytic vaccinia virus synergizes with irinotecan in colorectal cancer

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