Table 2.
Summary of oncolytic virus use in phase I clinical trials.
| Trial Name | Virus | Cancer | n | Administration, Adverse Events, Study Conclusions |
|---|---|---|---|---|
| Potential for efficacy of the oncolytic Herpes simplex virus 1716 in patients with oral squamous cell carcinoma [50] (Mace 2008). | HSV1716 | Oral squamous cell carcinoma | 20 | Study used intratumoral injection of HSV 1716; no reportable AE, but no detectable viral replication or effective oncolysis. Study of higher doses required. |
| Intratumoral injection of HSV1716, an oncolytic herpes virus, is safe and shows evidence of immune response and viral replication in young cancer patients [51] (Streby 2017). | HSV1716 | Pediatric extracranial cancers | 9 | Study used intratumoral injection of HSV1716; no major AE: mild constitutional symptoms (fever, chills, cyotopenia) reported. No clinical responses seen by RECIST criteria but viral replication was detected, and signs of inflammatory response was seen on PET/CT. |
| A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor [52] (Hu 2006). | OncoVEXGM–CSF (Herpes Virus JS1/34·5-/47-/GM-CSF) | Breast, head and neck, GI, melanoma | 30 | Study used intratumoral injection at different dose levels in 30 patients. AEs: fever, and injection site reaction. Three patients with SD. Some evidence of tumor necrosis was seen on biopsy which was strongly positive for HSV. |
| A phase 1 trial of oncolytic HSV-1, G207, given in combination with radiation for recurrent GBM demonstrates safety and radiographic responses [53] (Markert 2014). | G207 (HSV-1) | GBM | 9 | Intratumoral injection of G207 given 24 h prior to radiation. 67% with SD or PR. 3 patients with measurable response to radiation. No HSV encephalitis occurred. |
| A herpes oncolytic virus can be delivered via the vasculature to produce biologic changes in human colorectal cancer [54] (Fong 2009). | NV1020 | Metastatic colon cancer in liver previously refractory to chemotherapy (5 FU and leucovorin) | 12 | Study used IV injection of NV1020 into the hepatic artery. CEA levels dropped in patients, and one patient saw 75% reduction of tumor volume. Study reports 7 with SD, 3 with PD, 2 patients with reduction in tumor size at 28 days. Subsequent chemotherapy was hepatic artery injection of floxuridine with dexamethasone. All patients had PR. Results confounded by varying systemic chemotherapy regimens (7 had irinotecan, 2 with oxaliplatin and 3 got both). |
| Intradermal injection of Newcastle disease virus-modified autologous melanoma cell lysate and interleukin-2 for adjuvant treatment of melanoma patients with resectable stage III disease [55] (Voit 2003). | Newcastle disease virus (modified with autologous melanoma cell lysate and IL-2) | Melanoma | 29 | Double blind study with placebo or viral injection after resection of melanoma. No clinical efficacy demonstrated. |
| Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers [56] (Pecora 2002). | PV701 (Newcastle virus) | Advanced solid cancers | 79 | Patients with advanced solid cancers refractory to traditional therapies were divided into 4 groups of differing dosing schedules (single and multiple dosing schedules). Virus was administered via IV. 62 patients were available for assessment with 1 PR and 1 CR. AE included fever, chills, nausea, hypotension. |
| A phase 1 clinical study of intravenous administration of PV701, an oncolytic virus, using two-step desensitization [57] (Laurie 2006). | PV701 (Newcastle virus) | Advanced solid tumors | 16 | Previous studies (citation) demonstrated that patients could tolerate a much higher dose of the virus if they were desensitized first, so this study executed a two-step desensitization. Minimal constitutional symptoms reported, that decreased with subsequent doses. Symptoms were also less severe than in previous studies. Study reports, 1 tumor regression, and 4 SD. |
| An optimized clinical regimen for the oncolytic virus PV701 [58] (Hotte 2007). | PV701 (Newcastle virus) | Advanced cancers | 18 | Study used IV infusions of PV701 at a slow rate. Decreasing the infusion rate allowed patients to receive higher doses of the virus, with fewer AE (particularly decreased constitutional symptoms) and minimized infusion site reaction. Study reports 1 CR, 3 PR, 2 with minor response, and 5 with SD. |
| Phase I trial of cyclophosphamide as an immune modulator for optimizing oncolytic reovirus delivery to solid tumors [59] (Roulstone 2015). | RT3D (Reovirus Type 3 Dearing) | Advanced solid tumors | 36 | Study used combination cyclophosphamide and RT3D (intravenously) to decrease neutralizing antibodies to the virus. While it was well tolerated, it did not reduce NARA (neutralizing antireovirus antibody) titer. |
| A phase I study of the combination of intravenous reovirus type 3 Dearing and gemcitabine in patients with advanced cancer [60] (Lolkema 2011). | RT3D (Reovirus Type 3 Dearing) | advanced solid cancers | 16 | First study to combine IV Reovirus with chemotherapy. AE were similar to previous studies with fever, nausea/vomiting, and chills. Protocol revised because there were grade 3 rises in LFTs (but these patients were also taking acetaminophen.) Reovirus may exacerbate gemcitabine-related liver toxicity. Clinical response was best in a patient with nasopharyngeal cancer, but OR minimal. |
| A phase I study of intravenous oncolytic reovirus type 3 Dearing in patients with advanced cancer [61] (Vidal 2008). | RT3D (Reovirus Type 3 Dearing) | Advanced cancers | 36 | Patients received escalating doses of IV Reovirus. There were no dose limiting toxicities, but some grade 1–2 flu-like symptoms were reported and were dose dependent. Some antitumor activity was observed by monitoring serum tumor marker levels, but not by RECIST criteria. Neutralizing Ab were detected in all patients |
| A phase I trial of intratumoral administration of reovirus in patients with histologically confirmed recurrent malignant gliomas [62] (Forsyth 2008). | Reolysin | Recurrent malignant gliomas | 12 | Study used intratumoral injection of reovirus with escalating doses. No grade 3–4 adverse events. Study reported 1 SD, 10 with PD. (1 was unable to be evaluated) |
| Two-stage phase I dose-escalation study of intratumoral reovirus type 3 dearing and palliative radiotherapy in patients with advanced cancers [63] (Harrington 2010) | Reolysin | Advanced solid cancers open to palliative radiation | 23 | Protocol used escalating doses of radiotherapy followed by intratumoral injections of RT3D. AE included flu-like symptoms (grade 2 or less) as well as neutropenia and lymphopenia. Low dose group had 2 with PR and 5 with SD, and in the high dose group 5/7 had PR and 2/7 with SD. No viral shedding seen in bodily fluids. |
| REO-10: a phase I study of intravenous reovirus and docetaxel in patients with advanced cancer [64] (Comins 2010). | Reolysin | Advanced solid cancers | 16 | Study used IV Reolysin in combination with docetaxel chemotherapy. There was 1 CR, 3 PR, and 10 with SD. Overall 88% of patients had some degree of disease control. One grade 4 neutropenia was reported. |
| REO-001: A phase I trial of percutaneous intralesional administration of reovirus type 3 dearing (Reolysin®) in patients with advanced solid tumors [65] (Morris 2013). | Reolysin | Advanced solid tumors | 19 | Study used intra-lesional injection of virus and was well tolerated. Most reactions were grade 1–2, including malaise, and some erythema around injection site. Study reported 37% with local tumor response, including 1 CR, 3 PR, and 4 with SD. |
| A phase I trial of single-agent reolysin in patients with relapsed multiple myeloma [66] (Sborov 2014) | Reolysin | Multiple myeloma | 12 | Virus administered intravenously. No dose limiting AE reported but grade 3 AE included hypophosphatemia, thrombocytopenia, and neutropenia. While the virus did replicate in MM cells, there was little viral protein recovered from cells. Researchers concluded it could work as part of a combination therapy, but not as monotherapy. |
| Phase 1 clinical trial of intratumoral reovirus infusion for the treatment of recurrent malignant gliomas in adults [67] (Kicielinski 2014) | Reolysin | Malignant glioma | 15 | Study used intratumoral injection. This was a dose finding study (previous study established safety). No MTD or dose limiting toxicity identified. Adverse effects related to underlying cancer, such as seizure, convulsions rather than virus. Study reported 1 PR, and a few with SD |
| A phase I trial and viral clearance study of reovirus (Reolysin) in children with relapsed or refractory extra-cranial solid tumors: a Children’s Oncology Group Phase I Consortium report [68] (Kolb 2015). | Reolysin | Extracranial solid tumors | 24 | Study used IV injection of Reolysin alone or with cyclophosphamide. No objective response to therapy, and only 1/3 of patients had a detectable viral load after 5 days; none did after 17 days. Study reports 1 grade 5 respiratory failure and 1 grade 5 thromboembolic event. |
| Recurrent glioblastoma treated with recombinant poliovirus [69] (Desjardins 2018) |
PVSRIPO (Polio Virus) |
Glioblastoma | 61 | Virus was injected intratumorally. Grade 4 ICH at the highest injection dose was the only dose-limiting toxicity. Survival rate was higher in those who received therapy as compared to historical controls, at both 24 and 36 months. |
| Immunological effects of low-dose cyclophosphamide in cancer patients treated with oncolytic adenovirus [70] (Cerullo 2011). | Ad5/3-(delta)24 | Advanced solid tumors resistant to chemotherapy | 21 | Study used intratumoral injection with adenovirus followed by cyclophosphamide treatment in different dosing groups. AE were mostly grade 1–2 constitutional symptoms. The one year PFS and OS was increased compared to traditional chemotherapy resistant cancers. Study reports 8/12 patients with RECIST response: 2 with MR, 6 with SD, and 4 with PD. |
| A phase I clinical trial of Ad5/3-Δ24, a novel serotype-chimeric, infectivity-enhanced, conditionally-replicative adenovirus (CRAd), in patients with recurrent ovarian cancer [71] (Kim 2013). | Ad5/3-(delta)24 | Ovarian Cancer | 9 | Study used intraperitoneal injection of the virus. AE were flu-like grade 1–2: fever/chills, myalgias, fatigue, and nausea. Study reported 3 patients with a decrease in CA-125 levels at 1 month. |
| A phase I study of a tropism-modified conditionally replicative adenovirus for recurrent malignant gynecologic diseases [72] (Kimball 2010). | Ad5/3-(delta)24 | Gynecologic malignancy | 21 | Study used intraperitoneal injection of virus. Reported grade 1-2 adverse events included fatigue, fever an abdominal pain. Study reported 71% of patients had SD, and the remainder had PD at 1 month. No CR or PR were achieved. |
| Integrin targeted oncolytic adenoviruses Ad5-D24-RGD and Ad5-RGD-D24-GMCSF for treatment of patients with advanced chemotherapy refractory solid tumors [73] (Pesonen 2012). | Ad5-D24-RGD and Ad5-RGD-D24-GMCSF | advanced solid tumors resistant to chemotherapy | 16 | 16 patients were injected with adenovirus, 9 treated with Ad5-D24-RGD, and 7 treated with Ad5-RGD-D24-GMCSF. Virus for one group contained GM-CSF; as large tumors have immunosuppressive characteristics, GM-CSF might stimulate the immune system. Some patients in the GMCSF group showed SD, while all patients in the other group progressed. AE were low grade (1–2); constitutional symptoms or injection site pain. |
| Antiviral and antitumor T cell immunity in patients treated with GM-CSF-coding oncolytic adenovirus [74] (Kanerva 2013). | CGTG-102 (Ad5/3-delta24-GMCSF) | Advanced solid tumors | 60 | 60 patients received intratumoral injections. The study compared single injection (39 patients) to multiple injections (21 patients) to establish safety of multiple. Stable disease or better was achieved in 50% with serial injection vs. 41% with single injection. Mostly grade 1–2 AE occurred (constitutional symptoms). |
| Immunological data from cancer patients treated with Ad5/3-E2F-Δ24-GMCSF suggests utility for tumor immunotherapy [75] (Hemminki 2015). | CGTG-602 (Ad5/3-E2F-delta24-GMCSF) | Advanced solid tumors | 13 | 13 patients enrolled with varying doses and treatment rounds of virus via IV. 50% of patients noted a response to treatment. AE were predominately grade 1–2 constitutional symptoms, but some grade 3 AE were seen. |
| A phase I trial of CV706, a replication-competent, PSA selective oncolytic adenovirus, for the treatment of locally recurrent prostate cancer following radiation therapy [76] (DeWeese 2001). | CV706 (PSA selective adenovirus) | Prostate cancer | 20 | Study used intraprostatic injection of virus into patients with locally recurrent prostate cancer. There were no grade 3 or greater toxicities. There was evidence of replication in biopsy tissues. Those treated with higher doses of the virus had at least 50% drop in PSA levels. |
| A phase I trial of intravenous CG7870, a replication-selective, prostate-specific antigen-targeted oncolytic adenovirus, for the treatment of hormone-refractory, metastatic prostate cancer [77] (Small 2006). | CG7870 | Hormone refractory metastatic prostate cancer | 23 | Patients received intravenous dosing of the virus. Most AE were constitutional symptoms such as fatigue, fevers, nausea. Three grade 3 reactions occurred, including severe fatigue. MTD was reached due to transaminitis and elevated d-dimer levels. Using PSA as the endpoint, study reported 5 patients with PSA reduction of 25–49% after 1 treatment, but no PR or CR were reported. |
| A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer [78] (Burke 2012). | CG0070 (GM-CSF expressing adenovirus) | Bladder cancer (non-muscle) | 35 | Patients received intravesical infusions of virus. Grade 1–2 bladder toxicities were the most frequent AE but 3 patients had grade 3 reactions for nocturia, dysuria and lymphopenia. Study reported CR of 48.6% across all groups, and higher (58.3%) in those with high Rb phosphorylation. |
| A Phase I study of KH901, a conditionally replicating granulocyte-macrophage colony-stimulating factor: armed oncolytic adenovirus for the treatment of head and neck cancers [79] (Chang 2009). | KH901 (GM-GSF Expressing Adenovirus) | recurrent head and neck cancers | 23 | KH901, selective for cells expressing telomerase, was injected intratumorally in patients with recurrent head and neck cancer. Groups included single, and multi-dose injections at escalating dosages. There were was no dose-limiting AE; majority were grade 1-2 constitutional symptoms. Study reports 7/19 patients with PD, 12 with SD. |
| Oncolytic adenovirus ICOVIR-7 in patients with advanced and refractory solid tumors [80] (Nokisalmi 2010). | ICOVIR-7 (adenovirus) | Advanced solid tumors | 21 | Study used intratumoral injection at varying doses. One grade 3 anemia was observed, while remaining side effects were grade 1–2 and included flu-like symptoms, increased liver transaminases, and hyponatremia. Study reported 5 objective responses including 1 PR, 2 minor, and 2 SD. All patients had PD prior to trial initiation. |
| A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients [81] (Li 2009). | Telomelysin/OBP-301 (adenovirus with human telomerase reverse transcriptase, hTERT) | Advanced solid tumors | 27 | Study used intratumoral injection of virus in a dose escalation phase I study. Rare grade III fever and grave IV thrombocytopenia at high doses were observed. Most AE were fever, reaction at the injection site, as well as thrombocytopenia, and depressed leukocyte and lymphocyte counts. Study reported a minimum of 48% with SD, and 11% had CR or PR. |
| A phase I open-label, dose-escalation, multi-institutional trial of injection with an E1B-Attenuated adenovirus, ONYX-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting [82] (Chiocca 2004). | ONYX-015 | Malignant glioma | 24 | 24 patients received varying doses of ONYX-015 injected into 10 areas of the resected glioma cavity. No severe AE were reported that were likely related to treatment (10 patient did have AE, including 1 grade 3–4 neuropathy) Only 1 patient did not have PD and No real treatment effect could be correlated with the viral treatment. |
| A phase I trial of intravenous infusion of ONYX-015 and Enbrel in solid tumor patients [83] (Nemunaitis 2007). | ONYX-015 | Advanced cancers | 9 | Nine patients divided in 3 groups received IV infusion of onyx-015 of varying doses, with a dose of Enbrel. Study reported 4/9 with SD, but no regression was seen. AE were mild. Circulating viral DNA was higher when virus infusion is given in combination with Enbrel |
| A phase I study of Onyx-015, an E1B attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer [84] (Ganly 2000). | ONYX-15 | Recurrent head and neck cancer | 22 | Study used single intratumoral injection that was well tolerated. Grade 1–2 constitutional symptoms were most common. Study reported no OR by RECIST criteria, but evidence of tumor necrosis seen on MRI in 5 patients with questionable PR was noted. |
| A phase I study of telomerase-specific replication competent oncolytic adenovirus (telomelysin) for various solid tumors [85] (Nemunaitis 2010). | H103 (Adenovirus expressing HSP70) | Advanced solid tumors | 27 | Study used intratumoral injection of virus in a dose escalation phase I study. Rare grade III fever and grave IV thrombocytopenia at high doses was observed. Most AE were fever, and a local reaction at the injection site, as well as thrombocytopenia, and depressed leukocyte and lymphocyte counts. Study reported 48% of patients had at least SD or better, and 11% had CR or PR. |
| Phase 1 study of intravenous administration of the chimeric adenovirus enadenotucirev in patients undergoing primary tumor resection [86] (Garcia-Carbonero 2017). | Enadenotucirev (adenovirus aka ColoAd1) | Colorectal, NSCLC, Urothelial, RCC | 17 | Study used IV infusion for NSCLC, RCC and urothelial cancers, and intrathehecal injection in colorectal cancer. Both demonstrated high local CD8+ cell infiltration, with no significant treatment-related AE. |
| Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer [87] (Freytag 2002). Five-year follow-up of trial of replication-competent adenovirus-mediated suicide gene therapy for treatment of prostate cancer [88] (Freytag 2007). |
Ad5-CD/TKrep | Prostate (recurrent) | 16 | Patients were injected with virus, and two days later received ganciclovir and 5-fluorocytosine prodrug. Study reported >25% decreased PSA levels in 44% of patients. A 5-year follow up showed PSA doubling time was extended in patients who received the virus treatment indicating that patients had longer until salvage treatment was needed. |
| Phase I study of replication-competent adenovirus-mediated double-suicide gene therapy in combination with conventional-dose three-dimensional conformal radiation therapy for the treatment of newly diagnosed, intermediate- to high-risk prostate cancer [89] (Freytag 2003). | Ad5-CD/TKrep | Prostate | 15 | Patients had intraprostatic injection of adenovirus with cytosine deaminase and HSV thymidine kinase genes. 2 days later the patients received 5-fluorocytosine and valganciclovir prodrug for up to 4 weeks along with radiation. PSA ½ life was decreased in those with more than 1 week of prodrug therapy. 94% of AE were mild to moderate; severe reactions were similar to reactions obtained with standard radiation therapy. |
| Phase I trial of replication-competent adenovirus-mediated suicide gene therapy combined with IMRT for prostate cancer [90] (Freytag 2007). | Ad5-yCD/mutTKSR39rep-ADP | Prostate | 9 | This study used a second generation virus with improved enzyme activity administered via intraprostatic injection. Reported AE include 13% with grade 3 lymphopenia; other AE were grade 1–2. Prostate biopsies at the end of the trial had fewer positives for residual adenocarcinoma than expected (22% rather than >40%) |
| Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial [91] (Park 2008). | Pexa-Vec/JX-594 (pexastimogene devacirepvec) | Primary or metastatic liver cancer | 14 | This was a dose-escalation study of intratumoral injection of JX-594. Grade 3 hyperbilirubinemia occurred in patients with the highest dose. All experienced flu-like symptoms, ranging grade I–III and 4 had short-lived grade I–III dose dependent thrombocytopenia. Study reported response in the injected as well as non-injected tumors; 3 PR, 6 with SD and 1 with PD (and 4 could not be evaluated via imaging for different reasons). |
| A mechanistic proof-of-concept clinical trial with JX-594, a targeted multi-mechanistic oncolytic poxvirus, in patients with metastatic melanoma [92] (Hwang 2011). | Pexa-Vec/JX-594 (pexastimogene devacirepvec) | Metastatic melanoma | 10 | Patients were injected intratumorally with 1/10th the dose of normal JX-594. Biopsies demonstrated evidence of tumor necrosis, as well as gene expression from JX-594. Clinical outcomes were not reported (not focus of study). Mild constitutional symptoms as previously reported were the only AE. |
| Phase 1 study of intratumoral Pexa-Vec (JX-594), an oncolytic and immunotherapeutic vaccinia virus, in pediatric cancer patients [93] (Cripe 2015). | Pexa-Vec/JX-594 (pexastimogene devacirepvec) | neuroblastoma, Ewing sarcoma, HCC | 3 | Intratumoral injection of Pexa-Vec in 3 patients. All 3 developed skin pustules (grade 1) that lasted 3–4 weeks. Study reported no OR by RECIST criteria; one patient had evidence of tumor necrosis on imaging. |
| Phase 1b trial of biweekly intravenous Pexa-Vec (JX-594), an oncolytic and immunotherapeutic vaccinia virus in colorectal cancer [94] (Park 2015). | Pexa-Vec/JX-594 (pexastimogene devacirepvec) | Colorectal | 15 | Study used IV infusion of Pexa-Vec in 15 patients. AE were grade 1–2, and mostly constitutional symptoms such as fever, malaise, chills, myalgias. Study reported 67% patients with SD as seen on imaging. |
| Vectorized gene therapy of liver tumors: proof-of-concept of TG4023 (MVA-FCU1) in combination with flucytosine [95] (Husseini 2017). | TG4023 (MVA-FCU1 modified vaccinia virus) | Primary or metastatic liver tumors resistant to other forms of treatment | 16 | TG4023 contains the gene for an enzyme to convert flucytosine into cytotoxic 5-fluorouracil. 16 patients had intratumoral injection at escalating doses, and then the prodrug (flucytosine) on day 2. Tumor biopsy demonstrated therapeutic levels of the active drug were reached. 7 patients had dose limiting toxicity with non-sustained rise in AST and ALT. Most frequent AE were constitutional symptoms including anorexia, fever, and fatigue. Study reported 50% of patients with SD, the other half with PD. |
| Phase I trial of intravenous oncolytic vaccinia virus (GL-ONC1) with cisplatin and radiotherapy in patients with locoregionally advanced head and neck carcinoma [96] (Mell 2017). | GL-ONC1 (Vaccinia Virus) | Head and Neck Cancer (locoregionally advances without metastasis) | 19 | Study used IV injection of virus along with cisplatin and radiotherapy. Most AE were grade 1–2 constitutional symptoms and rash, but 2 patients had grade 3 hypotension, nausea/vomiting and mucositis. Study reported 5/19 patients had virus present in the biopsy. At 1 year/2 years: 74.4%/64.1% with PFS and 84.6%/69.2% OS |
| First-in-man study of western reserve strain oncolytic vaccinia virus: safety, systemic spread, and antitumor activity [97] (Zeh 2015). | vvDD (Poxvirus – western reserve strain oncolytic vaccinia virus) | Advanced solid tumors | 16 | Study used intratumoral injection of virus. Selective viral replication reported in both injected and non-injected rumors. Study reported 1 grade 3 events occurred, which was pain in a breast cancer patient around the time of highest inflammation. |
| Phase 1 Study of intravenous oncolytic Poxvirus (vvDD) in patients with advanced solid cancers [98] (Downs-Canner 2016). | vvDD (Poxvirus – western reserve strain oncolytic vaccinia virus) | Advanced colorectal or other solid cancers | 11 | Study used IV administration. No dose limiting toxicities reported, and most AE were grade 1 or 2 constitutional symptoms. Study reported Th1 cytokines and inflammatory reaction occurred. A mixed response on some liver metastasis with improvement of cutaneous melanoma. |
| Oncolytic measles virus in cutaneous T cell lymphomas mounts antitumor immune responses in vivo and targets interferon-resistant tumor cells [99] (Heinzerling 2005). | MV (Measles Virus, Edmonston-Zagreb strain) | Cutaneous T cell Lymphoma | 5 | Study used intratumoral injections of live virus with dose escalation. Endpoint was TBI (Tumor Burden Index: 1 lesion resolved (CR); 2 showed evidence of regression in local but non-injected lesions; remaining tumors unchanged. AE included grade 1 injection site erythema, arthralgias, itching only |
| Phase I trial of systemic administration of Edmonston strain of measles virus genetically engineered to express the sodium iodide symporter in patients with recurrent or refractory multiple myeloma [100] (Dispenzieri 2017). | MV-NIS (measles virus with sodium iodide symporter) | Relapsed and refractory multiple myeloma | 29 | Study used IV injection; one group with MV-NIS alone, another with cyclophosphamide prior to MV-NIS treatment. Study reported grade 3–4 hematologic AEs including decreased blood counts neutropenia, thrombocytopenia, anemia, and lymphopenia for both groups. 1 CR reported with some cases of short lived decreased circulating free light chains (increased once the body cleared the virus). Iodine was used to identify infection in myeloma cells. |
| Phase I trial of intraperitoneal administration of an oncolytic measles virus strain engineered to express carcinoembryonic antigen for recurrent ovarian cancer [101] (Galanis 2010). | MV-CEA (Measles virus, Edmonston strain) | Taxol and platinum-refractory recurrent ovarian with normal CEA levels | 21 | Study used intraperitoneal injection of the virus with CEA as measure of viral replication. Study reports best response (per RECIST) was SD in 14/21 and was dose dependent; 5 patients had marked decrease of CA-125 levels. Median survival was 12·15 compared to 6 months for historical controls. |
| Phase I trial of Seneca Valley Virus (NTX-010) in children with relapsed/refractory solid tumors: a report of the Children’s Oncology Group [102] (Burke 2015). | NTX-010 (Seneca Valley Virus) | Pediatric patients wih neuroblastoma, rhabdomyosarcoma, rare tumors with NET features | 22 | Study designed in 2 parts: part A was dose finding, virus only, using 3 doses; part B added cyclophosphamide. Study reported AEs were leukopenia, neutropenia; tumor pain in 1 patient was the only grade 3 toxicity observed. Nearly all patients (17/18) had neutralizing antibodies which prohibited virus efficacy. |
| Phase I clinical study of Seneca Valley Virus (SVV-001), a replication-competent picornavirus, in advanced solid tumors with neuroendocrine features [103] (Rudin 2011). | SVV-001 (Seneca Valley Virus, a picornavirus) | Advanced solid tumors with neuroendocrine features | 30 | Study used IV injection of virus. 1 patient with SCLC was progression free at 10 months. AEs included flu like symptoms (fever, fatigue headache) and one grade 3 lymphopenia |
| A phase I dose-escalation clinical trial of intraoperative direct intratumoral injection of HF10 oncolytic virus in non-resectable patients with advanced pancreatic cancer [104] (Nakao 2011). | HF-10 | Pancreatic cancer | 6 | Study used 3 intratumoral injections of HF-10. Study reported PD in 2 patients, SD in 3 patients, and 1 had a PR. No AE reported. |
| A Phase I clinical trial of EUS-guided intratumoral injection of the oncolytic virus, HF10 for unresectable locally advanced pancreatic cancer [105] (Hirooka 2018). | HF-10 | Pancreatic cancer | 10 | Study used EUS injection of HF10 for unresectable pancreatic cancer up to 4 times, every 2 weeks. Co-treatment was erlotinib and gemcitabine. Study reported AEs: 5 patients with severe myelosuppression; 2 patients had severe events not due to HF10. Study outcomes: 2 PD, 4 SD, and 3 PR. PFS 6·3 months, OS 15·5 months. 2 patients achieved CR after downstaging and surgery. |
| Results of a randomized phase I gene therapy clinical trial of nononcolytic fowlpox viruses encoding T cell costimulatory molecules [106] (Kaufman 2014). | rF-B7.1 and rF-TRICOM (recombinant fowlpox virus with either B7.1 or three genes: B7.1, ICAM-1, and LFA-3) | Melanoma and colon cancer | 12 | Study used intratumoral injection of one of the two viruses and at varying doses, every 4 weeks. AE were minimal, including injection site pain and pyrexia (in only 4 patients). Study reported no objective clinical responses but safety was established, and some T cell activity specific to the tumors was seen Stable disease noted for 3 patients which included both colon cancer cases. |
AE, adverse event; CR, complete response; GI, gastrointestinal; ICH, intracerebral hemorrhage; LFT, liver function test; MM, multiple myeloma; MR, marginal response; MTD, maximum tolerated dose; NARA, neutralizing antivirus antibody; OR, overall response; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression free survival; PR, partial response; RECIST, response evaluation criteria in solid tumors; SCLC, small cell lung cancer SD, stable disease.