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• W2972392555 abstract "Seprehvir (HSV1716) is an oncolytic herpes simplex virus-1 (HSV-1) previously demonstrated to be well tolerated in pediatric patients when administered intratumorally. To determine the safety of administering Seprehvir systemically, we conducted the first-in-human phase I trial of intravenous injection in young patients with relapsed or refractory extra-cranial solid cancers. We delivered a single dose of 5 × 104 infectious units (iu)/kg (maximum dose of 2 × 106) or 2.5 × 105 iu/kg (maximum dose of 1 × 107 iu) of Seprehvir via the peripheral vein, monitored adverse events, and measured tumor responses by imaging. We monitored HSV-1 serology as well as viremia and shedding by PCR and culture. We administered a single dose of Seprehvir to seven patients and multiple doses to two patients. We did not observe any dose-limiting toxicities. All five HSV-1 seronegative patients seroconverted by day 28. Four of nine patients had detectable HSV-1 genomes in peripheral blood appearing on day +4 consistent with de novo virus replication. Two patients had stable disease in response to Seprehvir. Intravenous Seprehvir is well tolerated without viral shedding in children and young adults with late-stage cancer. Viremia consistent with virus replication holds promise for future Seprehvir studies at higher doses and/or in combination with other anti-neoplastic therapies. Seprehvir (HSV1716) is an oncolytic herpes simplex virus-1 (HSV-1) previously demonstrated to be well tolerated in pediatric patients when administered intratumorally. To determine the safety of administering Seprehvir systemically, we conducted the first-in-human phase I trial of intravenous injection in young patients with relapsed or refractory extra-cranial solid cancers. We delivered a single dose of 5 × 104 infectious units (iu)/kg (maximum dose of 2 × 106) or 2.5 × 105 iu/kg (maximum dose of 1 × 107 iu) of Seprehvir via the peripheral vein, monitored adverse events, and measured tumor responses by imaging. We monitored HSV-1 serology as well as viremia and shedding by PCR and culture. We administered a single dose of Seprehvir to seven patients and multiple doses to two patients. We did not observe any dose-limiting toxicities. All five HSV-1 seronegative patients seroconverted by day 28. Four of nine patients had detectable HSV-1 genomes in peripheral blood appearing on day +4 consistent with de novo virus replication. Two patients had stable disease in response to Seprehvir. Intravenous Seprehvir is well tolerated without viral shedding in children and young adults with late-stage cancer. Viremia consistent with virus replication holds promise for future Seprehvir studies at higher doses and/or in combination with other anti-neoplastic therapies. Children with recurrent and/or refractory solid tumors urgently need novel targeted and less toxic therapy to improve survival and limit treatment-related toxicities. Oncolytic viruses offer a new platform for cancer therapy because of their large therapeutic index and limited toxic effects. The majority of cancer patients entering phase I clinical trials have metastatic disease. Because preclinical studies of oncolytic viruses given intratumorally suggest that virus is mostly contained within the tumor with minimal systemic spread, localized virus injection may be efficacious for patients with metastatic disease only if there is a significant abscopal-like effect. Thus, systemically administered virus is likely to be the most useful as a cancer therapy for patients with metastases. Herpes simplex virus-1 (HSV-1) is an attractive oncolytic vector for multiple reasons. The pathogenesis of natural HSV-1 infections is well known, and diagnostic assays are commonly available.1McGeoch D.J. Dalrymple M.A. Davison A.J. Dolan A. Frame M.C. McNab D. Perry L.J. Scott J.E. Taylor P. The complete DNA sequence of the long unique region in the genome of herpes simplex virus type 1.J. Gen. Virol. 1988; 69: 1531-1574Crossref PubMed Scopus (1231) Google Scholar, 2Perry L.J. McGeoch D.J. The DNA sequences of the long repeat region and adjoining parts of the long unique region in the genome of herpes simplex virus type 1.J. Gen. Virol. 1988; 69: 2831-2846Crossref PubMed Scopus (113) Google Scholar In particular, clinicians are accustomed to treating HSV-1 infections, and it is one of the few human viral pathogens for which there are safe and clinically proven anti-viral therapies. Attenuating mutations have been well described that render the virus safe yet retain replication competency in cancer cells, as demonstrated by the clinical experience with talimogene laherparepvec, which was safe to administer by intralesional injection in melanoma patients and prolonged survival in patients with local and regional disease.3Andtbacka R.H. Ross M. Puzanov I. Milhem M. Collichio F. Delman K.A. Amatruda T. Zager J.S. Cranmer L. Hsueh E. et al.Patterns of Clinical Response with Talimogene Laherparepvec (T-VEC) in Patients with Melanoma Treated in the OPTiM Phase III Clinical Trial.Ann. Surg. Oncol. 2016; 23: 4169-4177Crossref PubMed Scopus (200) Google Scholar Seprehvir (HSV1716) is genetically altered to replicate in and lyse dividing tumor cells, but fails to replicate in normal non-cancer cells by virtue of deletion of the gene encoding ICP34.5.1McGeoch D.J. Dalrymple M.A. Davison A.J. Dolan A. Frame M.C. McNab D. Perry L.J. Scott J.E. Taylor P. The complete DNA sequence of the long unique region in the genome of herpes simplex virus type 1.J. Gen. Virol. 1988; 69: 1531-1574Crossref PubMed Scopus (1231) Google Scholar This virus additionally maintains its expression of thymidine kinase, serving as a safety net whereby the virus can be stopped with administration of acyclovir. In our previous study, we demonstrated the safety of Seprehvir, an oncolytic herpes simplex type 1 virus, delivered by direct intratumoral injection to children and young adults with non-CNS solid tumors.4Streby K.A. Geller J.I. Currier M.A. Warren P.S. Racadio J.M. Towbin A.J. Vaughan M.R. Triplet M. Ott-Napier K. Dishman D.J. et al.Intratumoral Injection of HSV1716, an Oncolytic Herpes Virus, Is Safe and Shows Evidence of Immune Response and Viral Replication in Young Cancer Patients.Clin. Cancer Res. 2017; 23: 3566-3574Crossref PubMed Scopus (83) Google Scholar Prior to our intratumoral trial, no one had prior experience administering oncolytic HSV to children and young adults. Other oncolytic viruses, such as Seneca Valley virus, reovirus, and vaccinia virus, have been studied in children with few toxicities but also little evidence of disease response.5Burke M.J. Ahern C. Weigel B.J. Poirier J.T. Rudin C.M. Chen Y. Cripe T.P. Bernhardt M.B. Blaney S.M. Phase I trial of Seneca Valley Virus (NTX-010) in children with relapsed/refractory solid tumors: a report of the Children’s Oncology Group.Pediatr. Blood Cancer. 2015; 62: 743-750Crossref PubMed Scopus (47) Google Scholar, 6Kolb E.A. Sampson V. Stabley D. Walter A. Sol-Church K. Cripe T. Hingorani P. Ahern C.H. Weigel B.J. Zwiebel J. Blaney S.M. 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.Pediatr. Blood Cancer. 2015; 62: 751-758Crossref PubMed Scopus (38) Google Scholar, 7Cripe T.P. Ngo M.C. Geller J.I. Louis C.U. Currier M.A. Racadio J.M. Towbin A.J. Rooney C.M. Pelusio A. Moon A. et al.Phase 1 study of intratumoral Pexa-Vec (JX-594), an oncolytic and immunotherapeutic vaccinia virus, in pediatric cancer patients.Mol. Ther. 2015; 23: 602-608Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar In younger patients, intratumoral injection has more limitations because of patient anxiety, need for sedation and/or coordination with multiple providers, radiation exposure for image-guided injection, and cost. Intravenous administration eliminates these limitations in addition to potentially exposing more tumor sites to oncolytic virus than with direct intratumoral injection. Here we report our single-institution phase 1 clinical trial aiming to determine the safety of intravenous injection of Seprehvir in children and young adults with non-CNS solid tumors by recording adverse events and any dose-limiting toxicities (DLTs) of intravenous Seprehvir at the doses given. We secondarily aimed to measure the antiviral immune response in patients with relapsed and/or refractory cancers by serologies, to measure the systemic viremia and viral shedding after intravenous Seprehvir injection by PCR and viral culture, and to preliminarily define the antitumor activity of Seprehvir within the confines of a phase 1 trial (https://clinicaltrials.gov/; ClinicalTrials.gov: NCT00931931) by modified RECIST (response evaluation criteria in solid tumors) criteria and metabolic activity on positron emission tomography (PET) scan. We also compared the findings of our previous intratumoral trial with the results of administering Seprehvir systemically. A total of nine patients aged 11–30 years were enrolled and fully evaluable for safety and toxicity. Three patients were accrued to each of two dose levels, and an additional three patients were enrolled at dose level one after the first patient had a potential serious adverse event (SAE; see below). The patients had varying pediatric cancer diagnoses, including osteosarcoma (n = 2), Ewing sarcoma, rhabdomyosarcoma (n = 2), neuroblastoma, chondrosarcoma, cholangiocarcinoma, and pancreatic neuroendocrine tumor (see Table 1). Most patients received multiple courses of therapy for relapsed or refractory disease prior to enrollment in this trial (chemotherapy and/or radiation therapy).Table 1Patient DemographicsPatient No.DiagnosisAge (years)Prior Chemotherapy Regimens (n)Previous Radiation TxDisease at Trial EntryTime from Dx to Tx (months)Seprehvir Dose (iu)HSV01pleomorphic rhabdomyosarcoma30VCR/Irino/Doxo/CTX/Etop, VCR/Dactino/CTX, Ifos/Carbo/Etop, liposomal Doxo/temsirolimus (4)45 Gy retroperitoneummultiple pleural and diaphragmatic nodules, paraspinal mass, lung mets192 × 106HSV02cholangiocarcinoma18cisplatin/gemcitabine, bevacizumab/5-FU/leucovorin/oxaliplatin, cisplatin/gemcitabine (3)noneintrahepatic biliary mass, multiple liver mets, mediastinal node182 × 106HSV03pancreatic neuroendocrine tumor28Temodar/Xeloda, everolimus, Doxo (3)nonemass in bed of pancreatic head, three liver lesions, mass near SMA, mesenteric nodes272 × 106HSV04Ewing sarcoma25VCR/Doxo/CTX/Ifos/Etop, Irino/Temodar, VCR/CTX/Topo/bevacizumab (3)56 Gy right knee, 18 Gy lungright tibial mass with two distal lesions and multiple pulmonary nodules502 × 106HSV05osteosarcoma17MTX/Doxo/Cisplat, high-dose ifosfamide, liposomal Doxo, gemcitabine/docetaxel, gemcitabine, and nab-paclitaxel (5)nonemultiple pleural, lung, and diaphragmatic nodules262 × 106HSV06rhabdomyosarcoma11VCR/Irino/Doxo/Dactino/CTX/Etop, vinorelbine/CTX/temsirolimus (2)37.5 Gy humeri; 41.4 Gy cervical, thoracic, and sacral spine; 37.5 Gy footpelvic mass, abdominal and inguinal nodes, thigh mass, bilateral lung and hilar nodules, liver nodules261.6 × 106HSV07osteosarcoma19Doxo/cisplatin/Zometa/HD-MTX/Ifos/Etop, high-dose ifos, gemcitabine/Taxotere, sorafenib, liposomal doxo (5)noneright upper lung mass with satellite nodules and right subcarinal node531 × 107HSV08neuroblastoma16CTX/Doxo/VCR/Cisplat/Etop; Carbo/Etop/Mel, retinoic acid, Irino/Temodar, CTX/Topo, anti-GD2 immunotherapy, oral etoposide, AZD1775/oral Irino (8)21.6 Gy abdomen and skull, XRT to thigh (dose unknown)entire right hip bone, right hip mass, left femoral head, right liver lobe mets, and L4/S1 vertebral bodies1321 × 107HSV09chondrosarcoma29MTX/Doxo/Cisplat, Doxo, Ifos/Etop, pazopanib, Ifos/Etop (5)proton XRT to thigh (dose unknown)large pelvic/sacral mass into the sacral canal, paraspinal, and gluteal muscles541 × 1075-FU, fluorouracil; Carbo, carboplatin; Cisplat, cisplatin; CTX, cyclophosphamide; Dactino, dactinomycin; Doxo, doxorubicin; Dx, diagnosis; Etop, etoposide; HD-MTX, high-dose methotrexate; Ifos, ifosfamide; Irino, irinotecan; Mel, melphalan; SMA, superior mesenteric artery; Tx, therapy; VCR, vincristine; XRT, radiation therapy. Open table in a new tab 5-FU, fluorouracil; Carbo, carboplatin; Cisplat, cisplatin; CTX, cyclophosphamide; Dactino, dactinomycin; Doxo, doxorubicin; Dx, diagnosis; Etop, etoposide; HD-MTX, high-dose methotrexate; Ifos, ifosfamide; Irino, irinotecan; Mel, melphalan; SMA, superior mesenteric artery; Tx, therapy; VCR, vincristine; XRT, radiation therapy. All nine patients were serologically negative for anti-HSV-1 antibodies at baseline, and all six patients for whom we had collected data seroconverted following injection by day 28 (Table 2). Seroconversion data were not available for HSV03 because the patient became acutely ill due to disease progression and was admitted to another institution. Patients HSV05 and HSV06 declined having these labs drawn. Of note, HSV03 was serologically positive for HSV-2 by immunoglobulin G (IgG) and immunoglobulin M (IgM) prior to Seprehvir, but had no evidence of HSV-1 immunity. In addition, HSV08 and HSV09 had evidence of HSV-1 PCR in the blood on day 0 after injection, and HSV08 had persistent evidence of HSV-1 DNA in the peripheral blood. HSV08 also was the only patient to seroconvert in both IgG and IgM by day 28. The seroconversion or detection of HSV-1 DNA in peripheral blood did not appear to depend on white blood cell count (WBC), absolute neutrophil count (ANC), or absolute lymphocyte count (ALC).Table 2Patient Serologic Responses to a Single Dose of Intravenous SeprehvirPatient No.WBCANCALCHSV-1 PCR BloodHSV-1 Seroconversion (IgG/IgM)DaySSSS0aMeasured at 3, 6, and 18 h after virus injection.147142128S28HSV019.15,6001,638−−−+++NANA−NAHSV026.24,0301,612−−−+−−−−−+IgMHSV0313.59,5851,620−−−−NDNDNDND−NDHSV044.22,772966−−−−−−−+−+IgMHSV055.43,078864−−−−−NDNDND−NDHSV065.85,046348−−−++++−−NDHSV073.52,100910−−−−−−−−−+IgMHSV088.85,2802,376−++++−++−+IgM, +IgGHSV094.63,634414−−−−−−−−−+IgMHSV09-II4.73,384705−+bMeasured only at 3 h after virus injection.−−−−−−+IgM+IgM, +IgGALC, absolute lymphocyte count; ANC, absolute neutrophil count; NA, not applicable (patient deceased); ND, not done; S, screening; WBC, white blood cell count.a Measured at 3, 6, and 18 h after virus injection.b Measured only at 3 h after virus injection. Open table in a new tab ALC, absolute lymphocyte count; ANC, absolute neutrophil count; NA, not applicable (patient deceased); ND, not done; S, screening; WBC, white blood cell count. No dose-limiting toxicities (DLTs) were noted in any of the patients. One patient had grade 3 hypotension and flu-like symptoms that were possibly attributed to Seprehvir or its administration. Grade 1 and 2 adverse events possibly or probably attributable to Seprehvir included laboratory abnormalities such as anemia, leukopenia, lymphopenia, and mild elevations in liver enzymes (Table 3). One patient had mild bleeding, and one patient had a pneumothorax after a biopsy of a lung parenchyma tumor was taken on day 7 as per clinical trial guidelines. One patient had a grade 5 gastrointestinal (GI) hemorrhage (HSV01) that was determined by the data safety monitoring board and by the US Food and Drug Administration (FDA) to be unrelated to Seprehvir and related to disease progression. However, because this patient was the first to receive intravenous Seprehvir, the FDA requested expansion of the first dose level to six patients, and the remaining doses in those patients were well tolerated.Table 3Adverse Events Possibly, Probably, or Definitely Attributable to Intravenous Seprehvir or Study ProceduresAdverse EventsGrade 1Grade 2Grade 3Attribution to SeprehvirAttribution to Study ProcedureBlood/Bone MarrowAnemia21possiblypossiblyLeukopenia42possiblyLymphopenia34possiblyNeutropenia11possiblyThrombocytopenia3possiblyCardiacHypotension1possiblyConstitutional SymptomsChills1possiblyFatigue3possiblypossiblyGastrointestinalAnorexia1possiblyDehydration1possiblyNausea111possiblyInjury, Poisoning, and Procedural ComplicationsPostoperative hemorrhage1definitelyInvestigationsAcidosis1possiblyALT increased2possiblyAST increased1possiblypossiblyHyperbilirubinemia1possiblySerum bicarbonate decreased1possiblypossiblyPainNeck pain1possiblyHeadache1possiblyRespiratoryPleural effusion2possiblyPneumothorax11definitelySyndromesFlu-like symptoms1possiblyAST, aspartate aminotransferase; ALT, alanine aminotransferase. Open table in a new tab AST, aspartate aminotransferase; ALT, alanine aminotransferase. Three patients met eligibility for part two of the trial (up to three additional doses of Seprehvir) based on stable disease at days +14 or +28. Two patients declined further injections because of the treating oncologist’s preference or concern for significant disease progression. Patient HSV09 received one additional dose of Seprehvir, with no significant adverse events noted, but declined further dosing after a 19% increase in overall tumor burden. Patient HSV06 had evidence of disease progression on day 14 imaging. This patient was removed from the study and started on oral pazopanib (450 mg/m2/day) on what would have been day 20 of the trial. Pazopanib is a small-molecule tyrosine kinase angiogenesis inhibitor shown to have potent activity against sarcomas.8Glade Bender J.L. Lee A. Reid J.M. Baruchel S. Roberts T. Voss S.D. Wu B. Ahern C.H. Ingle A.M. Harris P. et al.Phase I pharmacokinetic and pharmacodynamic study of pazopanib in children with soft tissue sarcoma and other refractory solid tumors: a children’s oncology group phase I consortium report.J. Clin. Oncol. 2013; 31: 3034-3043Crossref PubMed Scopus (120) Google Scholar Thirty days after Seprehvir and 10 days after starting pazopanib, imaging done at her local institution by computed tomography (CT)/MRI revealed stable disease (as well as a clinically relevant decrease in lymphedema secondary to vascular compression by the tumor). Although it was unclear whether this lack of further disease progression was due to pazopanib or Seprehvir, an expanded access use (EAU) protocol was submitted to and approved by the FDA on IND 13196 Serial No. 00058 for three doses of weekly Seprehvir at the same dose as previously, in combination with oral pazopanib at 450 mg/m2/day. In screening for the EAU protocol, the PET scan, obtained 42 days after her initial Seprehvir injection, showed a significant decrease in metabolic activity of her tumors diffusely (see Figure 1). HSV06 continued on Seprehvir injections weekly ×2 more doses while continuing to take oral pazopanib. She tolerated the combination therapy well with no dose-limiting toxicities attributable to either therapy, but unfortunately had further progression of her disease, which ultimately led to her death 1 month after starting the EAU protocol. No viral shedding was observed in any patient on this trial because all HSV-1 cultures, including blood, buccal swab, rectal swab, and urine, at all study visits through day 28 were negative. PCR for HSV-1 genomes were also negative in all urine samples and all buccal and rectal swabs. Blood PCRs for HSV-1 genomes were negative at baseline in all patients, and four of the nine patients had positive HSV-1 PCRs on day 4. Three of the four patients had persistence of the positive PCR beyond day 4, and HSV06 and HSV08 had positive PCRs throughout the remainder of the 28-day evaluation. HSV06 became PCR-negative during the EAU part of her treatment, and PCRs were negative in follow-up for HSV08. We obtained tumor biopsies on two patients over the age of 18 years (HSV07 and HSV09) but could not detect any evidence of virus by PCR or immunohistochemical staining within the tumor on day 7 after treatment. Two of the seven patients had stable disease; one had stable PET maximum standardized uptake value (SUVmax; HSV04), and the other had a slight decrease in PET SUVmax on day 28 (HSV09). As shown in Table 4, patient survival did not differ significantly by the dose of Seprehvir given, and a few patients lived more than 6 months. These patients did go on to receive other therapies such as erlotinib and bevacizumab in HSV02; liposomal doxorubicin, autologous tumor cell vaccine therapy, gemcitabine and nab-paclitaxel, pazopanib, and trabectedin and irinotecan in HSV04; tumor embolization in HSV05; bevacizumab and zoledronic acid in HSV07; and temozolomide, irinotecan, and dinutuximab, ceritinib and ribociclib, alectinib and oral cyclophosphamide, and 131I-mIBG (meta-iodobenzylguanidine) in HSV08. Because this is a very small number of patients and all were treated with different therapies before and/or after Seprehvir, we are unable to draw any conclusions about the role Seprehvir might have played in patient survival.Table 4Disease Response and PET SUV Changes after a Single Dose of Intravenous SeprehvirPatient No.Day 14 CT/MRIDay 14 PETDay 28 CT/MRIDay 28 PETTime from Tx to Death (months)HSV01stable diseaseSUV stableNANA0.5HSV02PDSUV ↑PDSUV ↑11.5HSV03stable diseaseNDPDND1HSV04stable diseaseSUV stablestable diseaseSUV stable26aPatient is still alive so time from treatment to follow-up.HSV05PDNDNDND3.5HSV06PDSUV ↑NANA2HSV07NEbTumor resected on day 7 for biopsy specimen and was the only site of active disease at the time.NEbTumor resected on day 7 for biopsy specimen and was the only site of active disease at the time.PDPD7HSV08PDSUV ↑↑PDSUV ↑11HSV09-Istable diseaseSUV stablestable diseaseSUV ↓HSV09-IINANAPDSUV ↑6aPatient is still alive so time from treatment to follow-up.NA, not applicable; ND, not done; NE, not evaluable; PD, progressive disease; SUV, standardized uptake valuemax; Tx, treatment.a Patient is still alive so time from treatment to follow-up.b Tumor resected on day 7 for biopsy specimen and was the only site of active disease at the time. Open table in a new tab NA, not applicable; ND, not done; NE, not evaluable; PD, progressive disease; SUV, standardized uptake valuemax; Tx, treatment. We found that intravenous administration of Seprehvir in children and young adults with relapsed and/or refractory non-CNS solid tumors is well tolerated. We saw no evidence of neurological toxicities or any other significant treatment-related toxicities in this clinical trial. All of the patients enrolled in this trial were HSV-1 seronegative, suggesting that pediatric and young adult patients may benefit the most from HSV virotherapy if pre-existing anti-HSV-1 immunity is ultimately found to diminish anti-tumor efficacy. Systemic administration of any oncolytic HSV by intravenous injection has never been used in humans prior to this clinical trial. However, other types of viruses have been administered systemically for cancer therapy. Arterial infusion (via the hepatic artery) of the oncolytic HSV NV1020 was safe in 13 adult subjects in a phase I dose-escalation study and 22 adult subjects in a subsequent phase II expanded study (using the highest “optimal biologic dose” determined from the phase I study of 1 × 108 plaque-forming units [PFU]/dose × 4 doses).9Fong Y. Kim T. Bhargava A. Schwartz L. Brown K. Brody L. Covey A. Karrasch M. Getrajdman G. Mescheder A. et al.A herpes oncolytic virus can be delivered via the vasculature to produce biologic changes in human colorectal cancer.Mol. Ther. 2009; 17: 389-394Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar Based on similar logic, there are a number of other virus studies that utilize systemic delivery, including loco-regional infusion of an oncolytic HSV (rRp450 via hepatic artery; ClinicalTrials.gov: NCT01071941) and intravenous infusions of reovirus (pediatric study ClinicalTrials.gov: NCT01240538 and other adult studies), Seneca valley virus (pediatric study ClinicalTrials.gov: NCT01048892 and other adult studies), Newcastle disease virus (ClinicalTrials.gov: NCT01174537), and vaccinia virus (ClinicalTrials.gov: NCT01380600 and others). Systemic administration of Seprehvir induced an anti-viral immune response in every patient for whom we had data, as evidenced by the development of HSV-1 IgM antibodies. In addition, the patients who were given repeated injections developed PCR+ viremia only after the first, but not after subsequent injections. These observations suggest the optimal dosing of systemic virotherapy is likely early, before anti-viral immunity develops. The anti-viral immunity could prove beneficial if combined with intratumoral dosing because it could boost the local immune response within the tumor microenvironment where the oncolytic virus was being injected. We previously showed that not all of the patients treated with intratumoral Seprehvir had seroconversion.4Streby K.A. Geller J.I. Currier M.A. Warren P.S. Racadio J.M. Towbin A.J. Vaughan M.R. Triplet M. Ott-Napier K. Dishman D.J. et al.Intratumoral Injection of HSV1716, an Oncolytic Herpes Virus, Is Safe and Shows Evidence of Immune Response and Viral Replication in Young Cancer Patients.Clin. Cancer Res. 2017; 23: 3566-3574Crossref PubMed Scopus (83) Google Scholar All of these data together suggest patients may receive maximum benefit from a combination of intravenous and intratumoral virus administration. Further research into the functionality of the immune system at various time points in cancer treatment may be warranted to guide immunotherapeutic clinical trials. Intravenous Seprehvir resulted in systemic viremia as evidenced by initially negative and subsequent appearance of HSV-1 by PCR in the peripheral blood in several patients. The lack of a PCR signal in the peripheral blood of the other patients may reflect insufficient dosing for systemic delivery, impaired delivery of virus because of tumor location, inadequate vascular supply of the tumor, or their particular tumors did not support robust virus replication. HSV08 had early evidence suggestive of viral replication. Whether or not neuroblastoma is particularly susceptible to oncolytic HSV infection is unknown, but our group and others have published on the anti-tumor efficacy in vitro and in vivo in human and murine models of neuroblastoma preclinically.10Wang P.Y. Swain H.M. Kunkler A.L. Chen C.Y. Hutzen B.J. Arnold M.A. Streby K.A. Collins M.H. Dipasquale B. Stanek J.R. et al.Neuroblastomas vary widely in their sensitivities to herpes simplex virotherapy unrelated to virus receptors and susceptibility.Gene Ther. 2016; 23: 135-143Crossref PubMed Scopus (25) Google Scholar, 11Currier M.A. Sprague L. Rizvi T.A. Nartker B. Chen C.Y. Wang P.Y. Hutzen B.J. Franczek M.R. Patel A.V. Chaney K.E. et al.Aurora A kinase inhibition enhances oncolytic herpes virotherapy through cytotoxic synergy and innate cellular immune modulation.Oncotarget. 2017; 8: 17412-17427Crossref PubMed Scopus (23) Google Scholar, 12Gillory L.A. Megison M.L. Stewart J.E. Mroczek-Musulman E. Nabers H.C. Waters A.M. Kelly V. Coleman J.M. Markert J.M. Gillespie G.Y. et al.Preclinical evaluation of engineered oncolytic herpes simplex virus for the treatment of neuroblastoma.PLoS ONE. 2013; 8: e77753Crossref PubMed Scopus (17) Google Scholar Unlike what was reported in our previous study with intratumoral administration of Seprehvir, the absolute lymphocyte count (ALC) did not appear to influence virus replication because two of the three patients with persistent viral DNA had a normal ALC. We previously hypothesized that the prolonged persistence of HSV detection could be caused by the inhibition of immunosuppressor cells within the tumor microenvironment, such as regulatory T cells. This idea could still hold true, because we were unable to examine the tumor microenvironment directly in either study, but there was a persistence of HSV-1 DNA with low and high ALC when Seprehvir was delivered by intravenous injection. ANC also does not appear to impact DNA replication. Due to the small number of patients accrued, definitive conclusions cannot be drawn. There are several potential explanations for the negative biopsies at 7 days after HSV1716 intravenous administration. We may have had a sampling error in geography or time, such that the region of the large tumors we tested or the time point at which it was collected were not optimal. It is also possible that virus was inactivated in the bloodstream and unable to reach the tumor site; we think this is less likely because both patients were negative for pre-existing anti-HSV antibodies and we were able to detect virus genomes in the blood at later time points. Another possibility is that the dose we used might have been insufficient to reach and intravasate into the tumor site, because the majority of intravenous HSV is taken up in the liver (at least in mice).13Schellingerhout D. Bogdanov Jr., A. Marecos E. Spear M. Breakefield X. Weissleder R. Mapping the in vivo distribution of herpes simplex virions.Hum. Gene Ther. 1998; 9: 1543-1549Crossref PubMed Scopus (59) Google Scholar To that point, we used a similar dose of HSV1716 as we used intratumorally because our preclinical data showed efficacy of systemic delivery at an equivalent dose level (albeit with two doses given instead of one as in our trial).14Braidwood L. Learmonth K. Graham A. Conner J. Potent efficacy signals from systemically administered oncolytic herpes simplex virus (HSV1716) in hepatocellular carcinoma xenograft models.J. Hepatocell. Carcinoma. 2014; 1: 149-161PubMed Google Scholar Finally, it is possible that these particular tumors were not susceptible or permissive to virus replication, so that the virus particles that did reach the tumor did not spread and were rapidly cleared. Preclinical studies demonstrate the ability of HSV1716 to home in to cancer cells. Braidwo" @default.
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• W2972392555 title "First-in-Human Intravenous Seprehvir in Young Cancer Patients: A Phase 1 Clinical Trial" @default.
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