Live Viruses in Cancer Treatment · than 200 years. One of the greatest clinical advances in...

Live Viruses in Cancer TreatmentPublished on Cancer Network (http://www.cancernetwork.com)

Live Viruses in Cancer TreatmentReview Article [1] | November 01, 2002 | Ovarian Cancer [2]By John Nemunaitis, MD [3]

Although antitumor activity and a low toxicity profile have been demonstrated for several oncolyticviruses, the development of viral therapy in cancer treatment has been limited by a lack of definitivephase III trials. The use

Most people think of "viral therapy" as an obscure, experimental approach to the treatment ofdisease. However, replicating viruses have been used as an effective therapeutic modality for morethan 200 years. One of the greatest clinical advances in medical history�the eradication ofsmallpox�was made with a replicating virus. In 1796, Edward Jenner discovered that pus from thewounds of infected patients contained live cowpox virus, which could be used as an effective vaccineagainst smallpox.[1] This discovery lead to the vaccination of several million people and worldclearance of the disease.[2]

Interestingly, rare reports of complete remission induced in cancer patients in association withsmallpox vaccination were sporadically reported.[3] Observations of tumor regression in associationwith other viral infections have also been described in cancer patients infected with herpeszoster,[4,5] hepatitis virus,[6,7] influenza,[8] varicella,[9] measles,[10-12] and other viruses.[13-15]The first published report of tumor destruction related to replication competent viruses occurred in1912 when a woman with cervical cancer developed significant tumor necrosis followingadministration of an attenuated rabies virus for prophylactic treatment after a dog bite.[16,17] Earlyin vitro demonstration of viral oncolysis was first shown in 1922 with vaccinia virus, which was shownto propagate in several malignant tumor lines.Following these observations, extensive work was performed investigating the potential use of viraltherapy to treat cancer. In 1950, a strain of encephalitis virus was shown to induce a dose-relatedoncolytic effect in vivo with a mouse sarcoma tumor.[18] Viral replication was shown to correlatewith tumor cell lysis; however, viral encephalitis developed in several mice. It was later found thatserial passaging of the encephalitis virus in vitro prior to tumor injection in vivo would reduce theproliferative capacity in normal tissues, thereby minimizing the occurrence of encephalitis andenhancing oncolytic capacity. Clinical investigation was stimulated following additional work withNewcastle disease virus (NDV), influenza virus, and other viruses in animal models that showedcessation of ascites tumor (Ehrlich cells) growth and eradication of the malignancy in someanimals.[19-23]Clinical trials were carried out in advanced cancer patients between 1950 and the early 1970s,investigating administration of replication-proficient viruses.[17,24-29] Transient responses wereseen. Several mechanisms of action were described, involving direct tumor lysis related to viralproliferation, tumor antigen induced immune activation, modulation of cancer oncogene expression(ie, c-fos, protein kinase C [PKC] modulation with measles injection), apoptosis related to expressionof unique viral proteins (ie, E1A),[30,31] release of immunostimulatory cytokines,[32,33] andactivation of other antitumor immune responses (ie, natural killer [NK] cell activation).[34] Viruseswith low pathogenicity for normal tissue and high oncolytic capacity were investigated. Such virusesinclude NDV, mumps virus, herpes simplex virus (HSV), Egypt 101 virus, influenza virus, adenovirusserotype 5, vaccinia, and ONYX-015. Historical and current studies will be discussed.

Viral Uptake and Release

Most oncolytic viruses require proliferation in the same species or cell lineage and depend on hostfactors for successful evolution through life-cycle stages (binding, entry, intracellular transport,genome replication, viral gene expression, assembly and release of progeny). To initiate thisprocess, the virus requires a suitable receptor at the surface of the cell for uptake[35] andtranscription factors to bind to the promoter/enhancer elements in the viral genome, to induceexpression of viral DNA.Manipulations of the viral coat protein genes and tumor-specific viral promoters have not adversely

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affected replication of oncolytic viruses in malignant tissue, but have limited replication capacity innormal tissue. Additional specificity to malignant tissue has been shown following modification of theviral coat protein thereby enabling specific binding to tumor antigens not expressed on normal cellsurfaces,[36] and engineering of tumor specific promoter and enhancer regions with the viralgenome to generate viruses with selective malignant cell replication capacity.[37,38]The release of oncolytic virus progeny (up to 104 viruses per cell) coincides with the death of thehost tumor cell. The first "burst" of replicating viruses[39] generally occurs less than 24 hours aftertreatment and may continue as long as conditions are favorable for replication and immunedestruction of released virus is limited. Malignant cells are capable of evading immune defenses, andthis effect may facilitate local spread of released virus.[40]

Egypt 101 Virus

Egypt 101 virus is a strain of the West Nile virus, which is an adenovirus subtype. Preclinical testingof Egypt 101 virus in the early 1950s showed oncolytic activity in a uterine/cervix cancer cell line(HeLa).[41] Testing of live virus administration via oral and intravenous routes in normal volunteersrevealed minimal toxicity (low-grade fever), thereby justifying clinical trials in cancerpatients,[42-44] although a small number of patients with hematologic malignancies did developtransient encephalitis.[45] Fever generally occurred within 48 hours after inoculation and oftencoincided with the detection of live virus in circulation or excretion.[42]Clinical TrialsIn the first such trial, involving 34 cancer patients (27 evaluable for response), tumor regression wasobserved in 4 patients, stabilization occurred in 5, and 18 showed no response to a single injection oflive virus.[42] A subsequent trial involving 30 patients with cervical carcinoma tested several routesof inoculation (direct intratumoral injection, arterial infusion, intravenous infusion).[43,45] Toxicitywas limited to low-grade fever, and regression or stabilization of disease was observed in themajority of patients. Unfortunately, most responses were transient (< 3 months), and no patientsachieved a durable complete response.Analysis of cervical tissue and vaginal smears revealed proliferating virus in 77 samples from 20patients studied. However, with analysis of 140 samples, 10 patients showed no evidence of viralpresence. Response did not necessarily correlate with recovery of virus, although patients achievingmore extensive necrosis generally harbored detectable virus. Studies to explore more intensivedosing of the virus or combination with other anticancer agents were not pursued.

Mumps Virus

Mumps, a paramyxovirus, has a tight helical RNA inner core enclosed in an outer lipid/protein shell.Oncolytic efficacy of mumps virus was initially demonstrated in a rat sarcoma model.[46]Clinical TrialsThe first clinical trial investigating mumps virus involved 90 patients with advanced cancer andexplored several routes of administration including oral, rectal, intratumor, inhalation, andintravenous, depending on the location of the tumor.[25] Initial hematologic response to treatmentincluded leukocytosis followed by lymphopenia. Transient fever, which could be inhibited byprophylactic treatment with low-dose prednisone, was also observed.The authors noted that elevated antibodies at baseline were associated with a lesser tumorresponse.[25] However, three of the four patients achieving an "optimal" response had elevatedneutralizing antibodies to mumps virus prior to treatment. Overall, 37 (41%) patients achieveda ≥ 50% reduction in tumor size, and 79 patients with stable disease or better demonstratedclinical improvement (improved appetite, reduced pain, increased body weight).Of the 90 patients, 65 received a combination of local intratumoral injection and/or intravenousinfusion of the virus, and 24 (37%) of these 65 patients showed a partial or complete response. Mostpartial or complete responses occurred in patients with gastric carcinoma. However, the highestproportion of complete or partial responses occurred in cutaneous carcinoma and uterine carcinoma.Additionally, 9 of 10 patients with metastatic pulmonary carcinoma achieved clinical improvementwith regression in tumor bulk.Patients receiving multiple intratumoral injections over a prolonged period achieved a higherresponse rate and longer duration of response.[46,47] Fifteen patients received intravenous mumpsvirus alone. Six of these patients received fewer than nine intravenous treatments, and none had apositive response. In contrast, of the nine patients receiving nine or more systemic treatments, sixachieved a response (P < .02).[48] This was the first study to suggest that a multitreatment

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administration schedule may have a clinical advantage.Further exploration of a systemic route of administration was not performed. A follow-up studyinvolving 200 cancer patients administered mumps virus intratumorally.[49] Toxicity was minimal.Transient tumor regression was noted in 26 patients. Responses were observed in patients withcancer of the breast, rectum, colon, thyroid gland, uterus, and skin. Due to the transient nature ofthe response and the difficulty in manufacturing a uniform product, further clinical testing of themumps virus was not pursued.NDV is an avian paramyxovirus. Initial oncolytic activity was observed in several human and murinecancer cell lines.[19-21,50,51] Preclinical data also suggested that NDV may enhance tumor-specificimmunity, possibly through induction of cytokines such as tumor necrosis factor, interferon,interleukin (IL)-6, and IL-1.[52-54] Replication of NDV was also suggested to be as much as10,000-fold increased in malignant cells compared to normal fibroblasts.Selective uptake of NDV is seen in Daudi cells compared to normal peripheral bloodlymphocytes.[55,56] The mechanism for the selectivity of replication is unclear. However, someresults suggest that it may be related to elevated myc oncogene expression within malignant cells.Sensitivity to NDV-induced oncolysis in B104-C6a neuroblastoma cell lines is increased following myc transfection.[51] It also appeared that antitumor activity was not related to nonviable NDV.Furthermore, no toxicity was seen in mice.[57,58]Clinical TrialsClinical activity was initially noted in a patient with advanced cervical cancer following directinoculation of the virus into the tumor.[50] Evidence of intratumor viral proliferation was suggestedbased on tumor necrosis and the detection of replicating virus within the urine 11 days afterinjection.[50] Since the initial patient, several variant strains of Newcastle disease virus have beenexplored in clinical trials.In 1993,[46] 33 patients with advanced cancer received NDV via inhalation twice a week and theresults were compared to those in 26 patients who received placebo inhalation. Seven patientsachieved a complete or partial response, and one patient achieved a minor response. All eightpatients achieving a response survived 1 or more years following treatment. No responses wereobserved in control patients. Of 33 patients receiving virus, 22 survived at least 1 year, compared toonly 4 of 26 of the control patients (P < .02), and 7 patients who received virus survived at least 2years, compared to no patients in the control group (P < .0001).Overall, 18 (55%) patients achieved a favorable response (regression or stabilization) vs only 2 (8%; P < .01) placebo-treated patients. Additionally, seven of eight patients with colorectal cancermetastatic to the liver survived 1 year compared to one in five control patients with similar diseaseinvolvement (P = .04). Quality of life also appeared to improve in patients treated with viruscompared to the patients receiving placebo. The mechanism of antitumor activity was unclear.Direct tumor lysis was induced, but induction of antitumor immune mechanism was alsosuggested.[54]• Viral Oncolysate�Safety of NDV in clinical testing as a single agent provided justification fortesting this virus as an agent for enhancing tumor vaccine potency. Clinical trials involving patientswith early-stage melanoma explored the use of irradiated autologous tumor cells mixed with liveNDV as a vaccine approach. The combined product following tumor lysis was termed a "viraloncolysate."In one trial, patients with high-risk stage II melanoma were tested following surgical excision ofmetastatic nodes. The viral oncolysate was administered weekly to week 4, then every 2 weeks toweek 52, every 3 weeks to week 120, and every 6 weeks to week 160. Evidence of progressivedisease was shown to be 6% at 1 year, 8% at 2 years, and 12% at 3 years. For 83 patients, the3-year survival rate was 88%, and 5-year survival was 68%. Similar historical control patients had asignificantly lower survival rate over a similar period.[34,59-61]In another trial, autologous NDV oncolysate was used to treat colorectal cancer following resection ofmetastatic liver lesions.[62] The administration schedule was initiated 2 weeks after surgery andrepeated five times at 2-week intervals followed by one boost 3 months later. Nine of 23 patients(40%) showed an increase in delayed-type hypersensitivity reactions to irradiated autologous tumorcells placed intradermally following vaccination. of the vaccinated patients, 61% developed recurrentdisease within 18 months of vaccination, compared to an 87% recurrence rate in 130 controlpatients who underwent the same surgical procedure.[62] No significant toxicity was observed ineither the melanoma trial or colorectal carcinoma trial. Side effects of the NDV-treated vaccine werelimited to local inflammation and occasional febrile responses.NDV has also been used as a surgical adjuvant vaccine in 208 patients with locally advanced renal

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cell carcinoma. These patients received low-dose IL-2 and interferon-alpha in combination with theNDV oncolysate. Toxicity was limited to low-grade fever, mild flu-like symptoms, and localinflammation at the injection site. Median disease-free survival was 21+ months, which was greaterthan would be expected with similar historical patients.[63]In yet another study, the NDV oncolysate was also administered on days 1, 7, and 42 to 63 patientswith primary breast cancer, 27 patients with recurrent breast cancer, and 31 patients withmetastatic ovarian cancer.[64] All patients also received low-dose IL-2 (1 × 106 IU dailysubcutaneously) on days 1 to 19 and 42 to 60 and interferon-alpha (3 × 106 IU subcutaneously 3days per week) for the first 18 days then 3 days per week between days 42 and 58. Patients withprimary breast cancer appeared to have a survival benefit compared to historical controls (P = .026),but no survival advantage was suggested in the other disease groups.In summary, NDV oncolysate is well tolerated, and clinical efficacy has been suggested. Preclinicaldata indicate that further improvements in the therapeutic effect may be possible. NDV oncolysateactivity can be enhanced using antibodies that facilitate viral uptake by attaching to the viralhemoglutinin neuraminidase molecule on the infected tumor cells.[65] Also, the combination of NDVoncolysate with low-dose cyclophosphamide (Cytoxan, Neosar) to reduce antiviral suppressorlymphocyte numbers,[66,67] and the enhanced induction of immune effector populations bycombining NDV with immune-modulation agents (IL-2, interferon) may also improve potentialefficacy.[34] Further clinical trials are ongoing.

Influenza Virus

Influenza viruses are grouped in the family orthomyxoviridae. They contain a single strand of RNAgenome encased in a spherical or filamentous envelope. Preclinical data suggest that the influenzavirus has significant oncolytic activity,[68] but, unfortunately, neurologic affinity also results incentral neurologic toxicity.[69] Thus, clinical investigation of influenza virus has focused on its use asan oncolytic agent for manufacturing tumor vaccines ("influenza oncolysate").Clinical TrialsInfluenza oncolysates have been shown to induce greater antitumor activity in vivo than virus aloneor unmodified tumor cell extracts.[52,70] In one trial, 40 patients with advanced ovarian cancer weretreated with influenza oncolysate. Administration was done biweekly, then weekly, followed bymonthly injection. Intraperitoneal injections were also administered to seven patients with ascitesand two patients with pleural effusions.Three patients showed complete resolution of ascites following infusion of influenza oncolysate,[68]and one patient had resolution of his pleural effusion. Partial responses were observed in threepatients. Response duration lasted from 3 to 19 months, and survival varied from 4 to 42 months.Two responders later developed pleural effusions, and both responded to reinjection with theoncolysate. Toxicity included transient fever, nausea, malaise, and abdominal pain. Treatment wasstopped in two patients because of toxicity. Combination with IL-2 appeared to further enhance theimmunologic response initially achieved with only the influenza oncolysate.[71] Further clinicalinvestigation is ongoing.

Vaccinia Virus

Vaccinia is a naturally occurring ortopox virus with a linear double-stranded DNA genome.[72] Theactivity of vaccinia virus was shown to be equivalent to that of the original cowpox virus used forvaccination of smallpox. The use of live vaccinia virus to vaccinate millions of people for smallpoxminimized concerns regarding the safety of the virus in human cancer investigation.Several strains of vaccinia virus have been examined for activity as an oncolysate.[73,74] As is thecase with influenza virus, neurotropism is associated with the degree of oncolytic activity.[75,76]Immune responses to viral antigens have been shown to play a role in tumor destruction followinginfection with vaccinia virus.[39] Animal results show that survival of mice with metastatic CC36colon tumors was improved following vaccinia oncolysate injection.[77,78] Activity was enhancedwith low doses of IL-2. Similar results with other solid tumors have also been shown in various animalmodels.[73,79-81] Cytotoxic T lymphocytes induced by vaccinia oncolysate vaccine appear to bindto tumor antigens as well as viral antigens.Clinical TrialsSeveral clinical trials have been performed with vaccinia oncolysate.[82-84] In one trial, stage IImelanoma patients received 13 weekly intradermal injections of the viral oncolysate for 12 monthsor until recurrence. Twenty-five of 39 patients had no evidence of disease at 1 year. Of patients

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treated with the oncolysate, 64% developed antimelanoma antibodies.[81] There was a correlationbetween the development of melanoma-neutralizing IgG antibody titers and disease-freesurvival.[81] Preliminary toxicity with vaccinia oncolysate was limited to transient fevers and pain atthe injection site.These results led to a randomized, double-blind, multi-institutional trial of vaccinia oncolysate forpatients with stage II melanoma.[85,86] A total of 250 patients were treated. One group receivedvaccinia oncolysate at a protein dose of 2 mg/mL, while the other group received vaccinia virusalone at a dose of 105 plaque-forming units (PFU)/mL. Treatment was given once a week for 13weeks, then once every 2 weeks for an additional 39 weeks or until recurrence.There were no statistical differences in survival between the two cohorts of patients, with a mediandisease-free survival of 38 months for patients treated with the virus oncolysate, and 37 months forpatients treated with virus alone. Although a survival advantage with vaccinia oncolysate wassuggested in subsets of patients (ie, males between age 44 and 57 who had one to five positivenodes), the number of patients was insufficient to achieve statistical significance. Unfortunately, theinvestigators did not include a control group of patients who did not receive virus.Recent clinical investigation has involved the use of a nonreplicatingvaccinia/granulocyte-macrophage colony-stimulating factor (GM-CSF) gene vector.[87] Sevenpatients with stage IV melanoma were treated by intratumoral injection. Transfer of transgeneproduct was confirmed using reverse transcriptase-polymerase chain reaction (RT-PCR) assay andprimers specific for vaccinia thymidine kinase (TK) and GM-CSF gene. The researchers noted acorrelation between gene transfer and transient local tumor regression.HSV is a DNA virus in which a core double strand of viral DNA is generally encapsulated within anicosahedron outer envelope. HSV is a natural pathogen of the mammalian host that replicates at aprimary site (skin, cornea or mucosa) and moves by axonal transport to a second site of replication(sensory ganglia). From there, HSV reestablishes infection. When dormant in the sensory ganglia,HSV is not detectable systemically.A better understanding of the controls that restrict HSV expression and DNA replication may enablethe use of HSV as a possible gene delivery vehicle in the future.[88-90] The TK-deficient HSV mutant"dlsptk" has been shown to replicate in dividing cells, but is severely impaired for replication innondividing cells.[91-93] A dose-related survival improvement was shown in nude mice followinginjection of dlsptk in xenograft models with U87 tumors and 9L glioma cells.[91,94]HSV Modifications• G207�Researchers have developed another HSV mutant, G207, which does not contain a deletedTK gene. Rather, it contains deletion of the g-34.5 gene and a lacZ gene insertion.[95] Clinicallyrelevant characteristics of G207 include hypersensitivity to antiviral drugs (acyclovir, gancyclovir[Cytovene]), growth selectivity in nondividing cells, lack of neurologic pathogenicity, and thepresence of lacZ gene under control of the HSV promoter, which facilitates the detection ofreplicating virus using histochemistry.[96]G207 shows activity following intraneoplastic inoculation in subcutaneous and intracerebral U87gliomas. Necrosis following intratumoral injection associated with viral replication occurs within 15days. Furthermore, viral titration studies and histochemistry analysis showed that replication of theHSV virus was restricted to tumor cells and did not adversely affect surrounding brain tissue.[96,97]No toxic effects on normal rat glial cells or neurons in culture were observed, and G207 was nontoxicin vivo. Additional work with G207 has shown activity against meningioma in cell culture and inimplanted nude mice.[98]• HSV-1716�Methods of attempting to improve the oncolytic effect of HSV have involved infectionof a producer cell line, PA-1. Intraperitoneal injection of PA-1 cells infected in vitro with HSV-1716resulted in significantly reduced tumor volume compared to administration of virus alone andproduced a significant survival advantage, suggesting that the use of producer cell lines mayaugment efficacy of HSV-1716.[99]Others have also shown that the combination of HSV-1716 with chemotherapy in animal modelsfurther improved the oncolytic effect. Specifically, mice implanted with non-small-cell lung cancercells exposed to HSV-1716 human large-cell carcinoma in vitro followed by treatment withchemotherapy (mitomycin-C [Mutamycin], cisplatin, methotrexate, doxorubicin) demonstratedreduction in tumor volume.[100,101]• Inserted Genes�HSV (G207) with an inserted IL-12 gene has also been tested in a CT26 coloncarcinoma animal model. The antitumor effect was significantly greater in the replication-competentIL-12-transfected virus, compared with IL-12-negative replication-competent virus. CytotoxicT-lymphocyte activity specific to the inoculated tumor was also demonstrated. There was no

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evidence of additional toxicity and no detection of systemic circulation of IL-12.[102]Preclinical StudiesIn vitro studies have demonstrated that G207 efficiently replicates in the majority of malignantbreast cancer cell lines tested. Furthermore, in athymic mice harboring subcutaneous orintracerebral breast cancer cells sensitive to G207 in vitro, growth inhibition and prolonged survivalwas identified.• hrR3�Another strain of replication-efficient herpes simplex virus type 1, called hrR3, has beenexplored in a rat glioma model.[103] Direct intratumoral injection of hrR3, which contains a smalllacZ transgene, was injected into subcutaneous human gliomas with subsequent excision at differenttime points from injection. A computer-assisted volumetric analysis of lacZ transduction showed thatlacZ expression was significantly higher in tumors inoculated with hrR3, compared to tumorsinoculated with a replication-defective adenoviral vector containing lacZ. This also correlated with anincreased lacZ-positive viral yield from tumors inoculated with hrR3. Furthermore, tumor growth wassuppressed when treated with hrR3 and occasional complete regressions were observed comparedto tumor injected with the replication-defective adenoviral vector.Finally, hrR3 has also been explored following intravascular infusion in a rat glioblastoma model.Survival of rats receiving hrR3 was improved particularly when concurrently treated with RMP-7 (ananalog that disrupts the blood-brain barrier).[104] Further clinical investigation with HSV is ongoing.

Adenovirus Serotype 5

Adenovirus contains a single DNA strand encased in a hexagonal envelope. Replication-deficientadenovirus serotype 5 vectors are common gene delivery vehicles for numerous gene therapy trials.A great deal of accumulated data suggest that adenovirus serotype-5 has a low toxicity profile inhumans.[105] Eighty percent of adults have existing antibodies to adenovirus serotype 5, but lessthan 15% of exposed patients become clinically symptomatic.[106] The most common symptoms ofan adenoviral serotype 5 infection are flu-like in nature and include cough, gastroenteritis,conjunctivitis, cystitis, and pneumonia. However, these symptoms are rarely seen, even inimmunocompromised patients.[107]Oral adenoviral vaccines were given to thousands of military recruits in the 1960s without adverseeffects or increase in cancer incidence.[108] Both long- and short-term safety of live adenoviralinjections has been shown in several animal models.[109-115] Live adenovirus inocula were alsogiven intratumorally and intra-arterially to patients with cervical carcinoma at the National CancerInstitute in the 1950s.[43] No significant toxicities, other than transient fever and malaise, wereobserved in these women, including subsets of patients treated with steroids and others in whomneutralizing adenovirus antibodies were not present.In humans, nonreplicating adenoviral b-GAL vector injection was administered to patients withendobronchial lung cancer. Evidence of replication-competent adenovirus was studied in caretakerstaff samples. Specifically, 73 staff provided 78 blood samples, 272 urine samples, and 193 sampleswith which to study antibody formation or the presence of replication-competent adenovirus. Noreplication-competent adenovirus was detected, and elevated antibody formation did not inhibitgene expression with repeat injections.[116] Other trials have involved the administration of atherapeutic gene using a nonreplicating gene-modified adenovirus. This strategy has been shown tobe safe in normal volunteers[117] and in cancer patients.[118,119]ONYX-015Wild-type adenoviruses capable of replication encode proteins that inactivate the p53 gene. Thisenables viral replication in infected cells.[120,121] Specifically, a 55-kD protein from the E1B regionof the adenovirus genotype binds and inactivates the p53 gene.[122] ONYX-015 is an adenovirusconstructed with an E1B gene-deleted region, so that it no longer produces the 55-kD protein.Inability to block p53 because of such a deletion enables normal cellular p53 protein to maintain itsfunction, thereby inhibiting viral replication. As a result, ONYX-015 has lower replicative capacity innormal cells, but enhanced replicative capacity in tumor cells (which have abnormal p53function).[123,124]In animal human xenograft studies, intratumorally injected ONYX-015 had greater efficacy inp53-deficient cancers. Efficacy was further enhanced when ONYX-015 was used in combination witheither fluorouracil (5-FU) or cisplatin.[124-126] Intravenous infusions of ONYX-015 in animalsrevealed limited toxicity and tumor regression related to intratumoral access and/or replication.Efficacy was again augmented when used in combination with 5-FU.[127]However, since the initial report on ONYX-015,[123] controversial data have emerged, leading to

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questions about the selective replication capacity of ONYX-015. Many tumor cell lines with normalp53 sequences have been found to be sensitive to the effects of ONYX-015 in vivo.[128-131]Although replication selectivity appears not to be limited to p53 mutant-containing cells, otherfactors that alter p53 function (HPV-E6 effect, p14ARF production, or increased MDM-2 expression)may play a role.[132-136] Despite the controversial findings in malignant tissue, cytopathic effectshave not been observed in normal tissue at clinically relevant multiplicity of infection (MOI) valueswhen tested in vivo.[128,130,137,138] Furthermore, it has been shown clinically that the presence ofa p53 gene mutation within the tumor tissue does correlate with the response to intratumoralinjection of ONYX-015 as a single agent.[139]• Clinical Trials�A phase I investigation documented the safety of ONYX-015 when administered atdoses up to 2 × 1012 particles, given daily once every 3 weeks, or 2 × 1011 particles for 5 consecutivedays once every 3 weeks to chemotherapy refractory head and neck cancer patients with accessibletumor.[140] Phase II investigation was subsequently done in patients with advanced recurrent headand neck cancer who received two treatment schedules. One group (n = 30) received intratumoralinjection for 5 days (once a day) over a 21-day cycle, and in a subsequent trial, 10 patients receiveda "hyperfractionated" schedule, which involved 10 injections over 5 days in a 21-day cycle.[141]The most common treatment-related toxicity was fever, which occurred in 60% of the ONYX-015injected patients. Transaminitis was not observed. The systemic distribution of ONYX-015 wasdocumented using quantitative PCR in 12 of 29 patients 24 hours after the last ONYX-015 injection incycle 1. Only 2 of 19 patients continued to show circulating viral genome 14 days after intratumoralinjection. No patients were found to have circulating genome 22 days later. Biopsy analysis ofmalignant tissue by in situ hybridization for adenoviral DNA demonstrated replication of ONYX-015within tumor cells, and not within normal tissues.[141]Intratumoral injection of ONYX-015 in combination with cisplatin and 5-FU (2 × 1011

particles/injection) was administered to 30 patients with recurrent (chemotherapy-naive) squamouscell cancer of the head and neck region.[142] Among evaluable patients, 63% achieved at least a50% decrease in two dimensions of the injected tumor, and 27% of this subgroup achieved acomplete response. However, as opposed to the results of single-agent administration, no correlationwas found with tumor p53 mutation status. Eleven patients had two lesions each; one lesion wasinjected with ONYX-015 by protocol design and another was not. Of 11 injected tumors, 9 responded,compared to only 3 of 11 responses in "same patient"-matched noninjected tumors (MacNamara’stest, P = .01).[142] Other than a similar incidence of fever, chills, and injection site pain, noadditional toxicity in excess of what would be expected with chemotherapy was observed.• Use in Refractory Cancer�Following preclinical evidence of safety in animal models, intravenousinfusion of ONYX-015 has also been explored in refractory cancer patients.[143] ONYX-015 wasadministered on a weekly basis at doses ranging from 2 × 1010 particles to 2 × 1013 particles.Combination chemotherapy (carboplatin [Paraplatin] and paclitaxel) was administered aftercompletion of cycle 2 in patients receiving initial low doses of ONYX-015. When the tolerability ofchemotherapy plus IV ONYX-015 was determined to be safe, the chemotherapy was moved up today 7 of cycle 1. A total of 126 IV infusions were given in 42 cycles to 10 patients. Mild transaminitisand fever developed in all patients receiving ≥ 2 × 1012 particles/infusion within 48 hours of theinitial infusion, but these parameters returned to baseline prior to cycle 2 with continued dosing anddid not recur in cycle 2. Toxicity appeared to be correlated with elevated serum IL-6 levelsNine patients underwent pharmacokinetic testing, and in all nine, evidence of viral genome wasdetected in the blood 90 minutes after the end of infusion. Similar pharmacokinetic profiles wereseen in cycles 1 and 2, suggesting the lack of relationship to either circulating viral genome orinduction of neutralizing antibodies. All patients showed marked elevation of neutralizing antibodies.Patients receiving ONYX-015 at a dose of ≥ 2 × 1012 particles appeared to have a more prolongedduration of circulating viral genome, and a higher proportion of these patients had detectablegenome 6 hours after infusion. Furthermore, evidence of replication was suggested in three patients,in whom the concentration of viral particles per mL increased 0.5- to 10-fold from 6 hours to 48hours after administration. These three patients underwent tumor biopsy, and one had sufficienttissue for immunohistochemical staining. This assay revealed extensive intranuclear presence ofviral particles in malignant cells with no evidence of viral inclusions in adjacent normal cells.Unfortunately, no clinical responses were observed in this trial.

Conclusions

Antitumor activity and a low toxicity profile have been demonstrated for a variety of oncolytic

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viruses. However, the establishment of this approach as a therapeutic option for cancer patients hasbeen limited by a lack of definitive phase III trials. Incorporation of replicating viruses to potentiatethe efficacy of standard therapeutic approaches to cancer awaits conclusive clinical testing.Nevertheless, based on preliminary results with new generations of oncolytic viruses, ongoingresearch in this area appears encouraging.Today, methods of using oncolytic viruses to enhance immunity, induce oncolysis, and transfertherapeutic genes are better defined, and preliminary clinical results suggest some efficacy.Ultimately, oncolytic viruses may play a small role as a locoregional therapeutic approach, but theselective intratumor replication capacity of some of these viruses may enable their use as selectivegene delivery vehicles in cancer patients. References: 1. Niemialtowski MG, Toka FN, Malicka E, et al: Controlling orthopox virus infections�200 years afterJenner’s revolutionary immunization. Archivum Immunologiae et Therapiae Experimentalis44:373-378, 1996.

2. Ellner PD: Smallpox: Gone but not forgotten. Infection 26(5):263-269, 1998.

3. Hansen RM, Libnoch JA: Remission of chronic lymphocytic leukemia after smallpox vaccination.Arch Intern Med 138:1137-1138, 1978.

4. Bousser J, Zittoun R: Remission spontanee prolongee D-une leucemie lymphoide chromique. NouvRev Fr Hematol 5:498-501, 1965.

5. Vladimirskaia EB: A case of prolonged spontaneous remission in a patient with chroniclymphocytic leukemia. Probl Gematol Pereliv Krovi 7:51-54, 1962.

6. Weintraub LR: Lymphosarcoma: Remission associated with viral hepatitis. JAMA 24:1590-1591,1969.

7. Sinkovics JG: Oncolytic viruses and viral oncolysates. Ann Immun Hungaricae 26:271-290, 1986.

8. Dock G: Influence of complicating diseases upon leukaemia. Am J Med Sci 127:563-592, 1904.

9. Bierman HR, Hammon WMcD, Eddie BU, et al: The effect of viruses and bacterial infections onneoplastic diseases (abstract). Cancer Res 10:203-204, 1950.

10. Bluming AZ, Ziegler JL: Regression of Burkitt’s lymphoma in association with measles infection.Lancet 2:105-106, 1971.

11. Taqi AM, Abdurraham MB, Yabubu AM, et al: Regression of Hodgkin’s disease after measles.Lancet 1:1112, 1981.

12. Hernandez A: Observacion de un caso de enfermedad de Hodgkin, con regresion de los sintomase infartos ganglionares, post-sarampion. Rev Med Cubana 60:120-125, 1949.

13. Bierman HR, Crile DM, Dod KS: Remissions in leukemia of childhood following acute infectiousdisease; staphylococcus and streptococcus, varicella, and feline panleukopenia. Cancer 6:591-605,1953.

14. Pelner L, Fowler GA, Nauts HC: Effects of concurrent infections and their toxins on the course ofleukaemia. Acta Med Scand 338(suppl):1-47, 1958.

15. London RE: Multiple myeloma: report of a case showing unusual remission lasting two yearsfollowing severe hepatitis. Ann Intern Med 43:191-201, 1955.

16. De Pace NG: Sulla scomparsa di un enorme cancro vegetante del callo dell’utero senza curachirurgica. Ginecologia 9:82, 1912.

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