Review article
CHECKvacc (HOV3, CF33-hNIS-anti-PD-L1), the next medical revolution against cancer
CHECKvacc (HOV3, CF33-hNIS-anti-PD-L1), la siguiente revolución médica contra el cáncer
Ali Adel Dawood
Corresponding author
Dept. of Medical Biology, College of Medicine, University of Mosul, Mosul, Iraq
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Khan, Faiz-ul Hassan, Hafiz Khawar Ali, Mehmet Ozaslan" "autores" => array:8 [ 0 => array:2 [ "nombre" => "Muhammad" "apellidos" => "Safdar" ] 1 => array:2 [ "nombre" => "Shafeeq Ur" "apellidos" => "Rehman" ] 2 => array:2 [ "nombre" => "Furqan" "apellidos" => "Shafqat" ] 3 => array:2 [ "nombre" => "Muhammad" "apellidos" => "Shan" ] 4 => array:2 [ "nombre" => "Samiha S." "apellidos" => "Khan" ] 5 => array:2 [ "nombre" => "Faiz-ul" "apellidos" => "Hassan" ] 6 => array:2 [ "nombre" => "Hafiz Khawar" "apellidos" => "Ali" ] 7 => array:2 [ "nombre" => "Mehmet" "apellidos" => "Ozaslan" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2445146023000675?idApp=UINPBA00004N" "url" => "/24451460/0000002400000004/v2_202401230726/S2445146023000675/v2_202401230726/en/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S2445146023000651" "issn" => "24451460" "doi" => "10.1016/j.vacune.2023.10.009" "estado" => "S300" "fechaPublicacion" => "2023-10-01" "aid" => "302" "copyright" => "Elsevier España, S.L.U." "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Vacunas. 2023;24:348-57" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review Article</span>" "titulo" => "ERX-41; Promising compound by targeting LIPA is a new Achilles heel therapeutic strategy for hard-to-treat solid tumors by induction of endoplasmic reticulum stress" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "348" "paginaFinal" => "357" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "ERX-41; El compuesto prometedor de targeting LIPA es una nueva estrategia terapéutica del talón de Aquiles para tumores sólidos difíciles de tratar mediante la inducción del estrés del retículo endoplásmico" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "f0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1929 "Ancho" => 2756 "Tamanyo" => 537865 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">ERX-41 binds LAL and is independent of lipase activity. ERX-41 binds to the LXXLL domain of LAL protein and induces ER stress, resulting in apoptosis and cell death. LAL localization to the ER is critical for ERX-41 activity. ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. Three ERS sensors IRE1α, PERK, and ATF6 cooperatively organize UPR signaling. ERX-41 is a potent therapeutic agent for hard treat tumor through disruption of protein folding and induction of ER stress.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Majid Eslami, Mohammad Memarian, Bahman Yousefi" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Majid" "apellidos" => "Eslami" ] 1 => array:2 [ "nombre" => "Mohammad" "apellidos" => "Memarian" ] 2 => array:2 [ "nombre" => "Bahman" "apellidos" => "Yousefi" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2445146023000651?idApp=UINPBA00004N" "url" => "/24451460/0000002400000004/v2_202401230726/S2445146023000651/v2_202401230726/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review article</span>" "titulo" => "CHECKvacc (HOV3, CF33-hNIS-anti-PD-L1), the next medical revolution against cancer" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "358" "paginaFinal" => "363" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Ali Adel Dawood" "autores" => array:1 [ 0 => array:4 [ "nombre" => "Ali Adel" "apellidos" => "Dawood" "email" => array:1 [ 0 => "aad@uomosul.edu.iq" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cr0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Dept. of Medical Biology, College of Medicine, University of Mosul, Mosul, Iraq" "identificador" => "af0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cr0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "CHECKvacc (HOV3, CF33-hNIS-anti-PD-L1), la siguiente revolución médica contra el cáncer" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "f0005" "etiqueta" => "Fig 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1216 "Ancho" => 2008 "Tamanyo" => 231913 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0005" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Schematic showing mechanism of action of CF33-hNIS-antiPDL1.<a class="elsevierStyleCrossRef" href="#bb0070"><span class="elsevierStyleSup">14</span></a></p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="s0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0025">Introduction</span><p id="p0005" class="elsevierStylePara elsevierViewall">At the turn of the twentieth century, experts found that certain cancer patients had viral infections with tumors. This unexpected finding sparked the development of some theories and ideas to investigate the association between viruses and cancer.<a class="elsevierStyleCrossRef" href="#bb0005"><span class="elsevierStyleSup">1</span></a> In a series of studies conducted in the 1950s, persons with cancer were purposely given infectious bodily fluids or infected tissue derived from other patients with persistent viral infections. Among the viruses used include hepatitis, influenza, and picornavirus. Miraculously, many of these patients showed some level of tumor remission shrinking the size of their tumors but the remission would only last one to two months.<a class="elsevierStyleCrossRef" href="#bb0010"><span class="elsevierStyleSup">2</span></a></p><p id="p0010" class="elsevierStylePara elsevierViewall">However, the negative effect of having the accompanying illness and the morbidity of having the virus and cancer are overruled. Between the 1950s and the 1980s, there were no positive clinical outcomes in potential benefit trials. As researchers sought to manage the effect of virulence over time with little effect on outcomes, enthusiasm waned and the concept was largely abandoned until the 1990s, when genetic engineering techniques rekindled interest in oncolytic viruses.<a class="elsevierStyleCrossRef" href="#bb0015"><span class="elsevierStyleSup">3</span></a></p><p id="p0015" class="elsevierStylePara elsevierViewall">Using this new technology, scientists have been able to modify viruses that insert or delete genetic information to make them more selective to cancerous cells and less dangerous to healthy cells. Fast-forwarding today a therapeutic known as CF33 developed by Imugene and specifically genetically engineered to infect, and combat cancer cells, while sparing human healthy cells has just entered to the first clinical phase.<a class="elsevierStyleCrossRef" href="#bb0020"><span class="elsevierStyleSup">4</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a></p><p id="p0020" class="elsevierStylePara elsevierViewall">In general, the class of anticancer viruses has a few diverse modes of action that are worth investigating. The mechanism starts with the basics viruses are biological machines that are masters of infiltrating cells. The genetic code is stored within these viruses. Viral-infected cells are productive factories in which virus particles amass until they explode, delivering the viruses to surrounding cells.<a class="elsevierStyleCrossRef" href="#bb0030"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0035"><span class="elsevierStyleSup">7</span></a></p><p id="p0025" class="elsevierStylePara elsevierViewall">On May 22nd, the news broke that the first patients have been injected with a breakthrough cancer-killing virus.<a class="elsevierStyleCrossRef" href="#bb0040"><span class="elsevierStyleSup">8</span></a> Tests conducted on animals have already shown it to be able to reduce the size of colon, lung, breast, ovarian, and pancreatic cancer.<a class="elsevierStyleCrossRef" href="#bb0045"><span class="elsevierStyleSup">9</span></a></p></span><span id="s0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0030">Pre-clinical studies</span><p id="p0030" class="elsevierStylePara elsevierViewall">Viruses has been demonstrated in pre-clinical animal studies to reduce lung, breast, ovarian, and pancreatic cancer.<a class="elsevierStyleCrossRef" href="#bb0050"><span class="elsevierStyleSup">10</span></a> Native and recombinant oncolytic viruses, alone or in combination with other therapy, show promising outcomes against several cancer types. A preclinical investigation conducted that the modified oncolytic vesicular stomatitis virus to express interferon- (VSV-IFN-ꞵ) could be used to treat malignant mesothelioma.<a class="elsevierStyleCrossRef" href="#bb0055"><span class="elsevierStyleSup">11</span></a> Another study found that combining recombinant oncolytic virus (SJ-815) and irinotecan dramatically reduced tumor growth in pancreatic cancer and increased survival in melanoma-bearing mice models.<a class="elsevierStyleCrossRef" href="#bb0060"><span class="elsevierStyleSup">12</span></a></p><p id="p0035" class="elsevierStylePara elsevierViewall">Some preclinical studies have been conducted using the CF33 virus to generate the firefly luciferase gene. Firefly luciferase produces a bioluminescent light signal in the presence of a suitable substrate. CF33-Fluc is the name given to this virus. Modern combination chemotherapeutics have resulted in months of survival advantage in advanced disease.<a class="elsevierStyleCrossRef" href="#bb0065"><span class="elsevierStyleSup">13</span></a></p></span><span id="s0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0035">What is the oncolytic viruses?</span><p id="p0040" class="elsevierStylePara elsevierViewall">Many oncolytic viruses have been produced and tested during the last three decades. Natural and genetically modified oncolytic both take advantage of the numerous genetic variations between malignant and healthy cells.<a class="elsevierStyleCrossRef" href="#bb0070"><span class="elsevierStyleSup">14</span></a> The viral treatment infects, multiplies, and kills cancer cells. The vaccine may also increase the quantity of pdl1 protein in cancer cells, making them more susceptible to immunotherapy approaches. Some cancer cells may also over-express certain receptors on the cell's surface that may further help the viruses to bind and to infect malignant cells. While they have been demonstrated to be safe, their efficacy has thus far been limited. CF33 has destroyed every known cancer in a laboratory petri dish and killed tumors in mice. The use of CF33 in cancer treatment dates back to the late twentieth century.<a class="elsevierStyleCrossRef" href="#bb0075"><span class="elsevierStyleSup">15</span></a></p><p id="p0045" class="elsevierStylePara elsevierViewall">Oncolytic (CF33: cancer-fighting) viruses are engineered by Imugene. They are designed to infect and destroy cancer cells. CF33 was produced using a technique that intended to optimize its effectiveness against cancer cells while keeping appropriate safety to improve its limited performance. Once CF33 enters a tumor cell, it replicates and eventually causes the tumor cell to break down and die releasing cancer antigens. CF33 can elicit immune responses that seek to eliminate any remaining tumor cells in the vicinity and possibly elsewhere in the body. In preclinical experiments, CF33 was demonstrated to preferentially target and destroy tumor cells while leaving healthy cells alone, <a class="elsevierStyleCrossRef" href="#f0005">Fig. 1</a>.<a class="elsevierStyleCrossRef" href="#bb0080"><span class="elsevierStyleSup">16</span></a></p><elsevierMultimedia ident="f0005"></elsevierMultimedia><p id="p0050" class="elsevierStylePara elsevierViewall">CF33 is a poxviridae family double-stranded DNA virus. It has a lengthy history of safe use in millions of individuals because it was an active component of the vaccination that eradicated smallpox. The first oncolytic virus proved viral oncolysis in the laboratory in 1922, and it is one of the most fatal diseases known to people.<a class="elsevierStyleCrossRef" href="#bb0085"><span class="elsevierStyleSup">17</span></a></p><p id="p0055" class="elsevierStylePara elsevierViewall">CF33 was created by infecting a cell line with several strains of the vaxinia virus, including smallpox, rabbit pox, cowpox, and raccoon pox. A 9 viral strains infect cells at the same time allowing the viral genes to be rearranged via homologous recombination, resulting in the formation of new chimeric daughter viruses with different gene combinations from the parental virus strains. A total of 100 distinct chimeric viruses were isolated and tested for effectiveness against cancer cell types.<a class="elsevierStyleCrossRef" href="#bb0090"><span class="elsevierStyleSup">18</span></a></p><p id="p0060" class="elsevierStylePara elsevierViewall">Human sodium-iodide symporter (hNIS) is a gene that enables imaging to track the virus in vivo and make accompanying targeted radiotherapy more accurate. The cell surface protein hNIS delivers iodine to the thyroid gland where it is transformed into thyroid hormone. hNIS releases rhenium (188Re) or radioactive iodine (131I) into cancer cells for imaging or treatment when expressed. No one knows if CF33-hNIS can do the same miracles in humans, but if it does, it will be the second FDA-approved anti-cancer drug.<a class="elsevierStyleCrossRef" href="#bb0095"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0100"><span class="elsevierStyleSup">20</span></a></p><p id="p0065" class="elsevierStylePara elsevierViewall">Engineered viruses have also been to encode transmembrane proteins responsible for the uptake of iodine. This indicates that brachytherapy and tumor imaging can both efficiently transport radioactive iodine to the damaged cancer cell. Patients with any metastatic or advanced solid tumor who have shown radiographic progression following RECIST after at least two prior lines of therapy, which may have included immunotherapy, are eligible for treatment.<a class="elsevierStyleCrossRef" href="#bb0090"><span class="elsevierStyleSup">18</span></a></p></span><span id="s0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0040">Effectiveness of CF33 in cancer animal models</span><p id="p0070" class="elsevierStylePara elsevierViewall">Virus transmission is easier in naked mice because their immune systems are weaker than in animals with strong immune systems. As a result, the mouse study indicates that slides labeled with the novel vaccination show tumor shrinkage in the absence of virus spread, as well as higher infiltration of both injected and uninjected tumors by CD8 + T cells and other immune cells.<a class="elsevierStyleCrossRef" href="#bb0105"><span class="elsevierStyleSup">21</span></a> While oncolytic viruses have repeatedly killed cancer cells in preclinical studies, few have sufficiently stimulated the immune system to have a therapeutic effect.</p><p id="p0075" class="elsevierStylePara elsevierViewall">Imugene seeks to circumvent this barrier by mixing CF33 with a checkpoint inhibitor.<a class="elsevierStyleCrossRef" href="#bb0110"><span class="elsevierStyleSup">22</span></a> The combination of oncolytic viral therapy and checkpoint inhibitor is typically suggested by pressing the accelerator (increased tumor-immune system recognition) while relaxing the brakes (tumor microenvironment by blockade of the immunosuppressive checkpoints).<a class="elsevierStyleCrossRef" href="#bb0115"><span class="elsevierStyleSup">23</span></a> Imugene's immunology product line focused on B-cell vaccines, which will be expanded with the CF33 license agreement. If shareholders approve the CF33 licensing agreement, Imugene's pipeline will include the CF33 oncolytic virus as well as two anti-HER2 cell vaccines. A phase II clinical trial for B-cells is currently underway, as is a preclinical immunization against PD-1 B-cells.<a class="elsevierStyleCrossRef" href="#bb0120"><span class="elsevierStyleSup">24</span></a></p><p id="p0080" class="elsevierStylePara elsevierViewall">Researchers are looking for opportunities that give viruses a genetic or reproductive advantage. A study has found that it can reproduce a missing protein known as p53 (tumor suppressor) from a particular gene. An unmodified virus normally replicates in human cells because the viral gene it contains inactivates p53 when removed from the virus. It can then proliferate exclusively in cells with a defective p53 gene.<a class="elsevierStyleCrossRef" href="#bb0100"><span class="elsevierStyleSup">20</span></a></p><p id="p0085" class="elsevierStylePara elsevierViewall">Another study revealed that the novel immunosuppressive medication CF33-hNIS-anti-PD-L1 was effective against pancreatic ductal cancer. The purpose of this paper is to discuss the optimal technique to deliver CF33-hNIS-anti-PD-L1 to treat localized peritonitis.<a class="elsevierStyleCrossRef" href="#bb0125"><span class="elsevierStyleSup">25</span></a></p></span><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0045">CHECKvacc (HOV3, CF33-hNIS-anti-PD-L1)</span><p id="p0090" class="elsevierStylePara elsevierViewall">Vaxinia is a mix of CF33 with the hNIS gene that allows imaging to monitor the virus in vivo and initiate targeted radiotherapy. CHECKVacc refers to the synonym of (CF33<span class="elsevierStyleHsp" style=""></span>+ hNIS) and “armed” of anti-PD-L1 genes to improve anti-cancer immunotherapy. This new chimeric orthopoxvirus will be tested as a monotherapy or in combination with pembrolizumab to evaluate the efficacy and safety of the treatment regimens, as well as immunological alterations in the tumor microenvironment. Pembrolizumab is a genetically modified antibody that increases stimulation of the immune system to combat cancer-causing cells. Cancer cells have the same features that make oncolytic viruses resistant to therapy or radiation.<a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">26</span></a></p><p id="p0095" class="elsevierStylePara elsevierViewall">Despite advances in modern medicine, many cancers still learn to evade the immune system. The human immunity system is either not able to recognize the tumor as foreign or the immune response is shut down. For example, programmed cell death ligand 1(PD-L1) is a receptor on the tumor cell that fusions to the PD-1 found on immune cells. When the PD-L1 binds to PD-1, this connection tells immune cells to stop and not attack, <a class="elsevierStyleCrossRef" href="#f0010">Fig. 2</a>.<a class="elsevierStyleCrossRef" href="#bb0135"><span class="elsevierStyleSup">27</span></a> PD-L1 is a cellular signaling pathway that helps cells tell the immune system not to attack them with these signals removed. This means that the immune system can actively start to target and combat the cancer cells. The gene generates an anti-PD-L1 that is transported to the surface of the tumor cell. This antibodies binds to the PD-L1 receptor and blocks PD-1 from binding to the PD-L1 receptor. This makes uncloaks the tumor cell and allows the immune system to attack.<a class="elsevierStyleCrossRef" href="#bb0140"><span class="elsevierStyleSup">28</span></a> The deadly kind of breast cancer is the first step but melanoma and lung bladder and colon cancers are next in line for the human trials. <a class="elsevierStyleCrossRef" href="#f0010">Fig. 2</a> depicts the suppression of (PD-1 and PD-L1) complex formation.</p><elsevierMultimedia ident="f0010"></elsevierMultimedia></span><span id="s0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0050">CHECKvacc performance</span><p id="p0100" class="elsevierStylePara elsevierViewall">For the first time, a novel cancer-killing virus was administered to a human patient. It has been successfully tested on animals. However, scientists intend to test the efficacy and safety of this new medicine in humans in this first human trial. Scientists believe that the virus can increase the immune system's reaction to cancer. The first patient was dosed in a phase 1 clinical trial to assess the treatment's safety in people with advanced solid tumors. The medicine will be administered either directly into the tumors or intravenously. The team created the cancer-killing virus to not only harm cancer cells but also to make them more visible to the immune system. Tumor reduction was a huge achievement in early animal and laboratory research. One clinical trial sought to enroll 100 cancer patients from the United States and Australia with metastatic or advanced solid tumors. The team has already conducted non-clinical animal testing to show the efficacy of this technology and it's just entered into phase one clinical trials.<a class="elsevierStyleCrossRef" href="#bb0040"><span class="elsevierStyleSup">8</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0110"><span class="elsevierStyleSup">22</span></a></p><p id="p0105" class="elsevierStylePara elsevierViewall">All enrolled patients will receive CF33-hNIS on days 1 and 8 of cycle 1, as well as on day 1 of each following cycle. Patients undergoing the combination regimen will also receive pembrolizumab on day 1 of each cycle commencing with cycle 2. Researchers will explore the safety and tolerability of CF33-hNIS in cancer patients during a phase I clinical study by injecting the virus directly into the blood or tumor.<a class="elsevierStyleCrossRef" href="#bb0070"><span class="elsevierStyleSup">14</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0110"><span class="elsevierStyleSup">22</span></a></p><p id="p0110" class="elsevierStylePara elsevierViewall">1st phase clinical trials typically last six to eighteen months and look at the side effects of the therapy. The dosing required and how the drug works within the body of 2nd phase trials are conducted on larger population sizes and try to refine the dosing process. Finally, 3rd phase trials are on a very large population and look to understand if there are any subpopulations where the therapy isn't effective like those that might have a compromised immune system.<a class="elsevierStyleCrossRef" href="#bb0080"><span class="elsevierStyleSup">16</span></a> They also have some other genetic traits that the whole process can last typically five to ten years depending on how complicated the studies are to conduct and the availability of clinical trials. The test subject is one of the most common reasons that clinical trials fail because they can't find enough patients to test on within the context of this technology. If the immune system is stimulated, there will undoubtedly be some challenges to overcome.<a class="elsevierStyleCrossRef" href="#bb0110"><span class="elsevierStyleSup">22</span></a></p><p id="p0115" class="elsevierStylePara elsevierViewall">Once the virus has infected the cells, the viruses can be promptly eliminated from circulation before the anti-cancer effects kick in.<a class="elsevierStyleCrossRef" href="#bb0145"><span class="elsevierStyleSup">29</span></a> Another issue that has been noticed is that pre-existing immunity is fairly common. Most people get vaccinated against or encounter viruses throughout their life, resulting in immunological memory. This might mean that we need a different viral vector for every single therapy so that we don't become immune to our medicines.<a class="elsevierStyleCrossRef" href="#bb0150"><span class="elsevierStyleSup">30</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0155"><span class="elsevierStyleSup">31</span></a></p><p id="p0120" class="elsevierStylePara elsevierViewall">We're still a long way from the results of the new vaccine, perhaps 5 to 10 years, which may seem like a long time, but in comparison to the rise of cancer, it's not. Many therapies fail to pass clinical testing after trials. There are significant prospects that will define the next few decades for the discovery of acceptable medicines for incurable diseases.</p></span><span id="s0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0055">Study outcomes</span><p id="p0125" class="elsevierStylePara elsevierViewall">The study's main findings are the frequency and severity of adverse responses, as well as the high dose that individuals can tolerate. Each of these characteristics will affect whether the patient receives a single treatment or a combination of drugs. Secondary goals will include objective response rate, progression-free survival, duration of response, CF33-hNIS virus criterion, and disease control rate. As a final secondary outcome measurement, the researchers can employ single-photon emission computed tomography to assess tumor infection with CF33-hNIS. The Phase I inquiry is planned to be finished in January 2025.</p></span><span id="s0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0060">Conclusions</span><p id="p0130" class="elsevierStylePara elsevierViewall">The innovative method was tested on animals and demonstrated the ability to diminish the size of colon, lung, breast, ovarian, and pancreatic cancer. Some oncolytic viruses can also insert genes into the cell that cause it to produce proteins and metabolize a separately administered. An active drug component effects making a compound toxic only in cells that have become infected with a virus to help track these tumors within the body.</p></span><span id="s0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0065">Funding</span><p id="p0135" class="elsevierStylePara elsevierViewall">This work was done with self-supporting.</p></span><span id="s0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0070">Author contributions</span><p id="p0140" class="elsevierStylePara elsevierViewall">Designing the idea, choosing programs, writing the manuscript, using software, writing the results, analyze and clarifying the purpose of the study were done by the corresponding author.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:16 [ 0 => array:3 [ "identificador" => "xres2078652" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "as0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1773366" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2078651" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "as0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1773365" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "s0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "s0010" "titulo" => "Pre-clinical studies" ] 6 => array:2 [ "identificador" => "s0015" "titulo" => "What is the oncolytic viruses?" ] 7 => array:2 [ "identificador" => "s0020" "titulo" => "Effectiveness of CF33 in cancer animal models" ] 8 => array:2 [ "identificador" => "s0025" "titulo" => "CHECKvacc (HOV3, CF33-hNIS-anti-PD-L1)" ] 9 => array:2 [ "identificador" => "s0030" "titulo" => "CHECKvacc performance" ] 10 => array:2 [ "identificador" => "s0035" "titulo" => "Study outcomes" ] 11 => array:2 [ "identificador" => "s0040" "titulo" => "Conclusions" ] 12 => array:2 [ "identificador" => "s0045" "titulo" => "Funding" ] 13 => array:2 [ "identificador" => "s0050" "titulo" => "Author contributions" ] 14 => array:2 [ "identificador" => "xack724189" "titulo" => "Acknowledgments" ] 15 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2022-08-16" "fechaAceptado" => "2023-01-31" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1773366" "palabras" => array:5 [ 0 => "CF33" 1 => "Oncolytic virus" 2 => "CHECKvacc" 3 => "Tumor" 4 => "pembrolizumab" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1773365" "palabras" => array:5 [ 0 => "CF33" 1 => "Virus oncolítico" 2 => "CHECKvacc" 3 => "Tumor" 4 => "Pembrolizumab" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="as0005" class="elsevierStyleSection elsevierViewall"><p id="sp0020" class="elsevierStyleSimplePara elsevierViewall">Despite advances in modern treatment, many cancers have evolved to bypass the immune system. The immune system either cannot perceive the tumor as foreign or the immune response is hindered. Oncolytic viruses are designed to infect and kill cancer cells. A huge variety of oncolytic viruses have been produced and tested over the last 30 years. The presence of 9 different virus strains in the cells (mouse) at the same time allowed the genes from the different strains to be rearranged via homologous recombination to generate unique chimeric daughter viruses. CHECKvacc is a genetically engineered oncolytic virus (CF33) that is equipped with the human sodium iodide symporter (hNIS) and an anti-PD-L1 antibody. The novel modified viruses will be examined as a monotherapy or in combination with pembrolizumab to determine the safety and efficacy of the treatment regimens. The first patient was dosed in a phase 1 clinical trial to assess the treatment's safety in people with advanced solid tumors. The medicine will be administered either directly into the tumors or intravenously.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="as0010" class="elsevierStyleSection elsevierViewall"><p id="sp0025" class="elsevierStyleSimplePara elsevierViewall">A pesar de los avances del tratamiento moderno, muchos cánceres han evolucionado para sortear al sistema inmunitario. Dicho sistema inmunitario no puede percibir el tumor como algo exterior, o bien se obstaculiza la respuesta inmunológica. Los virus oncolíticos están diseñados para infectar y matar a las células cancerígenas. A lo largo de los últimos 30 años se han producido y probado una gran variedad de virus oncolíticos. La presencia de 9 cepas diferentes de virus en las células (de ratón) al mismo tiempo ha permitido que los genes de diferentes cepas se reorganicen a través de una recombinación homóloga, para generar virus hijos quiméricos únicos. CHECKvacc es un virus oncolítico genéticamente diseñado (CF33) que está equipado con el simportador de yoduro de sodio humano (hNIS) y un anticuerpo anti-PD-L1. Los virus modificados noveles serán examinados como monoterapia, o en combinación con pembrolizumab, para determinar la seguridad y eficacia de los regímenes terapéuticos. Al primer paciente se le administró en un ensayo clínico de fase 1 para evaluar la seguridad del tratamiento en personas con tumores sólidos avanzados. El medicamento será administrado bien directamente al interior de los tumores, o por vía intravenosa.</p></span>" ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "f0005" "etiqueta" => "Fig 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1216 "Ancho" => 2008 "Tamanyo" => 231913 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0005" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Schematic showing mechanism of action of CF33-hNIS-antiPDL1.<a class="elsevierStyleCrossRef" href="#bb0070"><span class="elsevierStyleSup">14</span></a></p>" ] ] 1 => array:8 [ "identificador" => "f0010" "etiqueta" => "Fig 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1383 "Ancho" => 2008 "Tamanyo" => 317368 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0010" "detalle" => "Fig " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">On top, PD-1 and PD-L1 receptors on the cell surface. <span class="elsevierStyleBold">A</span>: 3D structure combination between PD-1(cyan) and PD-L1 (magenta) PDB (<span class="elsevierStyleInterRef" id="ir0005" href="pdb:4ZQK">4ZQK</span>). <span class="elsevierStyleBold">B</span>: PD-1 on the surface of the T-cell and PD-L1 on the surface of the tumor. This complex prevents T-cell to attack the tumor cell.</p> <p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">On down, the cancer cell is free from attaching to the T-cell on the down, <span class="elsevierStyleBold">C</span>: 3D structure of PD-1 on the T-cell surface. <span class="elsevierStyleBold">D</span>: 3D structure formation of the (anti-PD-L1 and PD-L1) complex (PDB: <span class="elsevierStyleInterRef" id="ir0010" href="pdb:5GGS">5GGS</span>). <span class="elsevierStyleBold">E</span>: Prevention formation of the (PD-1 with PD-L1) complex. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0005" "bibliografiaReferencia" => array:31 [ 0 => array:3 [ "identificador" => "bb0005" "etiqueta" => "1." 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