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Introduction: Intratumoral administration of pexa-vec (pexastimogene devacirepvec), an oncolytic and immunotherapeutic vaccinia virus, given to patients with hepatocellular carcinoma (HCC), is associated with both local and distant tumor responses. We hypothesized subsequent treatment with sorafenib could demonstrate superior efficacy. Methods: This random phase III open-label study evaluated the sequential treatment with pexa-vec followed by sorafenib compared to sorafenib in patients with advanced HCC and no prior systemic treatment. The primary endpoint is overall survival (OS). Key secondary endpoints included time to progression (TTP), progression-free survival, overall response rate (ORR), and disease control rate (DCR). Safety was assessed in all patients who received ≥1 dose of study treatment. Results: The study was conducted at 142 sites in 16 countries. From December 30, 2015, to the interim analysis on August 2, 2019, 459 patients were randomly assigned (pexa-vec plus sorafenib: 234, sorafenib: 225). At the interim analysis, the median OS was 12.7 months (95% CI: 9.89, 14.95) in the pexa-vec plus sorafenib arm and 14.0 months (95% CI: 11.01, 18.00) in the sorafenib arm. This led to the early termination of the study. The median TTP was 2.0 months (95% CI: 1.77, 2.96) and 4.2 months (95% CI: 2.92, 4.63); ORR was 19.2% (45 patients) and 20.9% (47 patients); and DCR was 50.0% (117 patients) and 57.3% (129 patients) in the pexa-vec plus sorafenib and sorafenib arms, respectively. Serious adverse events were reported in 117 (53.7%) patients in the pexa-vec plus sorafenib and 77 (35.5%) patients in the sorafenib arm. Liver failure was the most frequently reported in both groups. Conclusion: Sequential pexa-vec plus sorafenib treatment did not demonstrate increased clinical benefit in advanced HCC and fared worse compared to sorafenib alone. The advent of the added value of checkpoint inhibitors should direct any further development of oncolytic virus therapy strategies.
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Colorectal cancer is the third most diagnosed cancer and the second leading cause of cancer mortality worldwide, highlighting an urgent need for new therapeutic options and combination strategies for patients. The orchestration of potent T cell responses against human cancers is necessary for effective antitumour immunity. However, regression of a limited number of cancers has been induced by immune checkpoint inhibitors, T cell engagers (TCEs) and/or oncolytic viruses. Although one TCE has been FDA-approved for the treatment of hematological malignancies, many challenges exist for the treatment of solid cancers. Here, we show that TCEs targeting CEACAM5 and CD3 stimulate robust activation of CD4 and CD8-positive T cells in in vitro co-culture models with colorectal cancer cells, but in vivo efficacy is hindered by a lack of TCE retention in the tumour microenvironment and short TCE half-life, as demonstrated by HiBiT bioluminescent TCE-tagging technology. To overcome these limitations, we engineered Bispecific Engager Viruses, or BEVirs, a novel tumour-targeted vaccinia virus platform for intra-tumour delivery of these immunomodulatory molecules. We characterized virus-mediated TCE-secretion, TCE specificity and functionality from infected colorectal cancer cells and patient tumour samples, as well as TCE cytotoxicity in spheroid models, in the presence and absence of T cells. Importantly, we show regression of colorectal tumours in both syngeneic and xenograft mouse models. Our data suggest that a different profile of cytokines may contribute to the pro-inflammatory and immune effects driven by T cells in the tumour microenvironment to provide long-lasting immunity and abscopal effects. We establish combination regimens with immune checkpoint inhibitors for aggressive colorectal peritoneal metastases. We also observe a significant reduction in lung metastases of colorectal tumours through intravenous delivery of our oncolytic virus driven T-cell based combination immunotherapy to target colorectal tumours and FAP-positive stromal cells or CTLA4-positive Treg cells in the tumour microenvironment. In summary, we devised a novel combination strategy for the treatment of colorectal cancers using oncolytic vaccinia virus to enhance immune-payload delivery and boost T cell responses within tumours.
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Neoplasias Colorretais , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Camundongos , Animais , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia , Vaccinia virus , Modelos Animais de Doenças , Neoplasias Colorretais/terapia , Microambiente TumoralRESUMO
Oncolytic viral immunotherapy based on the MG1 Maraba platform has undergone extensive preclinical evaluation, resulting in the advancement of two programs into clinical trials. MG1 Maraba encoding tumor antigens (tumor associated antigens or viral antigens) are used to boost antitumor immunity, while MG1 Maraba infects tumors, causes oncolysis and transforms the tumor microenvironment. An overview of MG1 Maraba clinical development is outlined here, along with general considerations relating to the design of clinical trials for complex biologic products such as oncolytic viral immunotherapies. These include choice of patient population, optimized treatment regimen, and endpoints which provide early signals of activity and inform the late-stage development path of these agents with novel mechanisms of action.
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Vetores Genéticos/genética , Vírus Oncolíticos/genética , Rhabdoviridae/genética , Pesquisa Translacional Biomédica , Animais , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Engenharia Genética , Terapia Genética/métodos , Humanos , Imunoterapia/métodos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/imunologia , Projetos de Pesquisa , Rhabdoviridae/imunologiaRESUMO
Multiple immunotherapeutics have been approved for cancer patients, however advanced solid tumors are frequently refractory to treatment. We evaluated the safety and immunogenicity of a vaccination approach with multimodal oncolytic potential in non-human primates (NHP) (Macaca fascicularis). Primates received a replication-deficient adenoviral prime, boosted by the oncolytic Maraba MG1 rhabdovirus. Both vectors expressed the human MAGE-A3. No severe adverse events were observed. Boosting with MG1-MAGEA3 induced an expansion of hMAGE-A3-specific CD4+ and CD8+ T-cells with the latter peaking at remarkable levels and persisting for several months. T-cells reacting against epitopes fully conserved between simian and human MAGE-A3 were identified. Humoral immunity was demonstrated by the detection of circulating MAGE-A3 antibodies. These preclinical data establish the capacity for the Ad:MG1 vaccination to engage multiple effector immune cell populations without causing significant toxicity in outbred NHPs. Clinical investigations utilizing this program for the treatment of MAGE-A3-positive solid malignancies are underway (NCT02285816, NCT02879760).
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Oncolytic activity of the MG1 strain of the Maraba vesiculovirus has proven efficacy in numerous preclinical cancer models, and relied not only on a direct cytotoxicity but also on the induction of both innate and adaptive antitumor immunity. To further expand tumor-specific T-cell effector and long-lasting memory compartments, we introduced the MG1 virus in a prime-boost cancer vaccine strategy. To this aim, a replication-incompetent adenoviral [Ad] vector together with the oncolytic MG1 have each been armed with a transgene expressing a same tumor antigen. Immune priming with the Ad vaccine subsequently boosted with the MG1 vaccine mounted tumor-specific responses of remarkable magnitude, which significantly prolonged survival in various murine cancer models. Based on these promising results, we validated the safety profile of the Ad:MG1 oncolytic vaccination strategy in nonhuman primates and initiated clinical investigations in cancer patients. Two clinical trials are currently under way (NCT02285816; NCT02879760). The present review will recapitulate the discoveries that led to the development of MG1 oncolytic vaccines from bench to bedside.
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Oncolytic viruses pose many questions in their use in cancer therapy. In this study, we assessed the potential of mpJX-594 (mouse-prototype JX-594), a replication-competent vaccinia virus administered by intravenous injection, to target the tumor vasculature, produce immune activation and tumor cell killing more widespread than the infection, and suppress invasion and metastasis. These actions were examined in RIP-Tag2 transgenic mice with pancreatic neuroendocrine tumors that developed spontaneously and progressed as in humans. mpJX-594 initially infected tumor vascular endothelial cells, leading to vascular pruning and prolonged leakage in tumors but not in normal organs; parallel effects were observed in U87 gliomas. Viral infection spread to tumor cells, where tumor cell killing was much more widespread than the infection. Widespread tumor cell killing at 5 days was prevented by depletion of CD8+ T lymphocytes and did not require GM-CSF, as mpJX-594 variants that expressed human, mouse, or no GM-CSF produced equivalent amounts of killing. The antivascular, antitumor, and antimetastatic effects of mpJX-594 were amplified by concurrent or sequential administration of sunitinib, a multitargeted receptor tyrosine kinase inhibitor. These effects were not mimicked by selective inhibition of VEGFR2 despite equivalent vascular pruning, but were accompanied by suppression of regulatory T cells and greater influx of activated CD8+ T cells. Together, our results showed that mpJX-594 targets tumor blood vessels, spreads secondarily to tumor cells, and produces widespread CD8+ T-cell-dependent tumor cell killing in primary tumors and metastases, and that these effects can be amplified by coadministration of sunitinib.Significance: These findings reveal multiple unrecognized features of the antitumor properties of oncolytic vaccinia viruses, all of which can be amplified by the multitargeted kinase inhibitor sunitinib. Cancer Res; 78(4); 922-37. ©2017 AACR.
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Antineoplásicos/uso terapêutico , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/imunologia , Sunitinibe/uso terapêutico , Animais , Antineoplásicos/farmacologia , Humanos , Camundongos , Camundongos Transgênicos , Sunitinibe/farmacologia , Vaccinia virus/imunologiaRESUMO
Oncolytic viruses (OV) are replicating viral therapeutics for the treatment of cancer and have been in laboratory development for about twenty years. Recently, the FDA approved Imlygic, a herpes virus based therapeutic for the treatment of melanoma and thus OVs have entered a new era where they are a weapon in the armament of the oncologist. OVs are unique therapeutics with multiple mechanisms of therapeutic activity. The exact path for their development and eventual uptake by pharmaceutical companies is somewhat clouded by an uncertain identity. Are they vaccines, tumour lysing therapeutics, inducers of innate immunity, gene therapy vectors, anti-vascular agents or all of the above? Should they be developed as stand-alone loco-regional therapeutics, systemically delivered tumour hunters or immune modulators best tested as combination therapeutics? We summarize data here supporting the idea, depending upon the virus, that OVs can be any or all of these things. Pursuing a "one-size fits all" approach is counter-productive to their clinical development and instead as a field we should build on the strengths of individual virus platforms.
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Vetores Genéticos/genética , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Animais , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Ensaios Clínicos como Assunto , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Humanos , Imunomodulação , Imunoterapia/métodos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/imunologia , Resultado do Tratamento , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
We have conducted a phase 1 study of intravenous vvDD, a Western Reserve strain oncolytic vaccinia virus, on 11 patients with standard treatment-refractory advanced colorectal or other solid cancers. The primary endpoints were maximum tolerated dose and associated toxicity while secondary endpoints were pharmacokinetics, pharmacodynamics, immune responses, and antitumor activity. No dose-limiting toxicities and treatment related severe adverse events were observed. The most common adverse events were grades 1/2 flu-like symptoms. Virus genomes were detectable in the blood 15-30 minutes after virus administration in a dose-dependent manner. There was evidence of a prolonged virus replication in tumor tissues in two patients, but no evidence of virus replication in non-tumor tissues, except a healed injury site and an oral thrush. Over 100-fold of anti-viral antibodies were induced in patients' sera. A strong induction of inflammatory and Th1, but not Th2 cytokines, suggested a potent Th1-mediated immunity against the virus and possibly the cancer. One patient showed a mixed response on PET-CT with resolution of some liver metastases, and another patient with cutaneous melanoma demonstrated clinical regression of some lesions. Given the confirmed safety, further trials evaluating intravenous vvDD in combination with therapeutic transgenes, immune checkpoint blockade or complement inhibitors, are warranted.
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Terapia Genética , Vetores Genéticos/genética , Neoplasias/genética , Neoplasias/terapia , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Poxviridae/genética , Adulto , Idoso , Anticorpos Antivirais/imunologia , Terapia Combinada , Citocinas/metabolismo , Feminino , Vetores Genéticos/administração & dosagem , Vetores Genéticos/efeitos adversos , Vetores Genéticos/farmacocinética , Humanos , Mediadores da Inflamação , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias/diagnóstico , Neoplasias/mortalidade , Terapia Viral Oncolítica/efeitos adversos , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/imunologia , Poxviridae/imunologia , Retratamento , Resultado do TratamentoRESUMO
Oncolytic viruses designed to attack malignant cells can in addition infect and destroy tumor vascular endothelial cells. We show here that this expanded tropism of oncolytic vaccinia virus to the endothelial compartment is a consequence of VEGF-mediated suppression of the intrinsic antiviral response. VEGF/VEGFR2 signaling through Erk1/2 and Stat3 leads to upregulation, nuclear localization, and activation of the transcription repressor PRD1-BF1/Blimp1. PRD1-BF1 does not contribute to the mitogenic effects of VEGF, but directly represses genes involved in type I interferon (IFN)-mediated antiviral signaling. In vivo suppression of VEGF signaling diminishes PRD1-BF1/Blimp1 expression in tumor vasculature and inhibits intravenously administered oncolytic vaccinia delivery to and consequent spread within the tumor.
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Neoplasias/virologia , Vírus Oncolíticos/fisiologia , Fatores de Transcrição/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Células Cultivadas , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Interações Hospedeiro-Patógeno , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/virologia , Humanos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Neoplasias/irrigação sanguínea , Neoplasias/terapia , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/virologia , Fator 1 de Ligação ao Domínio I Regulador Positivo , Interferência de RNA , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética , Ativação Transcricional/efeitos dos fármacos , Vaccinia virus/fisiologiaRESUMO
Fifteen patients with treatment-refractory colorectal cancer were enrolled on a phase 1b study of Pexa-Vec (pexastimogene devacirepvec; JX-594), an oncolytic and immunotherapeutic vaccinia designed to selectively replicate in cancer cells. Pexa-Vec was administered intravenously every 14 days, at dose levels of 1 × 10(6), 1 × 10(7), or 3 × 10(7) plaque-forming units (pfu)/kg. The primary endpoint was to determine the maximum tolerated dose. Secondary endpoints were pharmacokinetics and pharmacodynamics as well as antitumor activity. Patients were heavily pretreated (mean 4.5 lines of therapy). All patients received at least two Pexa-Vec doses (median = 4; range = 2-4). No dose-limiting toxicities were reported, and the maximum tolerated dose was not reached. The most common adverse events were grade 1/2 flu-like symptoms, generally lasting <24 hours. During the first and last cycles, genome pharmacokinetics were unchanged. Infectious pfu could be detected in plasma up to 2 hours after cycle 1 and up to 30 minutes after cycle 4 (when antivaccinia antibody titers are known to have peaked). Ten patients (67%) had radiographically stable disease. Given the acceptable safety profile of multiple intravenous Pexa-Vec infusions in patients with treatment-refractory colorectal cancer, further trials evaluating efficacy of intravenous Pexa-Vec, as monotherapy or in combination with chemotherapeutic agents, is warranted in this patient population.
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Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/terapia , Vetores Genéticos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Imunoterapia , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Vaccinia virus/genética , Administração Intravenosa , Adulto , Idoso , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Terapia Combinada , Citocinas/sangue , Esquema de Medicação , Feminino , Vetores Genéticos/administração & dosagem , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Terapia Viral Oncolítica/efeitos adversos , Terapia Viral Oncolítica/métodos , Dermatopatias/etiologia , Dermatopatias/patologia , Resultado do TratamentoRESUMO
Primary liver cancer (hepatocellular carcinoma; HCC) in patients not eligible for surgery or transplant is currently treated by locoregional therapeutic approaches, including trans-arterial chemoembolization and radiofrequency ablation. Sorafenib (Nexavar; Bayer/Onyx) is currently the only approved systemic therapy for patients having failed locoregional interventions. Oncolytic viruses are designed to selectively replicate within, and subsequently lyse, cancer cells by a unique mechanisms-of-action that is not cross-resistant with approved therapies (Kirn et al., Nat Med 7:781-787, 2001; Parato et al., Nat Rev Cancer 5:965-976, 2005; Chiocca, Nat Rev Cancer 2:938-950, 2002; Heise and Kern, J Clin Invest 105:847-851, 2000). Given that these therapeutics are self-amplifying in tumors, the impact of dose on patient outcome is unclear. Pexa-Vec (JX-594) is an oncolytic and immunotherapeutic vaccinia virus which was shown to be well tolerated by intratumoral injection and intravenous infusions in Phase 1 trials (Park et al., Lancet Oncol 9:533-542, 2008; Breitbach et al., Nature 477:99-102, 2011). We present the design of a randomized dose-finding trial of Pexa-Vec in patients with advanced HCC in which Pexa-Vec was delivered by intratumoral injection three times every 2 weeks at one of two dose levels (1 × 10(8) plaque forming units (pfu) versus 1 × 10(9) pfu).
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Carcinoma Hepatocelular/terapia , Injeções Intralesionais , Neoplasias Hepáticas/terapia , Terapia Viral Oncolítica/métodos , Vaccinia virus/fisiologia , Carcinoma Hepatocelular/cirurgia , Seguimentos , Humanos , Processamento de Imagem Assistida por Computador , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/cirurgia , Terapia Viral Oncolítica/efeitos adversos , Resultado do TratamentoRESUMO
Developing a live anti-cancer agent derived in most cases from human pathogens presents a unique set of challenges to clinical development versus those anticipated with standard chemotherapeutics and small molecules. The selection of therapeutic targets for oncolytic virus (OV) clinical development, as is true with the development of any agent for cancer therapy, requires careful consideration beyond preclinical and early clinical data, especially when multiple indications may initially appear equally promising. Further, the added complexity of the potential for infectious complications following OV therapy must be anticipated in order to efficiently and safely conduct clinical studies. As more OV enter the clinic, these issues will become increasingly important to successful OV drug development.
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Neoplasias/terapia , Terapia Viral Oncolítica , Vírus Oncolíticos/fisiologia , Animais , Humanos , Neoplasias/virologia , Terapia Viral Oncolítica/tendências , Vírus Oncolíticos/genéticaRESUMO
Oncolytic immunotherapies (OI) selectively infect, amplify within and destroy cancer cells, thereby representing a novel class of anti-cancer therapy. In addition to this primary mechanism-of-action (MOA), OI based on vaccinia have been shown to selectively target tumor-associated vasculature, triggering an acute reduction in tumor perfusion. This review focuses on a third complementary MOA for this product class: the induction of active immunotherapy. While the active immunotherapy approach has been validated by recent product approvals, the field is still faced with significant challenges. Tumors have evolved diverse mechanisms to hide from immune-mediated destruction. Here we hypothesize that oncolytic immunotherapy replication within tumors may tip the immune balance to allow for the effective induction and execution of adaptive anti-tumor immunity, resulting in long-term tumor control following OI clearance. This immune activation against the cancer can be augmented through OI 'arming' for the expression of immunostimulatory transgene products from the virus genome. With the first vaccinia OI (Pexa-Vec, thymidine kinase-inactivated vaccinia expressing Granulocyte-colony stimulating factor [GM-CSF]) now in advanced-stage clinical trials, it has become more important than ever to understand the complimentary MOA that contributes to tumor destruction and control in patients.
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Imunoterapia , Neoplasias/terapia , Vírus Oncolíticos/genética , Vaccinia virus/genética , Animais , Humanos , Neoplasias/imunologia , Neoplasias/virologia , Vírus Oncolíticos/imunologia , Vaccinia virus/imunologiaRESUMO
Oncolytic viruses (OVs) have shown promising clinical activity when administered by direct intratumoral injection. However, natural barriers in the blood, including antibodies and complement, are likely to limit the ability to repeatedly administer OVs by the intravenous route. We demonstrate here that for a prototype of the clinical vaccinia virus based product Pexa-Vec, the neutralizing activity of antibodies elicited by smallpox vaccination, as well as the anamnestic response in hyperimmune virus treated cancer patients, is strictly dependent on the activation of complement. In immunized rats, complement depletion stabilized vaccinia virus in the blood and led to improved delivery to tumors. Complement depletion also enhanced tumor infection when virus was directly injected into tumors in immunized animals. The feasibility and safety of using a complement inhibitor, CP40, in combination with vaccinia virus was tested in cynomolgus macaques. CP40 pretreatment elicited an average 10-fold increase in infectious titer in the blood early after the infusion and prolonged the time during which infectious virus was detectable in the blood of animals with preexisting immunity. Capitalizing on the complement dependence of antivaccinia antibody with adjunct complement inhibitors may increase the infectious dose of oncolytic vaccinia virus delivered to tumors in virus in immune hosts.
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Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/imunologia , Vaccinia virus/imunologia , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Linhagem Celular Tumoral , Chlorocebus aethiops , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Estudos de Viabilidade , Feminino , Células HeLa , Humanos , Injeções Intralesionais , Macaca fascicularis/imunologia , Masculino , Neoplasias/sangue , Neoplasias/terapia , Testes de Neutralização , Piridonas/imunologia , Piridonas/farmacologia , Ratos , Ratos Endogâmicos F344 , Vacina Antivariólica/sangue , Vacina Antivariólica/imunologia , Vacinação , Células VeroRESUMO
Pexa-Vec (pexastimogene devacirepvec, JX-594) is an oncolytic and immunotherapeutic vaccinia virus designed to destroy cancer cells through viral lysis and induction of granulocyte-macrophage colony-stimulating factor (GM-CSF)-driven tumor-specific immunity. Pexa-Vec has undergone phase 1 and 2 testing alone and in combination with other therapies in adult patients, via both intratumoral and intravenous administration routes. We sought to determine the safety of intratumoral administration in pediatric patients. In a dose-escalation study using either 10(6) or 10(7) plaque-forming units per kilogram, we performed one-time injections in up to three tumor sites in five pediatric patients and two injections in one patient. Ages at study entry ranged from 4 to 21 years, and their cancer diagnoses included neuroblastoma, hepatocellular carcinoma, and Ewing sarcoma. All toxicities were ≤ grade 3. The most common side effects were sinus fever and sinus tachycardia. All three patients at the higher dose developed asymptomatic grade 1 treatment-related skin pustules that resolved within 3-4 weeks. One patient showed imaging evidence suggestive of antitumor biological activity. The two patients tested for cellular immunoreactivity to vaccinia antigens showed strong responses. Overall, our study suggests Pexa-Vec is safe to administer to pediatric patients by intratumoral administration and could be studied further in this patient population.
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Protocolos de Quimioterapia Combinada Antineoplásica , Vacinas Anticâncer/imunologia , Raios gama , Imunoterapia/métodos , Terapia Viral Oncolítica/métodos , Vaccinia virus/imunologia , Adolescente , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/patologia , Neoplasias Ósseas/terapia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Vacinas Anticâncer/administração & dosagem , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Criança , Pré-Escolar , Feminino , Vetores Genéticos/administração & dosagem , Vetores Genéticos/imunologia , Humanos , Injeções Intralesionais , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Estadiamento de Neoplasias , Neuroblastoma/imunologia , Neuroblastoma/patologia , Neuroblastoma/terapia , Sarcoma de Ewing/imunologia , Sarcoma de Ewing/patologia , Sarcoma de Ewing/terapia , Vacinação , Vaccinia virus/genética , Adulto JovemRESUMO
Oncolytic viral therapy utilizes a tumor-selective replicating virus which preferentially infects and destroys cancer cells and triggers antitumor immunity. The Western Reserve strain of vaccinia virus (VV) is the most virulent strain of VV in animal models and has been engineered for tumor selectivity through two targeted gene deletions (vvDD). We performed the first-in-human phase 1, intratumoral dose escalation clinical trial of vvDD in 16 patients with advanced solid tumors. In addition to safety, we evaluated signs of vvDD replication and spread to distant tumors, pharmacokinetics and pharmacodynamics, clinical and immune responses to vvDD. Dose escalation proceeded without dose-limiting toxicities to a maximum feasible dose of 3 × 10(9) pfu. vvDD replication in tumors was reproducible. vvDD genomes and/or infectious particles were recovered from injected (n = 5 patients) and noninjected (n = 2 patients) tumors. At the two highest doses, vvDD genomes were detected acutely in blood in all patients while delayed re-emergence of vvDD genomes in blood was detected in two patients. Fifteen of 16 patients exhibited late symptoms, consistent with ongoing vvDD replication. In summary, intratumoral injection of the oncolytic vaccinia vvDD was well-tolerated in patients and resulted in selective infection of injected and noninjected tumors and antitumor activity.
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Neoplasias da Mama/terapia , Neoplasias do Colo/terapia , Melanoma/terapia , Neoplasias Pancreáticas/terapia , Neoplasias Cutâneas/terapia , Vaccinia virus/imunologia , Replicação Viral/genética , Idoso , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Relação Dose-Resposta Imunológica , Feminino , Deleção de Genes , Humanos , Injeções Intralesionais , Masculino , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Vírus Oncolíticos/crescimento & desenvolvimento , Vírus Oncolíticos/imunologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Vaccinia virus/genética , Vaccinia virus/crescimento & desenvolvimentoRESUMO
Oncolytic immunotherapeutics (OIs) are viruses designed to preferentially replicate in and lyse cancer cells, thereby triggering antitumor immunity. Numerous oncolytic platforms are currently in clinical development. Here we review preclinical and clinical experience with Pexa-Vec (pexastimogene devacirepvec, JX-594). Pexa-Vec is derived from a vaccinia vaccine strain that has been engineered to target cancer cells and express the therapeutic transgene granulocyte macrophage colony-stimulating factor (GM-CSF) in order to stimulate antitumor immunity. Key to its ability to target metastatic disease is the evolution of unique vaccinia virus characteristics that allow for effective systemic dissemination. Multiple mechanisms of action (MOA) for Pexa-Vec have been demonstrated in preclinical models and patients: 1) tumor cell infection and lysis, 2) antitumor immune response induction, and 3) tumor vascular disruption. This review will summarize data on the Pexa-Vec MOA as well as provide an overview of the Pexa-Vec clinical development program from multiple Phase I studies, Phase II studies in renal cell cancer and colorectal cancer, through Phase IIb clinical testing in patients with advanced hepatocellular carcinoma (primary liver cancer).
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Recent clinical data have emphatically shown the capacity of our immune systems to eradicate even advanced cancers. Although oncolytic viruses (OVs) were originally designed to function as tumour-lysing therapeutics, they have now been clinically shown to initiate systemic antitumour immune responses. Cell signalling pathways that are activated and promote the growth of tumour cells also favour the growth and replication of viruses within the cancer. The ability to engineer OVs that express immune-stimulating 'cargo', the induction of immunogenic tumour cell death by OVs and the selective targeting of OVs to tumour beds suggests that they are the ideal reagents to enhance antitumour immune responses. Coupling of OV therapy with tumour antigen vaccination, immune checkpoint inhibitors and adoptive cell therapy seems to be ready to converge towards a new generation of multimodal therapeutics to improve outcomes for cancer patients.
Assuntos
Imunoterapia , Neoplasias/imunologia , Neoplasias/terapia , Terapia Viral Oncolítica , Animais , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Vetores Genéticos/genética , Vetores Genéticos/imunologia , Humanos , Fatores Imunológicos , Imunoterapia Adotiva , Neoplasias/genética , Vírus Oncolíticos/genética , Vírus Oncolíticos/imunologiaRESUMO
Human tumors develop multiple strategies to evade recognition and efficient suppression by the immune system. Therefore, a variety of immunotherapeutic strategies have been developed to reactivate and reorganize the human immune system. The recent development of new antibodies against immune check points may help to overcome the immune silencing induced by human tumors. Some of these antibodies have already been approved for treatment of various solid tumor entities. Interestingly, targeting antibodies may be combined with standard chemotherapy or radiation protocols. Furthermore, recent evidence indicates that intratumoral or intravenous injections of replicative oncolytic viruses such as herpes simplex-, pox-, parvo-, or adenoviruses may also reactivate the human immune system. By generating tumor cell lysates in situ, oncolytic viruses overcome cellular tumor resistance mechanisms and induce immunogenic tumor cell death resulting in the recognition of newly released tumor antigens. This is in particular the case of the oncolytic parvovirus H-1 (H-1PV), which is able to kill human tumor cells and stimulate an anti-tumor immune response through increased presentation of tumor-associated antigens, maturation of dendritic cells, and release of pro-inflammatory cytokines. Current research and clinical studies aim to assess the potential of oncolytic virotherapy and its combination with immunotherapeutic agents or conventional treatments to further induce effective antitumoral immune responses.
RESUMO
Oncolytic viruses cause direct cytolysis and cancer-specific immunity in preclinical models. The goal of this study was to demonstrate induction of functional anticancer immunity that can lyse target cancer cells in humans. Pexa-Vec (pexastimogene devacirepvec; JX-594) is a targeted oncolytic and immunotherapeutic vaccinia virus engineered to express human granulocyte-macrophage colony-stimulating factor (GM-CSF). Pexa-Vec demonstrated replication, GM-CSF expression, and tumor responses in previous phase 1 trials. We now evaluated whether Pexa-Vec induced functional anticancer immunity both in the rabbit VX2 tumor model and in patients with diverse solid tumor types in phase 1. Antibody-mediated complement-dependent cancer cell cytotoxicity (CDC) was induced by intravenous Pexa-Vec in rabbits; transfer of serum from Pexa-Vec-treated animals to tumor-bearing animals resulted in tumor necrosis and improved survival. In patients with diverse tumor types treated on a phase 1 trial, CDC developed within 4 to 8 weeks in most patients; normal cells were resistant to the cytotoxic effects. T lymphocyte activation in patients was evidenced by antibody class switching. We determined that patients with the longest survival duration had the highest CDC activity, and identified candidate target tumor cell antigens. Thus, we demonstrated that Pexa-Vec induced polyclonal antibody-mediated CDC against multiple tumor antigens both in rabbits and in patients with diverse solid tumor types.