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1.
Front Immunol ; 13: 826164, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35493448

RESUMO

Oncolytic Viruses (OVs) work through two main mechanisms of action: the direct lysis of the virus-infected cancer cells and the release of tumor antigens as a result of the viral burst. In this sc.enario, the OVs act as in situ cancer vaccines, since the immunogenicity of the virus is combined with tumor antigens, that direct the specificity of the anti-tumor adaptive immune response. However, this mechanism in some cases fails in eliciting a strong specific T cell response. One way to overcome this problem and enhance the priming efficiency is the production of genetically modified oncolytic viruses encoding one or more tumor antigens. To avoid the long and expensive process related to the engineering of the OVs, we have exploited an approach based on coating OVs (adenovirus and vaccinia virus) with tumor antigens. In this work, oncolytic viruses encoding tumor antigens and tumor antigen decorated adenoviral platform (PeptiCRAd) have been used as cancer vaccines and evaluated both for their prophylactic and therapeutic efficacy. We have first tested the oncolytic vaccines by exploiting the OVA model, moving then to TRP2, a more clinically relevant tumor antigen. Finally, both approaches have been investigated in tumor neo-antigens settings. Interestingly, both genetically modified oncolytic adenovirus and PeptiCRAd elicited T cells-specific anti-tumor responses. However, in vitro cross-representation experiments, showed an advantage of PeptiCRAd as regards the fast presentation of the model epitope SIINFEKL from OVA in an immunogenic rather than tolerogenic fashion. Here two approaches used as cancer oncolytic vaccines have been explored and characterized for their efficacy. Although the generation of specific anti-tumor T cells was elicited in both approaches, PeptiCRAd retains the advantage of being rapidly adaptable by coating the adenovirus with a different set of tumor antigens, which is crucial in personalized cancer vaccines clinical setting.


Assuntos
Vacinas Anticâncer , Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Adenoviridae , Antígenos de Neoplasias , Humanos , Vírus Oncolíticos/genética , Peptídeos , Medicina de Precisão , Vacinas de Subunidades
2.
Front Immunol ; 13: 866892, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35493490

RESUMO

Immunotherapy has seen tremendous strides in the last decade, acquiring a prominent position at the forefront of cancer treatment since it has been proven to be efficacious for a wide variety of tumors. Nevertheless, while immunotherapy has changed the paradigm of adult tumor treatment, this progress has not yet been translated to the pediatric solid tumor population. For this reason, alternative curative therapies are urgently needed for the most aggressive pediatric tumors. In recent years, oncolytic virotherapy has consolidated as a feasible strategy for cancer treatment, not only for its tumor-specific effects and safety profile but also for its capacity to trigger an antitumor immune response. This review will summarize the current status of immunovirotherapy to treat cancer, focusing on pediatric solid malignancies. We will revisit previous basic, translational, and clinical research and discuss advances in overcoming the existing barriers and limitations to translate this promising therapeutic as an every-day cancer treatment for the pediatric and young adult populations.


Assuntos
Neoplasias , Terapia Viral Oncolítica , Criança , Humanos , Imunoterapia , Neoplasias/terapia
3.
Dermatol Online J ; 28(1)2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-35499413

RESUMO

Merkel cell carcinoma (MCC) is a rare neuroendocrine neoplasm, warranting surgical excision with sentinel lymph node biopsy. In later stages, adjuvant chemotherapy and radiation are required owing to its aggressive malignant behavior. We describe a 62-year-old woman who presented with multifocal recurrence of MCC and was not a candidate for immunotherapy or surgery. The patient underwent four treatments of intratumoral talimogene laherparepvec (TVEC) and demonstrated a complete response with no histologic evidence of remaining MCC on four scouting biopsies. Although TVEC therapy is currently approved for the treatment of advanced stage melanoma, it is still being investigated in MCC. This case supports the use of TVEC as monotherapy in select patients with locally advanced MCC who are not candidates for surgery or systemic immunotherapy.


Assuntos
Carcinoma de Célula de Merkel , Melanoma , Terapia Viral Oncolítica , Neoplasias Cutâneas , Produtos Biológicos , Carcinoma de Célula de Merkel/tratamento farmacológico , Feminino , Herpesvirus Humano 1 , Humanos , Pessoa de Meia-Idade , Neoplasias Cutâneas/tratamento farmacológico
4.
Sci Transl Med ; 14(640): eabn2231, 2022 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-35417192

RESUMO

Oncolytic viruses (OVs) encoding a variety of transgenes have been evaluated as therapeutic tools to increase the efficacy of chimeric antigen receptor (CAR)-modified T cells in the solid tumor microenvironment (TME). Here, using systemically delivered OVs and CAR T cells in immunocompetent mouse models, we have defined a mechanism by which OVs can potentiate CAR T cell efficacy against solid tumor models of melanoma and glioma. We show that stimulation of the native T cell receptor (TCR) with viral or virally encoded epitopes gives rise to enhanced proliferation, CAR-directed antitumor function, and distinct memory phenotypes. In vivo expansion of dual-specific (DS) CAR T cells was leveraged by in vitro preloading with oncolytic vesicular stomatitis virus (VSV) or reovirus, allowing for a further in vivo expansion and reactivation of T cells by homologous boosting. This treatment led to prolonged survival of mice with subcutaneous melanoma and intracranial glioma tumors. Human CD19 CAR T cells could also be expanded in vitro with TCR reactivity against viral or virally encoded antigens and was associated with greater CAR-directed cytokine production. Our data highlight the utility of combining OV and CAR T cell therapy and show that stimulation of the native TCR can be exploited to enhance CAR T cell activity and efficacy in mice.


Assuntos
Glioma , Melanoma , Terapia Viral Oncolítica , Vírus Oncolíticos , Receptores de Antígenos Quiméricos , Animais , Glioma/terapia , Imunoterapia Adotiva , Melanoma/terapia , Camundongos , Vírus Oncolíticos/fisiologia , Receptores de Antígenos de Linfócitos T , Linfócitos T , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Signal Transduct Target Ther ; 7(1): 100, 2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35393389

RESUMO

Over the last decade, oncolytic virus (OV) therapy has shown its promising potential in tumor treatment. The fact that not every patient can benefit from it highlights the importance for defining biomarkers that help predict patients' responses. As particular self-amplifying biotherapeutics, the anti-tumor effects of OVs are highly dependent on the host factors for viral infection and replication. By using weighted gene co-expression network analysis (WGCNA), we found matrix remodeling associated 8 (MXRA8) is positively correlated with the oncolysis induced by oncolytic virus M1 (OVM). Consistently, MXRA8 promotes the oncolytic efficacy of OVM in vitro and in vivo. Moreover, the interaction of MXRA8 and OVM studied by single-particle cryo-electron microscopy (cryo-EM) showed that MXRA8 directly binds to this virus. Therefore, MXRA8 acts as the entry receptor of OVM. Pan-cancer analysis showed that MXRA8 is abundant in most solid tumors and is highly expressed in tumor tissues compared with adjacent normal ones. Further study in cancer cell lines and patient-derived tumor tissues revealed that the tumor selectivity of OVM is predominantly determined by a combinational effect of the cell membrane receptor MXRA8 and the intracellular factor, zinc-finger antiviral protein (ZAP). Taken together, our study may provide a novel dual-biomarker for precision medicine in OVM therapy.


Assuntos
Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Microscopia Crioeletrônica , Humanos , Imunoglobulinas , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/terapia , Vírus Oncolíticos/genética
6.
Nat Commun ; 13(1): 1898, 2022 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-35393414

RESUMO

Recent advances in cancer therapeutics clearly demonstrate the need for innovative multiplex therapies that attack the tumour on multiple fronts. Oncolytic or "cancer-killing" viruses (OVs) represent up-and-coming multi-mechanistic immunotherapeutic drugs for the treatment of cancer. In this study, we perform an in-vitro screen based on virus-encoded artificial microRNAs (amiRNAs) and find that a unique amiRNA, herein termed amiR-4, confers a replicative advantage to the VSVΔ51 OV platform. Target validation of amiR-4 reveals ARID1A, a protein involved in chromatin remodelling, as an important player in resistance to OV replication. Virus-directed targeting of ARID1A coupled with small-molecule inhibition of the methyltransferase EZH2 leads to the synthetic lethal killing of both infected and uninfected tumour cells. The bystander killing of uninfected cells is mediated by intercellular transfer of extracellular vesicles carrying amiR-4 cargo. Altogether, our findings establish that OVs can serve as replicating vehicles for amiRNA therapeutics with the potential for combination with small molecule and immune checkpoint inhibitor therapy.


Assuntos
Vesículas Extracelulares , MicroRNAs , Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , MicroRNAs/genética , Neoplasias/terapia , Vírus Oncolíticos/genética
7.
Virol J ; 19(1): 74, 2022 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-35459242

RESUMO

BACKGROUND: Selectively replicating herpes simplex virus-2 (HSV-2) vector is a promising treatment for cancer therapy. The insertion of multiple transgenes into the viral genome has been performed to improve its oncolytic activity. METHODS: Herein, we simultaneously constructed five "armed" oncolytic viruses (OVs), designated oHSV2-IL12, -IL15, GM-CSF, -PD1v, and IL7 × CCL19. These OVs delete the ICP34.5 and ICP47 genes with the insertion of transgenes into the deleted ICP34.5 locus. The anti-tumor efficacy in vivo was tested in the syngeneic 4T1 and CT26 tumor-bearing mice model. RESULTS: The OVs showed comparable oncolytic capability in vitro. The combination therapy of oHSV2-IL12, -IL15, GM-CSF, -PD1v, and IL7 × CCL19 exhibited the highest tumor inhibition efficacy compared with the treatment of single OV or two OVs combination. CONCLUSIONS: The OVs armed with different transgenes combination therapy also named 5-valent oHSV2 (also called cocktail therapy) might be an effective therapeutic strategy for solid tumors.


Assuntos
Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Animais , Vetores Genéticos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Herpesvirus Humano 2/genética , Interleucina-12/genética , Interleucina-15/genética , Interleucina-7/genética , Camundongos , Neoplasias/tratamento farmacológico , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética
8.
JCI Insight ; 7(7)2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35393952

RESUMO

Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors, and patient survival has not changed despite many therapeutic efforts, emphasizing the urgent need for effective treatments. Here, we evaluated the anti-DIPG effect of the oncolytic adenovirus Delta-24-ACT, which was engineered to express the costimulatory ligand 4-1BBL to potentiate the antitumor immune response of the virus. Delta-24-ACT induced the expression of functional 4-1BBL on the membranes of infected DIPG cells, which enhanced the costimulation of CD8+ T lymphocytes. In vivo, Delta-24-ACT treatment of murine DIPG orthotopic tumors significantly improved the survival of treated mice, leading to long-term survivors that developed immunological memory against these tumors. In addition, Delta-24-ACT was safe and caused no local or systemic toxicity. Mechanistic studies showed that Delta-24-ACT modulated the tumor-immune content, not only increasing the number, but also improving the functionality of immune cells. All of these data highlight the safety and potential therapeutic benefit of Delta-24-ACT the treatment of patients with DIPG.


Assuntos
Neoplasias do Tronco Encefálico , Glioma Pontino Intrínseco Difuso , Terapia Viral Oncolítica , Adenoviridae , Animais , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/terapia , Humanos , Camundongos
9.
Mol Biol (Mosk) ; 56(2): 334-335, 2022.
Artigo em Russo | MEDLINE | ID: mdl-35403626

RESUMO

Vesicular stomatitis virus has been known as a potent antitumor agent because of its selective replication and lysis of tumor cells and immune-stimulating properties. In response to cellular stress and enhanced metabolism, tumor cells activate autophagy, to provide energy for the cells and preventing tumor destruction. Inhibition of autophagy can increase the therapeutic potential of many antitumor methods. This study aimed to check the efficacy of combined VSV and three-methyl adenine (3-MA) in treating a tumor model in mice. TC-1, a line of C57BL/6 mouse lung cells transformed by HPV-16 E7 and E6 oncoproteins, as well as human Ras, were used for experiments. The viability after treatment with the optimized concentration of 3-MA with or without combination with VSV was assessed by MTT. C57BL/6 male mice were injected with TC-1, and after tumor formation, 3-MA and VSV alone or in combination in two different protocols were injected into tumor mice. Tumor size, tumor-specific CTL response, and apoptosis rate were evaluated. The results showed that 3-MA combined with VSV causes more lethality in tumor cells in vitro. In vivo studies also showed that combined VSV and 3-MA treatment inhibits the progression of TC-1 cancer cells with higher efficiency, especially in daily 3-MA treatment along with four doses of VSV injection with four days' intervals. In addition, the rate of apoptosis and cytotoxic T cells activity in the groups injected with 3-MA and the virus were higher than groups receiving each agent alone. In conclusion, the association of VSV with 3-MA increases its oncolysis activity and subsequently more stimulates the immune system against the tumor. This finding suggests a combinational approach for tumor therapy with therapy. Combining oncolytic VSV with 3-MA as an autophagy inhibitor agent can improve the efficacy of tumor treatment. This combination therapy approach enhances apoptosis in tumors as well as T cell cytotoxicity against tumor cells.


Assuntos
Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Animais , Autofagia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Terapia Viral Oncolítica/métodos
10.
J Immunother Cancer ; 10(4)2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35383116

RESUMO

BACKGROUND: Melanoma in people of Asian descent presents primarily in non-sun-exposed areas, such as acral and mucosal melanoma. Compared with the predominant sun-exposed area melanomas in Caucasians, acral and mucosal melanomas do not respond as well to immunotherapy and are associated with a worse prognosis. Hence, there is an urgent need for improved treatment for melanoma in Asians. This phase Ib trial evaluated the safety and efficacy of the modified herpes simplex virus-1 oncolytic virus OrienX010 in Chinese patients with unresectable stage IIIC-IV melanoma. METHODS: Patients were treated in two different cohorts. In cohort 08 (n=12), patients received up to 5 mL of 8×107 pfu/mL OrienX010 intratumoral injections every 2 weeks until disease progression and responses were evaluated every 6 weeks. In cohort 09 (n=14), patients received up to 10 mL of 8×107 pfu/mL OrienX010 intratumoral injections and responses were evaluated every 8 weeks. RESULTS: Between June 2014 and May 2017, 26 patients were enrolled, including 18 (69.2%) patients with acral melanoma. Fever and injection site reaction were the most frequent adverse events. Only one patient experienced a grade ≥3 adverse event and no dose-limiting toxicities were observed. The objective response rate was 19.2% and the disease control rate was 53.8%. The median duration of response was 6.0 months. Antitumor effects were observed in 54.6% of injected lesions and 48.8% of non-injected lesions, including one (16.7%) of six evaluable distant lung metastases. The median progression-free survival was 2.9 months and overall survival was 19.2 months. Compared with patients treated in cohort 08, patients treated in cohort 09 had an improved objective response rate (28.6% vs 8.3%) and a median progression-free survival of 3.0 months vs 2.8 months. CONCLUSIONS: OrienX010 oncolytic virotherapy has a tolerable safety profile with antitumor effects in both injected and non-injected metastases and warrants further evaluation in patients with melanoma. Based on these results, the higher cohort 09 dose (up to 10 mL of 8×107 pfu/mL every 2 weeks) was selected as the recommended phase II dose for ongoing trials. TRIAL REGISTRATION NUMBER: CTR20140631 (cohort 08), CTR20150881 (cohort 09).


Assuntos
Melanoma , Terapia Viral Oncolítica , Vírus Oncolíticos , Neoplasias Cutâneas , Humanos , Imunoterapia , Melanoma/patologia , Terapia Viral Oncolítica/efeitos adversos , Terapia Viral Oncolítica/métodos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/etiologia
11.
Signal Transduct Target Ther ; 7(1): 117, 2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-35387984

RESUMO

Oncolytic viruses (OVs) are emerging as potentially useful platforms in treatment methods for patients with tumors. They preferentially target and kill tumor cells, leaving healthy cells unharmed. In addition to direct oncolysis, the essential and attractive aspect of oncolytic virotherapy is based on the intrinsic induction of both innate and adaptive immune responses. To further augment this efficacious response, OVs have been genetically engineered to express immune regulators that enhance or restore antitumor immunity. Recently, combinations of OVs with other immunotherapies, such as immune checkpoint inhibitors (ICIs), chimeric antigen receptors (CARs), antigen-specific T-cell receptors (TCRs) and autologous tumor-infiltrating lymphocytes (TILs), have led to promising progress in cancer treatment. This review summarizes the intrinsic mechanisms of OVs, describes the optimization strategies for using armed OVs to enhance the effects of antitumor immunity and highlights rational combinations of OVs with other immunotherapies in recent preclinical and clinical studies.


Assuntos
Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia/métodos , Neoplasias/genética , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética
12.
Math Biosci Eng ; 19(5): 4429-4457, 2022 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-35430822

RESUMO

Combining chimeric antigen receptor T (CAR-T) cells with oncolytic viruses (OVs) has recently emerged as a promising treatment approach in preclinical studies that aim to alleviate some of the barriers faced by CAR-T cell therapy. In this study, we address by means of mathematical modeling the main question of whether a single dose or multiple sequential doses of CAR-T cells during the OVs therapy can have a synergetic effect on tumor reduction. To that end, we propose an ordinary differential equations-based model with virus-induced synergism to investigate potential effects of different regimes that could result in efficacious combination therapy against tumor cell populations. Model simulations show that, while the treatment with a single dose of CAR-T cells is inadequate to eliminate all tumor cells, combining the same dose with a single dose of OVs can successfully eliminate the tumor in the absence of virus-induced synergism. However, in the presence of virus-induced synergism, the same combination therapy fails to eliminate the tumor. Furthermore, it is shown that if the intensity of virus-induced synergy and/or virus oncolytic potency is high, then the induced CAR-T cell response can inhibit virus oncolysis. Additionally, the simulations show a more robust synergistic effect on tumor cell reduction when OVs and CAR-T cells are administered simultaneously compared to the combination treatment where CAR-T cells are administered first or after OV injection. Our findings suggest that the combination therapy of CAR-T cells and OVs seems unlikely to be effective if the virus-induced synergistic effects are included when genetically engineering oncolytic viral vectors.


Assuntos
Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Receptores de Antígenos Quiméricos , Humanos , Modelos Teóricos , Neoplasias/terapia , Vírus Oncolíticos/fisiologia , Linfócitos T
13.
Biomaterials ; 284: 121488, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35367840

RESUMO

Due to intrinsic and acquired chemo/radiotherapy-resistance, renal cell carcinoma shows limited therapeutic response to clinically utilized targeting drugs. Here a tumor-activated oncolytic peptide nanomachine is devised to selectively lysing tumor cell membrane without causing drug resistance. Specifically, in the acidic tumor microenvironment, the oncolytic peptide nanomachine automatically activated through morphologically transformation from nanoparticles to nanofibrils with restoring α-helical conformation, which physically bind to tumor cell membrane with multiple (spatially correlated and time-resolved) interactions and subsequently lyse local cell membrane. The IC50 of the oncolytic peptide nanomachine is as low as 2.44 µM and it inhibit up to 90% of tumor cells within 2 h with unique bystander killing effect. In vivo, the tumor inhibition rate of the oncolytic peptide nanomachine is 71% without off-target activity and hemolytic activity. These results support that tumor-selective oncolytic peptide nanomachine represent a promising alternative approach for multidrug-resistant tumor treatments by inducing cell membrane lysis.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Terapia Viral Oncolítica , Vírus Oncolíticos , Carcinoma de Células Renais/terapia , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Renais/terapia , Masculino , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/fisiologia , Peptídeos/química , Microambiente Tumoral
14.
Cancer Treat Rev ; 106: 102392, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35436729

RESUMO

Immunotherapy has revolutionized the oncology field during the last years, mainly with the introduction of immune checkpoint inhibitors in the clinical routine. Despite the recent approval of these drugs for the treatment of triple-negative breast cancer, most breast cancer patients cannot benefit from immunotherapy as most tumors are not considered immunoreactive. Therefore, new strategies must be developed to bring immunotherapy closer to breast cancer patients. The introduction of oncolytic viruses in the immuno-oncology field has shown promising results in cancer treatment, including breast cancer. However, a better understanding of their mechanisms of action, increase evidence of safety and efficacy, and the implications of its use as a systemic therapy must be examined in more depth. This review provides a summary of oncolytic virotherapy in the context of breast cancer, both in the pre-clinical and clinical setting.


Assuntos
Terapia Viral Oncolítica , Vírus Oncolíticos , Neoplasias de Mama Triplo Negativas , Humanos , Inibidores de Checkpoint Imunológico , Imunoterapia/métodos , Terapia Viral Oncolítica/métodos
15.
Oncogene ; 41(19): 2663-2671, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35430605

RESUMO

Brain tumors result in significant morbidity and mortality in both children and adults. Recent data indicate that immunotherapies may offer a survival benefit after standard of care has failed for malignant brain tumors. Modest results from several late phase clinical trials, however, underscore the need for more refined, comprehensive strategies that incorporate new mechanistic and pharmacologic knowledge. Recently, oncometabolism has emerged as an adjunct modality for combinatorial treatment approaches necessitated by the aggressive, refractory nature of high-grade glioma and other progressive malignant brain tumors. Manipulation of metabolic processes in cancer and immune cells that comprise the tumor microenvironment through controlled targeting of oncogenic pathways may be utilized to maximize the efficacy of immunotherapy and improve patient outcomes. Herein, we summarize preclinical and early phase clinical trial research of oncometabolism-based therapeutics that may augment immunotherapy by exploiting the biochemical and genetic underpinnings of brain tumors. We also examine metabolic pathways related to immune cells that target tumor cells, termed "tumor immunometabolism". Specifically, we focus on glycolysis and altered glucose metabolism, including glucose transporters, hexokinase, pyruvate dehydrogenase, and lactate dehydrogenase, glutamine, and we discuss targeting arginase, adenosine, and indoleamine 2,3-dioxygenase, and toll-like receptors. Lastly, we summarize future directions targeting metabolism in combination with emerging therapies such as oncolytic virotherapy, vaccines, and chimeric antigen receptor T cells.


Assuntos
Neoplasias Encefálicas , Glioma , Terapia Viral Oncolítica , Adulto , Neoplasias Encefálicas/genética , Criança , Glioma/terapia , Humanos , Imunoterapia/métodos , Terapia Viral Oncolítica/métodos , Microambiente Tumoral
16.
J Immunother Cancer ; 10(4)2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35414592

RESUMO

Surgical removal of tumors remains a front-line therapy for many types of cancer. However, this treatment often fails to eradicate disease due to either recurrence of the original tumor or development of distant micrometastases. To address these challenges, patients are often given non-curative treatments presurgery with the intent of improving surgical outcomes. These treatments, collectively known as neoadjuvant therapies, have traditionally focused on the presurgical use of chemotherapeutics. Recently, however, a variety of immunotherapies have also been identified as potentially effective in the neoadjuvant setting. One of these immunotherapies is oncolytic virotherapy, whose clinical use has exploded with the Food and Drug Administration approval of Talimogene Laherparepvec. This review summarizes both the preclinical and clinical literature examining the use of oncolytic virotherapy in the neoadjuvant setting for different types of cancers and discusses some of the major questions that still need to be addressed in order for this unique use of immunotherapy to become clinically viable.


Assuntos
Melanoma , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Imunoterapia , Melanoma/terapia , Terapia Neoadjuvante , Vírus Oncolíticos/genética
18.
J Immunother Cancer ; 10(3)2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35296558

RESUMO

BACKGROUND: Novel therapies are needed to improve outcomes for women diagnosed with ovarian cancer. Oncolytic viruses are multifunctional immunotherapeutic biologics that preferentially infect cancer cells and stimulate inflammation with the potential to generate antitumor immunity. Herein we describe Parapoxvirus ovis (Orf virus (OrfV)), an oncolytic poxvirus, as a viral immunotherapy for ovarian cancer. METHODS: The immunotherapeutic potential of OrfV was tested in the ID8 orthotopic mouse model of end-stage epithelial ovarian carcinoma. Immune cell profiling, impact on secondary lesion development and survival were evaluated in OrfV-treated mice as well as in Batf3 knockout, mice depleted of specific immune cell subsets and in mice where the primary tumor was removed. Finally, we interrogated gene expression datasets from primary human ovarian tumors from the International Cancer Genome Consortium database to determine whether the interplay we observed between natural killer (NK) cells, classical type 1 dendritic cells (cDC1s) and T cells exists and influences outcomes in human ovarian cancer. RESULTS: OrfV was an effective monotherapy in a murine model of advanced-stage epithelial ovarian cancer. OrfV intervention relied on NK cells, which when depleted abrogated antitumor CD8+ T-cell responses. OrfV therapy was shown to require cDC1s in experiments with BATF3 knockout mice, which do not have mature cDC1s. Furthermore, cDC1s governed antitumor NK and T-cell responses to mediate antitumor efficacy following OrfV. Primary tumor removal, a common treatment option in human patients, was effectively combined with OrfV for optimal therapeutic outcome. Analysis of human RNA sequencing datasets revealed that cDC1s correlate with NK cells in human ovarian cancer and that intratumoral NK cells correlate positively with survival. CONCLUSIONS: The data herein support the translational potential of OrfV as an NK stimulating immunotherapeutic for the treatment of advanced-stage ovarian cancer.


Assuntos
Terapia Viral Oncolítica , Vírus Oncolíticos , Vírus do Orf , Neoplasias Ovarianas , Animais , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Células Matadoras Naturais , Licenciamento , Camundongos , Vírus do Orf/genética , Vírus do Orf/metabolismo , Ovinos
19.
Front Immunol ; 13: 826876, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35273607

RESUMO

Immunotherapy holds enormous promise to create a new outlook of cancer therapy by eliminating tumors via activation of the immune system. In immunotherapy, polymeric systems play a significant role in improving antitumor efficacy and safety profile. Polymeric systems possess many favorable properties, including magnificent biocompatibility and biodegradability, structural and component diversity, easy and controllable fabrication, and high loading capacity for immune-related substances. These properties allow polymeric systems to perform multiple functions in immunotherapy, such as immune stimulants, modifying and activating T cells, delivery system for immune cargos, or as an artificial antigen-presenting cell. Among diverse immunotherapies, immune checkpoint inhibitors, chimeric antigen receptor (CAR) T cell, and oncolytic virus recently have been dramatically investigated for their remarkable success in clinical trials. In this report, we review the monotherapy status of immune checkpoint inhibitors, CAR-T cell, and oncolytic virus, and their current combination strategies with diverse polymeric systems.


Assuntos
Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Receptores de Antígenos Quiméricos , Humanos , Inibidores de Checkpoint Imunológico , Fatores Imunológicos , Imunoterapia , Receptores de Antígenos Quiméricos/genética
20.
J Immunother Cancer ; 10(3)2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35246474

RESUMO

BACKGROUND: Pancreatic cancer is one of the leading causes of cancer death, with a 5-year -year survival rate of less than 10%. This results from late detection, high rates of metastasis, and resistance to standard chemotherapies. Furthermore, chemotherapy and radiation are associated with significant morbidity, underscoring the need for novel therapies. Recent clinical studies have shown that immunotherapies can provide durable outcomes in cancer patients, but successes in pancreatic cancer have been limited. It is likely that novel and combined therapies will be needed to achieve clinical benefits. METHODS: Using experimental mouse models of pancreatic ductal adenocarcinoma, we examined natural killer T (NKT) cell activation therapy in combination with a recombinant oncolytic vesicular stomatitis virus (VSVΔM51) engineered to express the cytokine IL-15 (VSV-IL-15). Panc02 pancreatic ductal carcinoma cells were implanted subcutaneously or orthotopically into syngeneic C57BL/6 mice. Mice were then treated with VSV expressing green fluorescent protein (VSV-GFP) or VSV-IL-15 and/or NKT cell activation therapy via delivery of α-GalCer-loaded DCs. We further assessed whether the addition of PD-1 blockade could increase the therapeutic benefit of our combination treatment. Three days after NKT cell activation, some groups of mice were treated with anti-PD-1 antibodies weekly for 3 weeks. RESULTS: VSV-GFP and VSV-IL-15 mediated equal killing of human and mouse pancreatic cancer lines in vitro. In vivo, VSV-IL-15 combined with NKT cell activation therapy to enhance tumor regression and increase survival time over individual treatments, and was also superior to NKT cell therapy combined with VSV-GFP. Enhanced tumor control was associated with increased immune cell infiltration and anti-tumor effector functions (cytotoxicity and cytokine production). While ineffective as a monotherapy, the addition of blocking PD-1 antibodies to the combined protocol sustained immune cell activation and effector functions, resulting in prolonged tumor regression and complete tumor clearance in 20% of mice. Mice who cleared the initial tumor challenge exhibited reduced tumor growth uponon rechallenge, consistent with the formation of immune memory. CONCLUSION: TThese results demonstrate that NKT cell immunotherapy combined with oncolytic VSV-IL-15 virotherapy and PD-1 blockade enhances tumor control and presents a promising treatment strategy for targeting pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático , Células T Matadoras Naturais , Terapia Viral Oncolítica , Vírus Oncolíticos , Neoplasias Pancreáticas , Animais , Carcinoma Ductal Pancreático/terapia , Linhagem Celular Tumoral , Citocinas/metabolismo , Humanos , Imunoterapia , Interleucina-15/genética , Interleucina-15/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Terapia Viral Oncolítica/métodos , Neoplasias Pancreáticas/terapia , Receptor de Morte Celular Programada 1/metabolismo , Vírus da Estomatite Vesicular Indiana/metabolismo , Vesiculovirus
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