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1.
Future Oncol ; : 1-16, 2024 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-39101448

RESUMEN

We describe in this review the historical evidence leading up to the concept and design of Vigil and subsequent clinical applications including safety and efficacy in a randomized, controlled Phase IIB trial. Vigil (gemogenovatucel-T) is a unique triple function targeted immunotherapy that demonstrates preclinical and clinical systemic anticancer activity. Construction of Vigil involves harvest of autologous malignant tissue for neoantigen targeting (ideally containing clonal neoantigens) followed by a two-day process involving transfection with a plasmid to provide a permissive 'training environment' for the patient's immune system. Transfected plasmid components contain an expressive human GMCSF DNA segment to enhance anticancer immune functional response and a second component expressing bi-shRNAfurin which reduces TGFß isomers (TGFß1 and TGFß2) thereby reducing cancer inhibition of the targeted immune response. Results generated to date justify advancement to confirmatory clinical trials supporting product regulatory approval.


Vigil is an anticancer treatment that employs three methods of enhancing the body's immune system to identify and kill cancer cells. The construction of Vigil involves cancer cells from the same person being treated (personalized therapy) in combination with added anticancer genetic signals to enhance the number and function anti-anticancer immune cells and to guide the immune cells to the cancer and not to normal organs of the body. In this manner, an army of immune cells are created that can move to attacking the cancer using blood vessels to get to the cancer anywhere it tries to grow in the body. One study (Phase I) performed with this product to determine safety and dose range demonstrated an optimal dose and schedule. Another study (Phase IIA) showed initial clinical benefit. A third more complex study (Phase IIB) in patients treated with Vigil compared with standard of care without Vigil demonstrated the ability to prolong the patients life and time without their cancer getting worse without any significant side effects associated with the treatment in a unique subset of ovarian cancer patients, those with the ability to repair their DNA. Based on the composite of these results, Vigil is an attractive targeted immunotherapy justified for late-stage clinical testing.

2.
Sci Rep ; 14(1): 15556, 2024 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-38969656

RESUMEN

Previously, we reported successful cellular expansion of a murine colorectal carcinoma cell line (CT-26) using a three-dimensional (3D) engineered extracellular matrix (EECM) fibrillar scaffold structure. CCL-247 were grown over a limited time period of 8 days on 3D EECM or tissue culture polystyrene (TCPS). Cells were then assayed for growth, electroporation efficiency and Vigil manufacturing release criteria. Using EECM scaffolds, we report an expansion of CCL-247 (HCT116), a colorectal carcinoma cell line, from a starting concentration of 2.45 × 105 cells to 1.9 × 106 cells per scaffold. Following expansion, 3D EECM-derived cells were assessed based on clinical release criteria of the Vigil manufacturing process utilized for Phase IIb trial operation with the FDA. 3D EECM-derived cells passed all Vigil manufacturing release criteria including cytokine expression. Here, we demonstrate successful Vigil product manufacture achieving the specifications necessary for the clinical trial product release of Vigil treatment. Our results confirm that 3D EECM can be utilized for the expansion of human cancer cell CCL-247, justifying further clinical development involving human tissue sample manufacturing including core needle biopsy and minimal ascites samples.


Asunto(s)
Matriz Extracelular , Inmunoterapia , Andamios del Tejido , Humanos , Andamios del Tejido/química , Inmunoterapia/métodos , Ingeniería de Tejidos/métodos , Células HCT116 , Neoplasias Colorrectales/patología , Animales , Ratones , Proliferación Celular , Línea Celular Tumoral , Técnicas de Cultivo Tridimensional de Células/métodos
3.
Future Oncol ; 20(19): 1367-1380, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38652041

RESUMEN

CD39 is the rate-limiting enzyme for the molecular signal cascade leading to the generation of ADP and adenosine monophosphate (AMP). In conjunction with CD73, CD39 converts adenosine triphosphate (ATP) to ADP and AMP, which leads to the accumulation of immunosuppressive adenosine in the tumor microenvironment. This review focuses on the role of CD39 and CD73 in immune response and malignant progression, including the expression of CD39 within the tumor microenvironment and its relationship to immune effector cells, and its role in antigen presentation. The role of CD39- and CD73-targeting therapeutics and cancer-directed clinical trials investigating CD39 modulation are also explored.


[Box: see text].


Asunto(s)
5'-Nucleotidasa , Apirasa , Neoplasias , Microambiente Tumoral , Humanos , 5'-Nucleotidasa/metabolismo , 5'-Nucleotidasa/inmunología , Apirasa/metabolismo , Apirasa/inmunología , Neoplasias/inmunología , Neoplasias/metabolismo , Microambiente Tumoral/inmunología , Animales , Proteínas Ligadas a GPI/inmunología , Proteínas Ligadas a GPI/metabolismo , Antígenos CD/metabolismo , Antígenos CD/inmunología , Presentación de Antígeno/inmunología
4.
Int J Mol Sci ; 25(6)2024 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-38542143

RESUMEN

The emergence of targeted therapeutics in ovarian cancer, particularly poly (ADP-ribose) polymerase inhibitors (PARPi's), has created additional opportunities for patients seeking frontline and recurrent disease management options. In particular, PARPi's have shown clinical benefits in BRCA mutant and/or homologous recombination deficient (HRD) ovarian cancer. Until recently, response was thought to be limited in BRCA wild-type, homologous recombination proficient (HRP) cancers. Therefore, attempts have been made at combination therapy involving PARPi to improve patient outcomes. Additionally, immune checkpoint inhibitors (ICIs) have demonstrated underwhelming results involving ovarian cancer. Many are searching for reliable biomarkers of immune response to increase efficacy of ICI therapy involving ovarian cancer. In this review, we examine the evidence supporting the combination of PARPi and ICIs in ovarian cancer, which is still lacking.


Asunto(s)
Neoplasias Ováricas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Humanos , Femenino , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Recombinación Homóloga , Biomarcadores
5.
Cancers (Basel) ; 15(23)2023 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-38067319

RESUMEN

Clonal mutations represent the initiating molecular defects related to cellular transition of a normal phenotype to a malignant phenotype. Molecular genomic assessment utilizing next generation and whole exome sequencing is now being increasingly applied to biomarker determination to refine the use of targeted immune therapies. Case examples followed by retrospective study assessment have convincingly demonstrated clonal neoantigens provide a relevant predictor of response to checkpoint inhibition. A meta-analysis, by Litchfield et al., of over 1000 cancer patients from 12 landmark trials demonstrated no clinical benefit to checkpoint inhibitor (CPI) therapy in correlation to high subclonal tumor mutational burden (TMB), whereas high clonal TMB was found to be significantly correlated with better overall survival (p = 0.000000029). We discuss the mechanism of clonal vs. subclonal neoantigen targeting relationship to homologous recombination proficient (HRP) profile, evidence of preclinical and clinical benefit related to clonal neoantigens, and review a novel developing therapy called Vigil®, designed to expand the clonal neoantigen targeting effector cell populations. Vigil® is an autologous cellular immunotherapy which is designed to carry the full set of personal clonal neoantigens. Phase 2b results demonstrate a durable recurrence-free survival (RFS) and overall survival (OS) advantage for Vigil® in a subset ovarian cancer population with an HRP cancer profile.

7.
J Clin Med ; 12(18)2023 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-37762931

RESUMEN

Cervical cancer is an international public health crisis, affecting several hundred thousand women annually. While not universally protective due to other risk factors, many such cases are preventable with vaccination against high-risk serotypes of the human papilloma virus (HPV 6, 11, 16, 18, 31, 33, 45, 53, 58). Advanced-stage and recurrent cervical cancers are typically lethal and have been the focus in recent years of the integration of immune checkpoint inhibitors (CPIs) to improve survival. We have consolidated information regarding the role of the immune system in both disease progression and disease clearance with the aid of targeted therapies and immunotherapeutic agents. Additionally, we have characterized the treatment modalities currently indicated as the standard of care-such as bevacizumab and the immune CPIs-and those recently approved or in development, including Tivdak, Vigil, and chimeric antigen receptor (CAR) T-cells.

8.
Clin Cancer Res ; 29(9): 1689-1697, 2023 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-36780200

RESUMEN

PURPOSE: Treatment options for recurrent or refractory Ewing's sarcoma (ES) are limited. Vigil is a novel autologous tumor cell therapy expressing bi-shRNA furin/GMCSF plasmid, which previously demonstrated monotherapy activity in advanced ES. Herein we report safety and evidence of benefit to Vigil for ES as potential treatment. PATIENTS AND METHODS: In this pilot trial, eligible patients with recurrent or refractory ES who failed initial standard-of-care therapy received treatment with temozolomide (TEM) 100 mg/m2/day oral and irinotecan (IRI) 50 mg/m2/day oral, Days 1 to 5, in combination with Vigil (1 × 106-107 cells/mL/day intradermal, Day 15), every 21 days (Vigil/TEM/IRI). Objective response rate (ORR) by RECIST v1.1, progression-free survival (PFS), and overall survival (OS) were assessed. Circulating tumor (ct) DNA analysis was done by patient-specific droplet digital PCR on baseline and serially collected on-treatment samples. RESULTS: Eight of 10 enrolled patients were evaluable for safety and efficacy (mean age 24.6; 12.6-46.1 years old); 2 did not receive Vigil. Seven of 8 patients previously received TEM/IRI. No Vigil-related adverse events were reported. Common ≥Grade 3 chemotherapy-related toxicity included neutropenia (50%) and thrombocytopenia (38%). We observed two partial response patients by RECIST; both showed histologic complete response without additional cancer therapy. Median PFS was 8.2 months (95% confidence interval, 4.3-NA). Five patients showed stable disease or better for ≥6 months. Patient-specific EWS/FLI1 ctDNA was detectable in all 8 evaluable patients at baseline. Changes in ctDNA levels corresponded to changes in disease burden. CONCLUSIONS: Results demonstrated safety of combination Vigil/TEM/IRI.


Asunto(s)
ADN Tumoral Circulante , Sarcoma de Ewing , Humanos , Adulto Joven , Adulto , Niño , Adolescente , Persona de Mediana Edad , Irinotecán/efectos adversos , Temozolomida/efectos adversos , Sarcoma de Ewing/tratamiento farmacológico , Sarcoma de Ewing/genética , Sarcoma de Ewing/patología , Proyectos Piloto , ADN Tumoral Circulante/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Modafinilo/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos
10.
Curr Probl Cancer ; 47(1): 100917, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36508886

RESUMEN

Folate is a B vitamin necessary for basic biological functions, including rapid cell turnover occurring in cancer cell proliferation. Though the role of folate as a causative versus protective agent in carcinogenesis is debated, several studies have indicated that the folate receptor (FR), notably subtype folate receptor alpha (FRα), could be a viable biomarker for diagnosis, progression, and prognosis. Several cancers, including gastrointestinal, gynecological, breast, lung, and squamous cell head and neck cancers overexpress FR and are currently under investigation to correlate receptor status to disease state. Traditional chemotherapies have included antifolate medications, such as methotrexate and pemetrexed, which generate anticancer activity during the synthesis phase of the cell cycle. Increasingly, the repertoire of pharmacotherapies is expanding to include FR as a target, with a heterogenous pool of directed therapies. Here we discuss the FR, expression and effect in cancer biology, and relevant pharmacologic inhibitors.


Asunto(s)
Carcinoma de Células Escamosas , Antagonistas del Ácido Fólico , Humanos , Antagonistas del Ácido Fólico/farmacología , Antagonistas del Ácido Fólico/uso terapéutico , Pronóstico , Carcinoma de Células Escamosas/tratamiento farmacológico , Ácido Fólico/uso terapéutico , Ácido Fólico/metabolismo , Biomarcadores
11.
Oncol Rev ; 16: 10568, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36531159

RESUMEN

Immune disorders and cancer share a common pathway involving NF-κb signaling. Through involvement with GM-CSF, NF-κB can contribute to proliferation and activation of T- and B- cells as well as immune cell migration to sites of inflammation. In breast cancer, this signaling pathway has been linked to resistance with endocrine and chemotherapies. Similarly, in ovarian cancer, NF-κB influences angiogenesis and inflammation pathways. Further, BRCA1 signaling common to both breast and ovarian cancer also has the capability to induce NF-κB activity. Immunotherapy involving NF-κB can also be implemented to combat chemoresistance. The complex signaling pathways of NF-κB can be harnessed for developing cancer therapeutics to promote immunotherapy for improving patient outcomes.

12.
Front Oncol ; 12: 987142, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36387120

RESUMEN

Evidence of a systemic response related to localized radiation therapy (RT) in cancer management is rare. However, enhancing the immune response via immunotherapy followed by localized RT has shown evidence of tumor shrinkage to non-irradiated metastatic disease thereby inducing an "abscopal effect." Combined induction of the cGAS-STING pathway and activation of IFN-gamma signaling cascade related to RT within an activated immune environment promotes neoantigen presentation and expansion of cytotoxic effector cells enabling enhancement of systemic immune response. A proposed mechanism, case examples, and clinical trial evidence of "abscopal effect" benefit are reviewed. Results support strategic therapeutic testing to enhance "abscopal effect."

13.
Commun Med (Lond) ; 2: 106, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36051466

RESUMEN

Background: Broadened use of predictive molecular and phenotypic profiling amongst oncologists has facilitated optimal integration of targeted- and immuno-therapeutics into clinical care. However, the use of predictive immunomarkers in ovarian cancer (OC) has not consistently translated into clinical benefit. Vigil (gemogenovatucel-T) is a novel plasmid engineered autologous tumor cell immunotherapy designed to knock down the tumor suppressor cytokines, TGFß1 and TGFß2, augment local immune function via increased GMCSF expression and enhance presentation of clonal neoantigen epitopes. Methods: All patients enrolled in the VITAL trial (NCT02346747) of maintenance Vigil vs. placebo as front-line therapy with homologous recombination proficient (HRP) stage IIIB-IV newly diagnosed ovarian cancer underwent NanoString gene expression analysis. Tissue was obtained from surgically resected ovarian tumor tissue following surgical debulking. A statistical algorithm was used to analyze the NanoString gene expression data. Results: Using the NanoString Statistical Algorithm (NSA), we identify high expression of ENTPD1/CD39 (which functions as the rate-limiting step in the production of the immune suppressor adenosine from ATP to ADP) as a presumptive predictor of response to Vigil versus placebo regardless of HRP status on the basis of relapse free survival (median not achieved vs 8.1 months, p = 0.00007) and overall survival (median not achieved vs 41.4 months, p = 0.013) extension. Conclusion: NSA should be considered for application to investigational targeted therapies in order to identify populations most likely to benefit from treatment, in preparation for efficacy conclusive trials.


Treatment options are limited in patients with advanced stage ovarian cancer. Treatments that stimulate the immune system to target the cancer are sometimes effective, however determining which patients will have benefit has been difficult. It is therefore important to develop new markers to predict which patients will respond to therapy. In this study, we looked at the levels of a large number of genes in tumors from patients treated with Vigil (gemogenovatucel-T), a treatment that modifies patient's own tumor cells to activate the immune system. We demonstrate that high expression of a gene named ENTPD1/CD39 predicts a positive response to Vigil therapy. This finding could help clinicians to determine which patients might benefit from Vigil treatment and therefore might guide decisions on who should receive this treatment.

14.
Clin Med Insights Oncol ; 16: 11795549221110501, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35957960

RESUMEN

Background: Gemogenovatucel-T (Vigil) is a triple-function autologous tumor cell immunotherapy which expresses granulocyte-macrophage colony-stimulating factor and decreases expression of furin and downstream TGF-ß1 and TGF-ß2. Vigil has suggested survival benefit in frontline maintenance ovarian cancer patients who are BRCA-wt. In addition, Vigil demonstrates relapse-free and overall survival advantage in homologous recombination-proficient patients with OC. Further evidence of clinical benefit and safety has been demonstrated in combination with atezolizumab. Methods: In this pilot study (NCT02725489), the concurrent combination of the programmed death-ligand 1 (PD-L1) inhibitor durvalumab and Vigil was explored in advanced BRCA-wt relapsed triple-negative breast cancer (TNBC) patients and stage III-IV recurrent/refractory OC patients. Patients received the combination regimen of Vigil (1 × 10e6-10e7 cells/dose intradermally, up to 12 doses) and durvalumab (1500 mg/dose intravenous infusion, up to 12 months) once every 4 weeks. The primary objective was to evaluate safety of this combination. The study included 13 BRCA-wt patients (TNBC, n = 8; OC, n = 5). Results: The most common treatment-emergent adverse events (⩾20%) in all patients included injection-site reaction (92.3%), myalgia (38.5%), bruise at injection site (23.1%), and pruritus (23.1%). Three grade 3 treatment-related adverse events were observed and related to durvalumab. There were no grade 4/5 treatment-related adverse events. Median progression-free survival was 7.1 months and the median overall survival was not reached. Prolonged progression-free survival was improved in patients with PD-L1+ tumors (n = 8, hazard ratio = 0.304, 95% confidence interval, 0.0593-1.56, 1-sided P = .04715) compared with those with PD-L1- tumors. Conclusions: Vigil plus durvalumab was well tolerated and showed promising clinical activity in advanced BRCA-wt TNBC and stage III-IV recurrent/refractory OC patients.

15.
Immunotherapy ; 2022 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-35481350

RESUMEN

Background: Small-cell carcinoma of the breast is a rare disease with little research outlining molecular targets or optimal therapeutic management. We summarize a young female patient with poorly differentiated high-grade carcinoma with neuroendocrine features/small-cell carcinoma. Case presentation: A 31-year-old female presented with a large left breast mass. Initial biopsy revealed small-cell, triple-negative breast carcinoma. Treatment consisted of cisplatin and etoposide but was poorly tolerated and discontinued after one cycle. Combination abraxane/atezolizumab resulted in transient partial response in tumor size with 7 months of progression-free stability. Worsening metastatic disease was found 8 months after initial biopsy on radiologic studies and the patient expired 10 months after initial biopsy. Conclusion: Transient benefit in response to combination abraxane/atezolizumab was demonstrated.


Immunotherapy is an emerging area in cancer research which utilizes the body's immune system to target cancerous cells. This offers oncologists an effective alternative to standard chemotherapy options, which often have significant side effects. Additionally, biomarkers including PD-L1 positivity to predict response to immunotherapy are currently under investigation. The patient presented with a rare type of aggressive breast cancer that previously had few treatment options. This report demonstrates the use of biomarker assessment (PD-L1) to predict immunotherapy response. The patient responded well to immunotherapy, and radiologic scans demonstrated tumor reduction. Further research into this field has the implication to improve treatments, decrease side effects of chemotherapy and improve patient outcomes for many cancers.

16.
Cancer Treat Res Commun ; 30: 100507, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35007928

RESUMEN

Tumor mutation burden (TMB) is often used as a biomarker for immunogenicity and prerequisite for immune checkpoint inhibitor (ICI) therapy. However, it is becoming increasingly evident that not all tumors with high TMB respond to ICIs as expected. It has been shown that the ability of T-cells to infiltrate the tumor microenvironment and elicit a specific immune response is dependent not only on the TMB, but also on intra-tumor heterogeneity and the fraction of low-frequency subclonal mutations that make up the tumor. High intra-tumor heterogeneity leads to inefficient recognition of tumor neoantigens by T-cells due to their diluted frequency and spatial heterogeneity. Clinical studies have shown that tumors with a high degree of intra-tumor heterogeneity respond poorly to ICI therapy, and previous cytotoxic treatment may increase the intra-tumor heterogeneity and render second-line ICI therapy less effective. This paper reviews the role of ICI therapy when following chemotherapy or radiation to determine if they may be better suited as first-line therapy in patients with high TMB, low intra-tumor heterogeneity, and high PD-1, PD-L1, or CTLA-4 expression.

17.
Cancer Gene Ther ; 29(3-4): 369-382, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-33753870

RESUMEN

Vigil® is a personalized vaccine that enhances tumor neoantigen expression. We investigated for the first time safety and efficacy of Vigil in combination with atezolizumab in relapsed ovarian cancer (OC) patients. This is a randomized, Phase 1 study of Vigil, an autologous tumor tissue transfected vaccine encoding for GMCSF and bi-shRNA-furin thereby creating enhanced immune activation and TGFß expression control. Part 1 is a safety assessment of Vigil (1 × 10e7 cells/mL/21 days) plus atezolizumab (1200 mg/21 days). Part 2 is a randomized study of Vigil first (Vigil-1st) or atezolizumab first (Atezo-1st) for two cycles followed by the combination of both agents. The primary endpoint of the study was the determination of safety. Twenty-four patients were enrolled in the study; three patients to Part 1 and 21 to Part 2. Patients in Part 1 completed combination therapy without dose-limiting toxicity justifying expansion to Part 2. Twenty-one patients were randomized (1:1) to Part 2 to Vigil-1st (n = 11) or Atezo-1st (n = 10). Grade 3/4 treatment-related adverse events of Atezo-1st vs. Vigil-1st were 17.2% vs. 5.1%. Median overall survival (OS) was not reached (NR) (Vigil-1st) vs. 10.8 months (Atezo-1st) (hazard ratio [HR] 0.33). The exploratory subset analysis of BRCAwt suggested improved OS benefit [NR in Vigil-1st vs. 5.2 months in Atezo-1st, HR 0.16, p 0.027]. The Vigil-1st combination therapy with atezolizumab was safe and results in support continued investigation in BRCAwt patients.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Ováricas , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Epitelial de Ovario , Femenino , Humanos , Modafinilo/uso terapéutico , Recurrencia Local de Neoplasia , Neoplasias Ováricas/tratamiento farmacológico
18.
Cancer Gene Ther ; 29(7): 993-1000, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-34785763

RESUMEN

Thus far immunotherapy has had limited impact on ovarian cancer. Vigil (a novel DNA-based multifunctional immune-therapeutic) has shown clinical benefit to prolong relapse-free survival (RFS) and overall survival (OS) in the BRCA wild type and HRP populations. We further analyzed molecular signals related to sensitivity of Vigil treatment. Tissue from patients enrolled in the randomized double-blind trial of Vigil vs. placebo as maintenance in frontline management of advanced resectable ovarian cancer underwent DNA polymorphism analysis. Data was generated from a 981 gene panel to determine the tumor mutation burden and classify variants using Ingenuity Variant Analysis software (Qiagen) or NIH ClinVar. Only variants classified as pathogenic or likely pathogenic were included. STRING application (version 1.5.1) was used to create a protein-protein interaction network. Topological distance and probability of co-mutation were used to calculated the C-score and cumulative C-score (cumC-score). Kaplan-Meier analysis was used to determine the relationship between gene pairs with a high cumC-score and clinical parameters. Improved relapse free survival in Vigil treated patients was found for the TP53m-BRCAwt-HRP group compared to placebo (21.1 months versus 5.6 months p = 0.0013). Analysis of tumor mutation burden did not reveal statistical benefit in patients receiving Vigil versus placebo. Results suggest a subset of ovarian cancer patients with enhanced susceptibility to Vigil immunotherapy. The hypothesis-generating data presented invites a validation study of Vigil in target identified populations, and supports clinical consideration of STRING-generated network application to biomarker characterization with other cancer patients targeted with Vigil.


Asunto(s)
Inmunoterapia , Modafinilo , Neoplasias Ováricas , Proteína BRCA1/genética , Femenino , Recombinación Homóloga , Humanos , Modafinilo/uso terapéutico , Recurrencia Local de Neoplasia/patología , Neoplasias Ováricas/tratamiento farmacológico
19.
Vaccines (Basel) ; 9(10)2021 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-34696309

RESUMEN

Colorectal cancer is the third most diagnosed cancer in the United States. Five-year survival rates remain low and many patients will develop liver metastasis. Vigil is an immunotherapy manufactured from autologous tumor cells and transfected ex vivo with a plasmid that encodes the GM-CSF gene and bifunctional shRNA construct to knockdown furin. Here, we report two patients with colorectal cancer and resectable liver metastasis entered into a clinical trial involving Vigil in combination with standard of care modified FOLFOX-6 chemotherapy. The first dose of Vigil was given two weeks before the modified FOLFOX-6 regimen. Vigil treatment continued until Vigil supply was exhausted. Both patients exhibited remarkable response to combination therapy, demonstrating no evidence of disease recurrence for over eight years. Additionally, both patients demonstrated systemic immune response to Vigil therapy as tested by ELISPOT.

20.
BMC Cancer ; 21(1): 1154, 2021 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-34711195

RESUMEN

Homologous recombination and DNA repair are important for genome maintenance. Genetic variations in essential homologous recombination genes, including BRCA1 and BRCA2 results in homologous recombination deficiency (HRD) and can be a target for therapeutic strategies including poly (ADP-ribose) polymerase inhibitors (PARPi). However, response is limited in patients who are not HRD, highlighting the need for reliable and robust HRD testing. This manuscript will review BRCA1/2 function and homologous recombination proficiency in respect to breast and ovarian cancer. The current standard testing methods for HRD will be discussed as well as trials leading to approval of PARPi's. Finally, standard of care treatment and synthetic lethality will be reviewed.


Asunto(s)
Neoplasias de la Mama/genética , Genes BRCA1/fisiología , Genes BRCA2/fisiología , Recombinación Homóloga/fisiología , Neoplasias Ováricas/genética , Reparación del ADN por Recombinación/fisiología , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Variación Genética , Humanos , Mutación , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Poli(ADP-Ribosa) Polimerasas/fisiología
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