ABSTRACT
Glioblastoma(GBM)is a lethal cancer with limited therapeutic options.Dendritic cell(DC)-based cancer vaccines provide a promising approach for GBM treatment.Clinical studies suggest that other immu-notherapeutic agents may be combined with DC vaccines to further enhance antitumor activity.Here,we report a GBM case with combination immunotherapy consisting of DC vaccines,anti-programmed death-1(anti-PD-1)and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy,and the patient remained disease-free for 69 months.The patient received DC vaccines loaded with multiple forms of tumor antigens,including mRNA-tumor associated antigens(TAA),mRNA-neoantigens,and hypochlorous acid(HOCl)-oxidized tumor lysates.Furthermore,mRNA-TAAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histo-compatibility complex(MHC)class Ⅰ and Ⅱ antigen presentation.The treatment consisted of 42 DC cancer vaccine infusions,26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions.The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells.No immunotherapy-related adverse events were observed during the treatment.Robust antitumor CD4+and CD8+T-cell responses were detected.The patient remains free of disease progression.This is the first case report on the combination of the above three agents to treat glioblastoma patients.Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient.A large-scale trial to validate these findings is warranted.
ABSTRACT
Patients exhibit good tolerance to messenger ribonucleic acid (mRNA) vaccines, and the choice of encoded molecules is flexible and diverse. These vaccines can be engineered to express full-length antigens containing multiple epitopes without major histocompatibility complex (MHC) restriction, are relatively easy to control and can be rapidly mass produced. In 2021, the U.S. Food and Drug Administration (FDA) approved the first mRNA-based coronavirus disease 2019 (COVID-19) vaccine produced by Pfizer and BioNTech, which has generated enthusiasm for mRNA vaccine research and development. Based on the above characteristics and the development of mRNA vaccines, mRNA cancer vaccines have become a research hotspot and have undergone rapid development, especially in the last five years. This review analyzes the advances in mRNA cancer vaccines from various perspectives, including the selection and expression of antigens/targets, the application of vectors and adjuvants, different administration routes, and preclinical evaluation, to reflect the trends and challenges associated with these vaccines.
ABSTRACT
Molecular-assisted precision oncology gained tremendous ground with high-throughput next-generation sequencing (NGS), supported by robust bioinformatics. The quest for genomics-based cancer medicine set the foundations for improved patient stratification, while unveiling a wide array of neoantigens for immunotherapy. Upfront pre-clinical and clinical studies have successfully used tumor-specific peptides in vaccines with minimal off-target effects. However, the low mutational burden presented by many lesions challenges the generalization of these solutions, requiring the diversification of neoantigen sources. Oncoproteogenomics utilizing customized databases for protein annotation by mass spectrometry (MS) is a powerful tool toward this end. Expanding the concept toward exploring proteoforms originated from post-translational modifications (PTMs) will be decisive to improve molecular subtyping and provide potentially targetable functional nodes with increased cancer specificity. Walking through the path of systems biology, we highlight that alterations in protein glycosylation at the cell surface not only have functional impact on cancer progression and dissemination but also originate unique molecular fingerprints for targeted therapeutics. Moreover, we discuss the outstanding challenges required to accommodate glycoproteomics in oncoproteogenomics platforms. We envisage that such rationale may flag a rather neglected research field, generating novel paradigms for precision oncology and immunotherapy.
ABSTRACT
Resumen La supervivencia global y la calidad de vida son objetivos primarios del tratamiento del cáncer. El desarrollo de terapias blanco promovió el concepto de tratamientos personalizados, los que se han evaluado principalmente mediante desenlaces centrados en el tumor y han tenido foco en tumores de baja frecuencia y estados avanzados. La inmunoterapia rompe esta tendencia y genera expectativa por su efecto en la supervivencia global y su potencial uso en una gama amplia de tumores. Dentro de esta, las vacunas basadas en neoantígenos han mostrado alta eficacia y seguridad debido a su afinidad con células T y su elevada especificidad. Basado en sus principios biológicos se revisa su posible impacto en la carga de enfermedad según la relación entre potencial inmunogénico y prevalencia por tipo de tumor, el posible efecto en la práctica clínica por su combinación con otras modalidades de tratamiento, y el efecto en el acceso al tratamiento dado su proceso de desarrollo y producción y la disponibilidad de información propia.
Abstract Overall survival and quality of life are primary goals of cancer treatment. The recent development of targeted therapies has fostered the concept of personalized treatments, which have been evaluated mainly through tumor-centered outcomes and have focused on low-prevalence tumors and advanced stages. Immunotherapy halts this trend and generates expectation regarding its impact on overall survival and its potential use in a wide range of tumors. As part of immunotherapy, neoantigen vaccines have shown high efficacy and safety due to their affinity with T cells and their high specificity. Based on biological principles, we reviewed their potential impact on the burden of disease given the immunogenicity and prevalence by tumor type, the possible effect on clinical practice due to their combination with other treatment modalities, and the effect on access to treatment, given the process of development and production and the availability of local data.