Use Of Cancer Vaccines Research Articles

Efficacy of novel allogeneic cancer cells vaccine to treat colorectal cancer.

Colorectal cancer (CRC) remains a significant global health burden, emphasizing the need for innovative treatment strategies. 95% of the CRC population are microsatellite stable (MSS), insensitive to classical immunotherapies such as anti-PD-1; on the other hand, responders can become resistant and relapse. Recently, the use of cancer vaccines enhanced the immune response against tumor cells. In this context, we developed a therapeutic vaccine based on Stimulated Tumor Cells (STC) platform technology. This vaccine is composed of selected tumor cell lines stressed and haptenated in vitro to generate a factory of immunogenic cancer-related antigens validated by a proteomic cross analysis with patient's biopsies. This technology allows a multi-specific education of the immune system to target tumor cells harboring resistant clones. Here, we report safety and antitumor efficacy of the murine version of the STC vaccine on CT26 BALB/c CRC syngeneic murine models. We showed that one cell line (1CL)-based STC vaccine suppressed tumor growth and extended survival. In addition, three cell lines (3CL)-based STC vaccine significantly improves these parameters by presenting additional tumor-related antigens inducing a multi-specific anti-tumor immune response. Furthermore, proteomic analyses validated that the 3CL-based STC vaccine represents a wider quality range of tumor-related proteins than the 1CL-based STC vaccine covering key categories of tumor antigens related to tumor plasticity and treatment resistance. We also evaluated the efficacy of STC vaccine in an MC38 anti-PD-1 resistant syngeneic murine model. Vaccination with the 3CL-based STC vaccine significantly improved survival and showed a confirmed complete response with an antitumor activity carried by the increase of CD8+ lymphocyte T cells and M1 macrophage infiltration. These results demonstrate the potential of this technology to produce human vaccines for the treatment of patients with CRC.

Advances in Cancer Vaccine Research.

The use of cancer vaccines is considered a promising therapeutic strategy in clinical oncology, which is achieved by stimulating antitumor immunity with tumor antigens delivered in the form of cells, peptides, viruses, and nucleic acids. The ideal cancer vaccine has many advantages, including low toxicity, specificity, and induction of persistent immune memory to overcome tumor heterogeneity and reverse the immunosuppressive microenvironment. Many therapeutic vaccines have entered clinical trials for a variety of cancers, including melanoma, breast cancer, lung cancer, and others. However, many challenges, including single antigen targeting, weak immunogenicity, off-target effects, and impaired immune response, have hindered their broad clinical translation. In this review, we introduce the principle of action, components (including antigens and adjuvants), and classification (according to applicable objects and preparation methods) of cancer vaccines, summarize the delivery methods of cancer vaccines, and review the clinical and theoretical research progress of cancer vaccines. We also present new insights into cancer vaccine technologies, platforms, and applications as well as an understanding of potential next-generation preventive and therapeutic vaccine technologies, providing a broader perspective for future vaccine design.

Developing Effective Cancer Vaccines Using Rendered-Inactive Tumor Cells.

Cancer is a major public health threat, and researchers are constantly looking for new ways to develop effective treatments. One approach is the use of cancer vaccines, which work by boosting the body's immune system to fight cancer. The goal of this study was to develop an effective cancer vaccine using rendered-inactive tumor cells. A CMS5 fibrosarcoma tumor model in BALB/c mice and an E.G7 lymphoma tumor model in C57BL/6 mice were used to evaluate how mitomycin C-inactivated tumor cells mediated tumor protection. The results showed that immunization with inactivated CMS5 cells significantly improved tumor suppression after a challenge with live CMS5 tumor cells, but no effect was observed using the E.G7 tumor model. The results suggested that DC (dendritic cell) responses to tumor antigens are critical. The maturation and activation of DCs were effectively promoted by mitomycin C-treated CMS5 cells, as well as enhanced phagocytosis ability in vitro. The tumor-protective effects established by the vaccination of inactivated CMS5 cells were CD8+ T cell-dependent, as the antitumor responses disappeared after eliminating CD8+ T cells. It was found that the tumor-prevention efficacy was dramatically increased by combining inactivated CM55 tumor cells with anti-CD25 antibodies to temporarily deplete Treg cells (regulatory T cells). This strategy could also significantly induce the rejection against E.G7 tumors. In addition, vaccination with anti-CD25 antibodies plus inactivated CMS5 cells elicited antitumor responses against heterologous tumors. According to the findings of this study, combining the immunization of inactivated tumor cells with an anti-CD25 antibody may be an effective method for cancer prevention.

Blood immune cells as potential biomarkers predicting relapse-free survival of stage III/IV resected melanoma patients treated with peptide-based vaccination and interferon-alpha.

Despite the recent approval of several therapies in the adjuvant setting of melanoma, tumor relapse still occurs in a significant number of completely resected stage III-IV patients. In this context, the use of cancer vaccines is still relevant and may increase the response to immune checkpoint inhibitors. We previously demonstrated safety, immunogenicity and preliminary evidence of clinical efficacy in stage III/IV resected melanoma patients subjected to a combination therapy based on peptide vaccination together with intermittent low-dose interferon-α2b, with or without dacarbazine preconditioning (https://www.clinicaltrialsregister.eu/ctr-search/search, identifier: 2008-008211-26). In this setting, we then focused on pre-treatment patient immune status to highlight possible factors associated with clinical outcome. Multiparametric flow cytometry was used to identify baseline immune profiles in patients' peripheral blood mononuclear cells and correlation with the patient clinical outcome. Receiver operating characteristic curve, Kaplan-Meier survival and principal component analyses were used to evaluate the predictive power of the identified markers. We identified 12 different circulating T and NK cell subsets with significant (p ≤ 0.05) differential baseline levels in patients who later relapsed with respect to patients who remained free of disease. All 12 parameters showed a good prognostic accuracy (AUC>0.7, p ≤ 0.05) and 11 of them significantly predicted the relapse-free survival. Remarkably, 3 classifiers also predicted the overall survival. Focusing on immune cell subsets that can be analyzed through simple surface staining, three subsets were identified, namely regulatory T cells, CD56dimCD16- NK cells and central memory γδ T cells. Each subset showed an AUC>0.8 and principal component analysis significantly grouped relapsing and non-relapsing patients (p=0.034). These three subsets were used to calculate a combination score that was able to perfectly distinguish relapsing and non-relapsing patients (AUC=1; p=0). Noticeably, patients with a combined score ≥2 demonstrated a strong advantage in both relapse-free (p=0.002) and overall (p=0.011) survival as compared to patients with a score <2. Predictive markers may be used to guide patient selection for personalized therapies and/or improve follow-up strategies. This study provides preliminary evidence on the identification of peripheral blood immune biomarkers potentially capable of predicting the clinical response to combined vaccine-based adjuvant therapies in melanoma.

Immune dysregulation in multiple myeloma: the current and future role of cell-based immunotherapy.

Immune dysregulation is a hallmark of clinically active multiple myeloma (MM). Interactions between malignant clonal cells and immune cells within the bone marrow microenvironment are associated with the formation of a milieu favorable to tumor progression. IL-10, TGF-β and other immunoregulatory pathways are upregulated, promoting angiogenesis, tumor cell survival and inhibition ofthenative immune response. Transcriptomic evaluation of the bone marrow microenvironment reveals polarization of the T cell repertoire towards exhaustion and predominance of accessory cells with immunosuppressive qualities. These changes facilitate the immune escape of tumor cells and functional deficiencies that manifest as an increased risk of infection and a reduction in response to vaccinations. Immunotherapy with Chimeric Antigen Receptor (CAR) T cells and other cellular-based approaches have transformed outcomes for patients with advanced MM. Characterization of the immune milieu and identification of biomarkers predictive of treatment response are essential to increasing durability and allowing for the incorporation of novel strategies such as cancer vaccines. This paper will review the current use of cancer vaccines and CAR T cell therapy in MM as well as potential opportunities to expand and improve the application of these platforms.

ATP128 Clinical Therapeutic Cancer Vaccine Activates NF-κB and IRF3 Pathways through TLR4 and TLR2 in Human Monocytes and Dendritic Cells.

Simple SummaryPeptide-based cancer vaccines require adjuvants to increase their immunogenicity to mount an antigen-specific reliable immune response. We have previously shown that immunization with self-adjuvanting peptide-based vaccines issued from our KISIMA vaccine platform, and targeting tumor-specific antigens, resulted in potent immune responses in preclinical models. The aim of our study was to assess the molecular mechanism of action of the first human candidate vaccine derived from the KISIMA platform, ATP128. By using an in vitro (THP-1 cell line) and ex vivo model system (human monocyte-derived dendritic cells), we were able to demonstrate that ATP128 relies on both the cell-penetrating peptide and TLR agonist domain present in the construct to activate the NF-κB and IRF3 pathways, in a self-adjuvanting manner. Importantly, we demonstrated that ATP128 is the first therapeutic vaccine able to activate human DCs through TLR2 and TLR4.The use of cancer vaccines is a promising therapeutic strategy able to stimulate anti-tumor immunity by inducing both humoral and cellular immunity. In this study, antigen presenting cells play a key role by inducing a strong activation of the T cell-mediated adaptive immune response, essential for the anti-tumor potential of cancer vaccines. The first human candidate vaccine created from the KISIMA platform, ATP128, bears three tumor-associated antigens highly expressed in colorectal cancer tissues. At the N-terminus, the cell-penetrating peptide allows the antigen delivery inside the cell and, together with the TLR agonist-derived peptide at the C-terminus, ensures the activation of the monocyte-derived dendritic cells. Here, we show that ATP128 leads to both NF-κB and IRF3 pathway activation, with subsequent pro-inflammatory cytokines and type I Interferon release, as well as an increase in the expression of costimulatory molecules, alongside an upregulation of MHC class I molecules. This cellular immune response involves TLR2 and TLR4, for both membrane and intracellular signaling. We demonstrated an endocytic component in ATP128’s activity by combining the use of a variant of ATP128 lacking the cell-penetrating peptide with endocytosis inhibitors. Importantly, this internalization step is detemined essential for the activation of the IRF3 pathway. This study validates the design of the self-adjuvanting ATP128 vaccine for cancer immunotherapy.

Advances in Nanotechnology for Cancer Immunoprevention and Immunotherapy: A Review.

One of the most effective cancer therapies, cancer immunotherapy has produced outstanding outcomes in the field of cancer treatment. However, the cost is excessive, which limits its applicability. A smart way to address this issue would be to apply the knowledge gained through immunotherapy to develop strategies for the immunoprevention of cancer. The use of cancer vaccines is one of the most popular methods of immunoprevention. This paper reviews the technologies and processes that support the advantages of cancer immunoprevention over traditional cancer immunotherapies. Nanoparticle drug delivery systems and nanoparticle-based nano-vaccines have been employed in the past for cancer immunotherapy. This paper outlines numerous immunoprevention strategies and how nanotechnology can be applied in immunoprevention. To comprehend the non-clinical and clinical evaluation of these cancer vaccines through clinical studies is essential for acceptance of the vaccines.

Cancer Vaccine in Cold Tumors: Clinical Landscape, Challenges, and Opportunities.

The idea of cancer immunotherapy is to stimulate the immune system to fight tumors without destroying normal cells. One of the anticancer therapy methods, among many, is based on the use of cancer vaccines that contain tumor antigens in order to induce immune responses against tumors. However, clinical trials have shown that the use of such vaccines as monotherapy is ineffective in many cases since they do not cause a strong immune response. Particular tumors are resistant to immunotherapy due to the absence or insufficient infiltration of tumors with CD8+ T cells, and hence, they are called cold or non-inflamed tumors. Cold tumors are characterized by a lack of CD8+ T cell infiltration, the presence of anti-inflammatory myeloid cells, tumor-associated M2 macrophages, and regulatory T cells. It is very important to determine the stage of the antitumor response that does not work properly in order to use the right strategy. Applying other therapeutic methods alongside cancer vaccines can be more rational for cold tumors, which do not provoke the immune system strongly. Herein, we indicate some combinational therapies that have been used or are in progress for cold tumor treatment alongside vaccines.

Fueling Cancer Vaccines to Improve T Cell-Mediated Antitumor Immunity.

Cancer vaccines offer the potential to enhance T cell-mediated antitumor immunity by expanding and increasing the function of tumor-specific T cells and shaping the recall response against recurring tumors. While the use of cancer vaccines is not a new immunotherapeutic approach, the cancer vaccine field continues to evolve as new antigen types emerge and vaccine formulations and delivery strategies are developed. As monotherapies, cancer vaccines have not been very efficacious in part due to pre-existing peripheral- and tumor-mediated tolerance mechanisms that limit T cell function. Over the years, various agents including Toll-like receptor agonists, cytokines, and checkpoint inhibitors have been employed as vaccine adjuvants and immune modulators to increase antigen-mediated activation, expansion, memory formation, and T effector cell function. A renewed interest in this approach has emerged as better neoepitope discovery tools are being developed and our understanding of what constitutes an effective cancer vaccine is improved. In the coming years, cancer vaccines will likely be vital to enhance the response to current immunotherapies. In this review, we discuss the various types of therapeutic cancer vaccines, including types of antigens and approaches used to enhance cancer vaccine responses such as TLR agonists, recombinant interleukin-2 and interleukin-2 derivatives, and checkpoint inhibitors.

Recent advances in cancer immunotherapy: Modulation of tumor microenvironment by Toll-like receptor ligands.

Immunotherapy is considered a promising approach for cancer treatment. An important strategy for cancer immunotherapy is the use of cancer vaccines, which have been widely used for cancer treatment. Despite the great potential of cancer vaccines for cancer treatment, their therapeutic effects in clinical settings have been limited. The main reason behind the lack of significant therapeutic outcomes for cancer vaccines is believed to be the immunosuppressive tumor microenvironment (TME). The TME counteracts the therapeutic effects of immunotherapy and provides a favorable environment for tumor growth and progression. Therefore, overcoming the immunosuppressive TME can potentially augment the therapeutic effects of cancer immunotherapy in general and therapeutic cancer vaccines in particular. Among the strategies developed for overcoming immunosuppression in TME, the use of toll-like receptor (TLR) agonists has been suggested as a promising approach to reverse immunosuppression. In this paper, we will review the application of the four most widely studied TLR agonists including agonists of TLR3, 4, 7, and 9 in cancer immunotherapy.

A New Generation of Vaccines in the Age of Immunotherapy

Purpose of reviewCancer vaccines are one of the most extensively studied immunotherapy type in solid tumors. Despite favorable presuppositions, so far, the use of cancer vaccines has been associated with disappointing results. However, a new generation of vaccines has been developed, promising to revolutionize the immunotherapy field.Recent findingsIn this review, we aim to highlight the advances in cancer vaccines and the remaining hurdles to overcome.SummaryCancer vaccination has experienced tremendous progress in the last decade, with myriad promising developments. Future efforts should focus on optimization of target identification, streamlining of most appropriate vaccination strategies, and adjuvant development, as well as predictive biomarker identification. Cautious optimism is warranted in the face of early successes seen in recent clinical trials for oncolytic vaccines. If an approach were to prove successful, it could revolutionize cancer therapy the way ICIs did in the previous decade.

MRNA-Based Cancer Vaccines: A Therapeutic Strategy for the Treatment of Melanoma Patients.

Malignant melanoma is one of the most aggressive forms of cancer and the leading cause of death from skin tumors. Given the increased incidence of melanoma diagnoses in recent years, it is essential to develop effective treatments to control this disease. In this regard, the use of cancer vaccines to enhance cell-mediated immunity is considered to be one of the most modern immunotherapy options for cancer treatment. The most recent cancer vaccine options are mRNA vaccines, with a focus on their usage as modern treatments. Advantages of mRNA cancer vaccines include their rapid production and low manufacturing costs. mRNA-based vaccines are also able to induce both humoral and cellular immune responses. In addition to the many advantages of mRNA vaccines for the treatment of cancer, their use is associated with a number of challenges. For this reason, before mRNA vaccines can be used for the treatment of cancer, comprehensive information about them is required and a large number of trials need to be conducted. Here, we reviewed the general features of mRNA vaccines, including their basis, stabilization, and delivery methods. We also covered clinical trials involving the use of mRNA vaccines in melanoma cancer and the challenges involved with this type of treatment. This review also emphasized the combination of treatment with mRNA vaccines with the use of immune-checkpoint blockers to enhance cell-mediated immunity.

Immunoinformatics design of multiepitopes peptide-based universal cancer vaccine using matrix metalloproteinase-9 protein as a target

A new approach toward cancer therapy is the use of cancer vaccine, yet the different molecular bases of cancers, reduce the effectiveness of this approach. In this article, we aim to use matrix metalloproteinase-9 protein (MMP9) which is an essential molecule in the survival and metastasis of all types of cancers as a target for universal cancer vaccine design. The reference sequence of MMP9 protein was obtained from NCBI databases. Furthermore, the B-cell and T cell-related peptides were analyzed using the IEDB website and other related soft wares. The best candidate peptides were then visualized using chimera software. Three peptides were found to be good candidates for interactions with B cells (SLPE, RLYT, and PALPR), while 10 peptides were found as good targets for interactions with MHC1 and another 10 peptides founded suitable for interactions with MHC2 with population coverages of 94.77 and 90.67%, respectively. Finally, the immune response simulation and molecular docking were done using the C-IMMSIM simulator and AutoDock Vina to confirm the effectiveness of the proposed vaccine. By the end of this project: twenty-three peptide-based vaccine was designed for use as a universal cancer vaccine which has a high world population coverage for MHC1 (94.77%) and MHC2 (90.67%) related alleles.

Human pDCs Are Superior to cDC2s in Attracting Cytolytic Lymphocytes in Melanoma Patients Receiving DC Vaccination

Plasmacytoid dendritic cells (pDCs) and type 2 conventional dendritic cells (cDC2s) are currently under evaluation for use in cancer vaccines. Although both DC subsets can activate adaptive and innate lymphocytes, their capacity to recruit such cells is rarely considered. Here, we show that pDCs and cDC2s display a striking difference in chemokine secretion, which correlates with the recruitment of distinct types of immune effector cells. Activated pDCs express high levels of CXCR3 ligands and attract more CD8+ Tcells, CD56+ Tcells, and γδ Tcells invitro, compared to cDC2s. Skin from melanoma patients shows an influx of immune effector cells following intradermal vaccination with pDCs or cDC2s, with pDCs inducing the strongest influx of lymphocytes known to possess cytolytic activity. These findings suggest that combining both DC subsets could unite the preferred chemoattractive properties of pDCs with the superior Tcell priming properties of cDC2s to ultimately enhance vaccine efficacy.

High Molecular Weight Chitosan-Complexed RNA Nanoadjuvant for Effective Cancer Immunotherapy.

Nucleic acid-based adjuvants have recently emerged as promising candidates for use in cancer vaccines to induce tumor-suppressing immune cells. In this study, we tested whether complexation of a nucleic acid-based adjuvant with chitosan (CTS) modulates immune adjuvant functions. As a nucleic acid-based adjuvant, we used toll-like receptor 3-recognizing RNA adjuvant (RA). Negatively charged RA formed nanoscale polyplexes with cationic CTS that possessed positive zeta potentials. RA/CTS polyplexes exerted dendritic cell (DC)-maturation effects without causing significant DC toxicity. This DC-maturation effect was CTS molecular weight dependent, with RA/CTS polyplexes with a CTS molecular weight of 340 kDa (RA/CTS 340K) producing the greatest effect. Subcutaneous injection of RA/CTS 340K polyplexes with the model tumor antigen ovalbumin exerted a preventive effect against challenge by ovalbumin-expressing tumor cells. It also provided greater inhibitory effects against a second challenge with the same tumor cells compared with other treatments. These protective effects of subcutaneous RA/CTS polyplex treatment were associated with the highest tumor antigen-specific humoral and cellular immune responses after tumor challenge, and with the greatest infiltration of CD4 helper T cell and CD8 T cell into the tumor tissues. Mice vaccinated with ovalbumin and RA/CTS polyplexes showed complete survival, even after repeated challenge with tumor cells. Our results suggest the potential of RA/CTS polyplexes as effective nanoadjuvants in the design of tumor vaccines and cancer immunotherapy.

Cancer vaccine: how far are we from curing cancer?

Although cancer treatment has developed considerably in the 21st century, there are still 8–9 million people dying of this disease each year. One strategy, using a patient's own immune system to combat their cancer, has recently led to a significant improvement in survival rates. The concept of immunotherapy is not new; as far back as 1893, William Coley reported tumour regression following repeated injections of bacterial toxin from Streptococcus pyogenes in a patient with advanced sarcoma. Over 100 years later, the use of cancer vaccine has come a long way, with a better understanding of the immune system's interaction with the tumour microenvironment.

A STUDY ON HEAMPHILUS INFLUANZAE TYPE B DISEASE CAUSING ANTIGENS: AN APPROACH OF EPITOPE PREDICTION, ANTIGENICITY AND IMMUNOGENICITY PREDICTION

Vaccines work by mimicking disease agents and stimulating the immune system which in turn builds a defence mechanism against the disease causing agents. Some of the vaccines contain a part of the disease causing agents which are either weakened or dead. Apart from using vaccines only for viral infections, utilizing the same against Cancers both as therapeutic and preventative has captured huge interest. The use of Cancer vaccines in cancer therapies is called immunotherapy which is done either by specific cancer vaccine or universal cancer vaccine which contain tumour antigens that stimulate the immune system which in turn initiate various mechanisms that terminate tumour cells and prevents recurrence of these tumours. Hemophilus influanzae is a disease causing virus &amp; here we have done a brief study about the different antigens of the b strain of Haemophilus influenzae and compare them using various bioinformatics tools to get the most effective antigen of the above mentioned strain.

Identification of new MUC1 epitopes using HLA-transgenic animals: implication for immunomonitoring

BackgroundThe success of immunotherapeutics in oncology and the search for further improvements has prompted revisiting the use of cancer vaccines. In this context, knowledge of the immunogenic epitopes and the monitoring of the immune response cancer vaccines generate are essential. MUC1 has been considered one of the most important tumor associated antigen for decades.MethodsTo identify HLA-restricted MUC1 peptides we used eight human MHC class I transgenic mouse lines, together covering more than 80% of the human population. MUC1 peptides were identified by vaccinating each line with full length MUC1 coding sequences and using an IFNγ ELIspot restimulation assay. Relevant peptides were tested in a flow cytometry-based tetramer assay and for their capacity to serve as target in an in vivo killing assay.ResultsFour previously identified MUC1 peptides were confirmed and five are described here for the first time. These nine peptide-MHC combinations were further characterized. Six gave above-background tetramer staining of splenocytes from immunized animals and three peptides were induced more than 5% specific in vivo killing.ConclusionsThese data describe for the first time five new HLA class I-restricted peptides and revisit some that were previously described. They also emphasize the importance of using in vivo/ex vivo models to screen for immunogenic peptides and define the functions for individual peptide-HLA combinations.

Emerging applications of exosomes in cancer therapeutics and diagnostics.

Exosomes are nanoscale extracellular vesicles that are shed from different cells in the body. Exosomes encapsulate several biomolecules including lipids, proteins, and nucleic acids, and can therefore play a key role in cellular communication. These vesicles can be isolated from different body fluids and their small sizes make them attractive in various biomedical applications. Here, we review state‐of‐the art approaches in exosome isolation and purification, and describe their potential use in cancer vaccines, drug delivery, and diagnostics.

Review on the immunotherapy strategies against metastatic colorectal carcinoma.

Colorectal cancer (CRC) is one of the most common malignancies throughout the world and the leading cause of cancer-related mortality in Western countries. Recent progress in CRC treatment options, such as surgery, chemotherapy, radiotherapy and target therapy, has improved the prognosis, but advanced disease with recurrence or distant metastasis is usually incurable and has an unfavorable prognosis. The introduction of immunotherapy-associated strategies, both active and passive, to the treatment of CRC aims to overcome the limits of classical treatments. We review the state of the art for CRC with respect to different immunotherapeutic approaches, such as the use of cancer vaccines and/or adoptive cellular therapy, their most current advances and limitations and perspectives for further improvements.