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SA-4-1BBL as a novel adjuvant for the development of therapeutic cancer vaccines.

ABSTRACT: Tumor associated antigen (TAA)-based therapeutic vaccines have great potential as a safe, practical, and cost-efficient alternative to standard treatments for cancer. Clinical efficacy of TAA-based vaccines, however, has yet to be realized and will require adjuvants with pleiotropic functions on immune cells. Such adjuvants need not only to generate/boost T cell responses, but also reverse intrinsic/extrinsic tumor immune evasion mechanisms for therapeutic efficacy. This review focuses on a novel agonistic ligand, SA-4-1BBL, for 4-1BB costimulatory receptor as an adjuvant of choice because of its ability to: i) serve as a vehicle to deliver TAAs to dendritic cells (DCs) for antigen uptake and cross-presentation to CD8(+) T cells; ii) augment adaptive Th1 and innate immune responses; and iii) overcome various immune evasion mechanisms, cumulatively translating into therapeutic efficacy in preclinical tumor models.

SUBMITTER: Sharma RK

PROVIDER: S-EPMC4721633 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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SA-4-1BBL as a novel adjuvant for the development of therapeutic cancer vaccines.

Sharma Rajesh K RK Yolcu Esma S ES Shirwan Haval H

Expert review of vaccines 20140301 3

Tumor associated antigen (TAA)-based therapeutic vaccines have great potential as a safe, practical, and cost-efficient alternative to standard treatments for cancer. Clinical efficacy of TAA-based vaccines, however, has yet to be realized and will require adjuvants with pleiotropic functions on immune cells. Such adjuvants need not only to generate/boost T cell responses, but also reverse intrinsic/extrinsic tumor immune evasion mechanisms for therapeutic efficacy. This review focuses on a nove ...[more]

PMID: 24521311

Similar Datasets

SA-4-1BBL and monophosphoryl lipid A constitute an efficacious combination adjuvant for cancer vaccines.

Project description:Vaccines based on tumor-associated antigens (TAA) have limited therapeutic efficacy due to their weak immunogenic nature and the various immune evasion mechanisms active in advanced tumors. In an effort to overcome these limitations, we evaluated a combination of the T-cell costimulatory molecule SA-4-1BBL with the TLR4 agonist monophosphoryl lipid A (MPL) as a novel vaccine adjuvant system. In the TC-1 mouse allograft model of human papilloma virus (HPV)-induced cancer, a single administration of this combination adjuvant with HPV E7 protein caused tumor rejection in all tumor-bearing mice. On its own, SA-4-1BBL outperformed MPL in this setting. Against established tumors, two vaccinations were sufficient to elicit rejection in the majority of mice. In the metastatic model of Lewis lung carcinoma, vaccination of the TAA survivin with SA-4-1BBL/MPL yielded superior efficacy against pulmonary metastases. Therapeutic efficacy of SA-4-1BBL/MPL was achieved in the absence of detectable toxicity, correlating with enhanced dendritic cell activation, CD8(+) T-cell function, and an increased intratumoral ratio of CD8(+) T effector cells to CD4(+)FoxP3(+) T regulatory cells. Unexpectedly, use of MPL on its own was associated with unfavorable intratumoral ratios of these T-cell populations, resulting in suboptimal efficacy. The efficacy of MPL monotherapy was restored by depletion of T regulatory cells, whereas eliminating CD8(+) T cells abolished the efficacy of its combination with SA-4-1BBL. Mechanistic investigations showed that IFNγ played a critical role in supporting the therapeutic effect of SA-4-1BBL/MPL. Taken together, our results offer a preclinical proof of concept for the use of a powerful new adjuvant system for TAA-based cancer vaccines.

| S-EPMC4233189 | biostudies-literature

Therapeutic Cancer Vaccines-Antigen Discovery and Adjuvant Delivery Platforms.

Project description:For decades, vaccines have played a significant role in protecting public and personal health against infectious diseases and proved their great potential in battling cancers as well. This review focused on the current progress of therapeutic subunit vaccines for cancer immunotherapy. Antigens and adjuvants are key components of vaccine formulations. We summarized several classes of tumor antigens and bioinformatic approaches of identification of tumor neoantigens. Pattern recognition receptor (PRR)-targeting adjuvants and their targeted delivery platforms have been extensively discussed. In addition, we emphasized the interplay between multiple adjuvants and their combined delivery for cancer immunotherapy.

| S-EPMC9325128 | biostudies-literature

An Oncolytic Adenovirus Encoding SA-4-1BBL Adjuvant Fused to HPV-16 E7 Antigen Produces a Specific Antitumor Effect in a Cancer Mouse Model.

Project description:Human papillomaviruses (HPVs) are responsible for about 25% of cancer cases worldwide. HPV-16 E7 antigen is a tumor-associated antigen (TAA) commonly expressed in HPV-induced tumors; however, it has low immunogenicity. The interaction of 4-1BBL with its receptor induces pleiotropic effects on innate, adaptive, and regulatory immunity and, if fused to TAAs in DNA vaccines, can improve the antitumor response; however, there is low transfection and antitumor efficiency. Oncolytic virotherapy is promising for antitumor gene therapy as it can be selectively replicated in tumor cells, inducing cell lysis, and furthermore, tumor cell debris can be taken in by immune cells to potentiate antitumor responses. In this study, we expressed the immunomodulatory molecule SA-4-1BBL fused to E7 on an oncolytic adenovirus (OAd) system. In vitro infection of TC-1 tumor cells and NIH-3T3 non-tumor cells with SA/E7/4-1BBL OAd demonstrated that only tumor cells are selectively destroyed. Moreover, protein expression is targeted to the endoplasmic reticulum in both cell lines when a signal peptide (SP) is added. Finally, in an HPV-induced cancer murine model, the therapeutic oncolytic activity of OAd can be detected, and this can be improved when fused to E7 and SP.

| S-EPMC7917608 | biostudies-literature

A DNA Vaccine Encoding SA-4-1BBL Fused to HPV-16 E7 Antigen Has Prophylactic and Therapeutic Efficacy in a Cervical Cancer Mouse Model.

Project description:The SA-4-1BBL, an oligomeric novel form of the natural ligand for the 4-1BB co-stimulatory receptor of the tumor necrosis factor (TNF) superfamily, as a recombinant protein has potent pleiotropic effects on cells of innate, adaptive, and regulatory immunity with demonstrated therapeutic efficacy in several tumor models. However, the production of soluble form of SA-4-1BBL protein and quality control is time and resource intensive and face various issues pertinent to clinical development of biologics. The present study sought to take advantage of the simplicity and translatability of DNA-based vaccines for the production and delivery of SA-4-1BBL for cancer immune prevention and therapy. A chimeric HPV-16 E7 DNA vaccine (SP-SA-E7-4-1BBL) was constructed that contains the signal peptide (SP) of calreticulin (CRT), streptavidin (SA) domain of SA-4-1BBL, HPV-16 E7 double mutant gene, and the extracellular domain of mouse 4-1BBL. Immunization by gene gun with SP-SA-E7-4-1BBL induced greater prophylactic as well as therapeutic effects in C57BL/6 mice against TC-1 tumor model compared with immunization with E7wt, SP-SA-4-1BBL or reference-positive control CRT-E7wt. The therapeutic efficacy of the DNA vaccine was associated with increased frequency of E7-specific T cells producing interferon (IFN)-γ. Overall, our data suggest that this DNA-based vaccine strategy might represent a translational approach because it provides a simpler and versatile alternative to a subunit vaccine based on SA-4-1BBL and E7 proteins.

| S-EPMC6356763 | biostudies-literature

Development of Therapeutic Vaccines for Ovarian Cancer.

Project description:Ovarian cancer remains the deadliest of all gynecologic malignancies. Our expanding knowledge of ovarian cancer immunology has allowed the development of therapies that generate systemic anti-tumor immune responses. Current immunotherapeutic strategies include immune checkpoint blockade, cellular therapies, and cancer vaccines. Vaccine-based therapies are designed to induce both adaptive and innate immune responses directed against ovarian cancer associated antigens. Tumor-specific effector cells, in particular cytotoxic T cells, are activated to recognize and eliminate ovarian cancer cells. Vaccines for ovarian cancer have been studied in various clinical trials over the last three decades. Despite evidence of vaccine-induced humoral and cellular immune responses, the majority of vaccines have not shown significant anti-tumor efficacy. Recently, improved vaccine development using dendritic cells or synthetic platforms for antigen presentation have shown promising clinical benefits in patients with ovarian cancer. In this review, we provide an overview of therapeutic vaccine development in ovarian cancer, discuss proposed mechanisms of action, and summarize the current clinical experience.

| S-EPMC7711901 | biostudies-literature

SA-4-1BBL as the immunomodulatory component of a HPV-16 E7 protein based vaccine shows robust therapeutic efficacy in a mouse cervical cancer model.

Project description:Cervical cancer is the leading cause of cancer-related deaths among women worldwide. Current prophylactic vaccines based on HPV (Human papillomavirus) late gene protein L1 are ineffective in therapeutic settings. Therefore, there is an acute need for the development of therapeutic vaccines for HPV associated cancers. The HPV E7 oncoprotein is expressed in cervical cancer and has been associated with the cellular transformation and maintenance of the transformed phenotype. As such, E7 protein represents an ideal target for the development of therapeutic subunit vaccines against cervical cancer. However, the low antigenicity of this protein may require potent adjuvants for therapeutic efficacy. We recently generated a novel chimeric form of the 4-1BBL costimulatory molecule engineered with core streptavidin (SA-4-1BBL) and demonstrated its safe and pleiotropic effects on various cells of the immune system. We herein tested the utility of SA-4-1BBL as the immunomodulatory component of HPV-16 E7 recombinant protein based therapeutic vaccine in the E7 expressing TC-1 tumor as a model of cervical cancer in mice. A single subcutaneous vaccination was effective in eradicating established tumors in approximately 70% of mice. The therapeutic efficacy of the vaccine was associated with robust primary and memory CD4(+) and CD8(+) T cell responses, Th1 cytokine response, infiltration of CD4(+) and CD8(+) T cells into the tumor, and enhanced NK cell killing. Importantly, NK cells played an important role in vaccine mediated therapy since their physical depletion compromised vaccine efficacy. Collectively, these data demonstrate the utility of SA-4-1BBL as a new class of multifunctional immunomodulator for the development of therapeutic vaccines against cancer and chronic infections.

| S-EPMC2921468 | biostudies-literature

Therapeutic cancer vaccines.

Project description:Therapeutic cancer vaccines have the potential of being integrated in the therapy of numerous cancer types and stages. The wide spectrum of vaccine platforms and vaccine targets is reviewed along with the potential for development of vaccines to target cancer cell "stemness," the epithelial-to-mesenchymal transition (EMT) phenotype, and drug-resistant populations. Preclinical and recent clinical studies are now revealing how vaccines can optimally be used with other immune-based therapies such as checkpoint inhibitors, and so-called nonimmune-based therapeutics, radiation, hormonal therapy, and certain small molecule targeted therapies; it is now being revealed that many of these traditional therapies can lyse tumor cells in a manner as to further potentiate the host immune response, alter the phenotype of nonlysed tumor cells to render them more susceptible to T-cell lysis, and/or shift the balance of effector:regulatory cells in a manner to enhance vaccine efficacy. The importance of the tumor microenvironment, the appropriate patient population, and clinical trial endpoints is also discussed in the context of optimizing patient benefit from vaccine-mediated therapy.

| S-EPMC6324585 | biostudies-literature

ProtEx technology for the generation of novel therapeutic cancer vaccines.

Project description:Therapeutic vaccines present an attractive alternative to conventional treatments for cancer. However, tumors have evolved various immune evasion mechanisms to modulate innate, adaptive, and regulatory immunity for survival. Therefore, successful vaccine formulations may require a non-toxic immunomodulator or adjuvant that not only induces/stimulates innate and adaptive tumor-specific immune responses, but also overcomes immune evasion mechanisms. Given the paramount role costimulation plays in modulating innate, adaptive, and regulatory immune responses, costimulatory ligands may serve as effective immunomodulating components of therapeutic cancer vaccines. Our laboratory has developed a novel technology designated as ProtEx that allows for the generation of recombinant costimulatory ligands with potent immunomodulatory activities and the display of these molecules on the cell surface in a rapid and efficient manner as a practical and safe alternative to gene therapy for immunomodulation. Importantly, the costimulatory ligands not only function when displayed on tumor cells, but also as soluble proteins that can be used as immunomodulatory components of conventional vaccine formulations containing tumor-associated antigens (TAAs). We herein discuss the application of the ProtEx technology to the development of effective cell-based as well as cell-free conventional therapeutic cancer vaccines.

| S-EPMC2917214 | biostudies-literature

Advances in the development of personalized neoantigen-based therapeutic cancer vaccines.

Project description:Within the past decade, the field of immunotherapy has revolutionized the treatment of many cancers with the development and regulatory approval of various immune-checkpoint inhibitors and chimeric antigen receptor T cell therapies in diverse indications. Another promising approach to cancer immunotherapy involves the use of personalized vaccines designed to trigger de novo T cell responses against neoantigens, which are highly specific to tumours of individual patients, in order to amplify and broaden the endogenous repertoire of tumour-specific T cells. Results from initial clinical studies of personalized neoantigen-based vaccines, enabled by the availability of rapid and cost-effective sequencing and bioinformatics technologies, have demonstrated robust tumour-specific immunogenicity and preliminary evidence of antitumour activity in patients with melanoma and other cancers. Herein, we provide an overview of the complex process that is necessary to generate a personalized neoantigen vaccine, review the types of vaccine-induced T cells that are found within tumours and outline strategies to enhance the T cell responses. In addition, we discuss the current status of clinical studies testing personalized neoantigen vaccines in patients with cancer and considerations for future clinical investigation of this novel, individualized approach to immunotherapy.

| S-EPMC7816749 | biostudies-literature

Editorial overview: Vaccines: Reinvigorating therapeutic cancer vaccines.

Project description:Lessons learned from the rapid deployment of vaccines during the COVID-19 pandemic are reinvigorating the cancer vaccine field. Using delivery platforms including mRNA and synthetic long peptides, recent clinical trials have demonstrated that cancer vaccines are safe, feasible, and can be associated with the generation of antigen-specific memory T cells and, in some cases, durable clinical responses. Despite these advances, fundamental questions remain regarding the optimal delivery platforms and antigen targets to use in cancer vaccines. Ongoing and future studies that harness advances in the identification of novel sources of antigens, the prediction of immunogenic antigens, and the use of single-cell technologies to profile antigen-specific T cells will hopefully reveal correlates with clinical outcomes and provide a mechanistic basis for future progress.

| S-EPMC9612210 | biostudies-literature

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