Vaccine-based Immunotherapy Research Articles

Phosphodiesterase-5 inhibition collaborates with vaccine-based immunotherapy to reprogram myeloid cells in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is highly lethal and resistant to immunotherapy. Although immune recognition can be enhanced with immunomodulatory agents including checkpoint inhibitors and vaccines, few patients experience clinical efficacy because the tumor immune microenvironment (TiME) is dominated by immunosuppressive myeloid cells that impose T cell inhibition. Inhibition of phosphodiesterase-5 (PDE5) was reported to downregulate metabolic regulators arginase and inducible NOS in immunosuppressive myeloid cells and enhance immunity against immune-sensitive tumors, including head and neck cancers. We show for the first time to our knowledge that combining a PDE5 inhibitor, tadalafil, with a mesothelin-specific vaccine, anti-programmed cell death protein 1, and anti-cytotoxic T lymphocyte-associated protein 4 yields antitumor efficacy even against immune-resistant PDAC. To determine immunologic advantages conferred by tadalafil, we profiled the TiME using mass cytometry and single-cell RNA-sequencing analysis with Domino to infer intercellular signaling. Our analyses demonstrated that tadalafil reprograms myeloid cells to be less immunosuppressive. Moreover, tadalafil synergized with the vaccine, enhancing T cell activation including mesothelin-specific T cells. Tadalafil treatment was also associated with myeloid/T cell signaling axes important for antitumor responses (e.g., Cxcr3, Il12). Our study shows that PDE5 inhibition combined with vaccine-based immunotherapy promotes pro-inflammatory states of myeloid cells, activation of T cells, and enhanced myeloid/T cell crosstalk to yield antitumor efficacy against immune-resistant PDAC.

Nanomedicines for an Enhanced Immunogenic Cell Death-Based In Situ Cancer Vaccination Response.

Cancer vaccines have shown tremendous potential in preventing and treating cancer by providing immunogenic antigens to initiate specific tumor immune responses. An in situ vaccine prepared from an autologous tumor can mobilize a patient's own tumor cell lysate as a reservoir of specific antigens, thus triggering a broad immune response and diverse antitumor immunity in an individually tailored manner. Its efficacy is much better than that of conventional vaccines with a limited number of epitopes. Several conventional therapies, including radiotherapy (RT), chemotherapeutics, photodynamic therapy (PDT), and photothermal therapy (PTT) can activate an anticancer in situ vaccine response by inducing immunogenic cell death (ICD), triggering the exposure of tumor-associated antigens (TAAs), cancerous testis antigens, neoantigens, and danger-associated molecular patterns (DAMPs) with low cost. However, the immunogenicity of dying tumor cells is low, making released antigens and DAMPs insufficient to initiate a robust immune response against malignant cancer. Moreover, the immunosuppressive tumor microenvironment (TME) severely hinders the infiltration and sensitization of effector immune cells, causing tolerogenic immunological effects.Herein, we mainly focus on the research in developing nanoplatforms to surmount the major challenges met by ICD-based in situ vaccines. We first summarized a variety of nanotechnologies that enable enhanced immunogenicity of dying cancer cells by enhancing antigenicity and adjuvanticity. The robust antigenicity was obtained via regulating the tumor cells death mode or the dying state to amplify the recognition of tumor debris by professional antigen-presenting cells (APCs). The adjuvanticity was potentiated by raising the level or intensifying the activity of endogenous adjuvants or promoting the intelligent delivery of exogenous immunostimulants to activate immune cell recruitment and promote antigen presentation. Additionally, versatile approaches to reverse immunosuppressive TME to boost the in situ tumor vaccination response are also highlighted in detail. On one hand, by modulating the cell metabolism in TME, the expansion and activity of effector versus immunosuppressive cells can be optimized to improve the efficiency of in situ vaccines. On the other hand, regulating cellular components in TME, such as reversing adverse immune cell phenotypes or inhibiting the activity of interstitial cells, can also significantly enhance the ICD-based antitumor immunotherapy effect. Finally, our viewpoint on the future challenges and opportunities in this hopeful area is presented. We expect that this Account can offer much more insight into the design, planning, and development of cutting-edge in situ tumor vaccine platforms, promoting more attention and academic-industry collaborations, accelerating the advanced progress of in situ tumor vaccine-based immunotherapy in the clinic.

Synergistic Glutathione Depletion and STING Activation to Potentiate Dendritic Cell Maturation and Cancer Vaccine Efficacy.

Dendritic cell (DC) maturation and antigen presentation are key factors for successful vaccine-based cancer immunotherapy. This study developed manganese-based layered double hydroxide (Mn-LDH) nanoparticles as a self-adjuvanted vaccine carrier that not only promoted DC maturation through synergistically depleting endogenous glutathione (GSH) and activating STING signaling pathway, but also facilitated the delivery of model antigen ovalbumin (OVA) into lymph nodes and subsequent antigen presentation in DCs. Significant therapeutic-prophylactic efficacy of the OVA-loaded Mn-LDH (OVA/Mn-LDH) nanovaccine was determined by the tumor growth inhibition in the mice bearing B16-OVA tumor. Our results showed that the OVA/Mn-LDH nanoparticles could be a potent delivery system for cancer vaccine development without the need of adjuvant. Therefore, the combination of GSH exhaustion and STING pathway activation might be an advisable approach for promoting DC maturation and antigen presentation, finally improving cancer vaccine efficacy.

The self-adjuvant heterocyclic lipid nanoparticles encapsulated with vaccine and STAT3 siRNA boost cancer immunotherapy through DLN-targeted and STING pathway

A great potential of tumor vaccine-based immunotherapy has been emerged; however, the low cross-presentation of tumor antigens, intrinsic immunosuppressive signaling of dendritic cells (DCs) and the immunosuppression in tumor microenvironment (TME) hindered the progress of tumor vaccine. In this article, approaches employed heterocyclic lipid nanoparticles (LNP) as a tumor vaccine and signal transduction and activator of transcription 3 (STAT3) siRNA carrier as well as a “self-adjuvant” by targeting draining lymph node (DLN) and stimulating stimulator of interferon genes (STING)-mediated type I interferon (IFN) innate immune response were proposed. Model antigens ovalbumin peptide 257–264 (OVA) were cross-presented to activate T cells; STAT3 siRNA acted synergistically with OVA to improve DCs maturation, enhance antigen presentation and abrogate immunosuppressive TME; heterocyclic lipids induced the production of type I IFN via activating the STING pathway. Compared to DLin-MC3-DMA LNP, heterocyclic LNPs, especially A18-LNP, targeted DLN, delivered much OVA and STAT3 siRNA into cytoplasm of antigen-presenting cells (APCs, mainly DCs), activated STING pathway, promoted DCs maturation and antigen presentation, abrogated immunosuppression in TME, therefore, leading to robust anti-cancer response. Thus, heterocyclic LNPs efficiently delivered tumor vaccine and STAT3 siRNA and simultaneously activated the immune system through DLN-targeted and STING pathway, provided better antitumor effects, suggesting a promising strategy for cancer immunotherapy.

Antigenicity and adjuvanticity co-reinforced personalized cell vaccines based on self-adjuvanted hydrogel for post-surgical cancer vaccination

Cancer vaccine-based postsurgical immunotherapy is emerging as a promising approach in patients following surgical resection for inhibition of tumor recurrence. However, low immunogenicity and insufficient cancer antigens limit the widespread application of postoperative cancer vaccines. Here, we propose a “trash to treasure” cancer vaccine strategy to enhance postsurgical personalized immunotherapy, in which antigenicity and adjuvanticity of purified surgically exfoliated autologous tumors (with whole antigen repertoire) were co-reinforced. In the antigenicity and adjuvanticity co-reinforced personalized vaccine (Angel-Vax), polyriboinosinic: polyribocytidylic acid (pIC) and tumor cells that have undergone immunogenic death are encapsulated in a self-adjuvanted hydrogel formed by cross-linking of mannan and polyethyleneimine. Angel-Vax exhibits an enhanced capacity on antigen-presenting cells stimulation and maturation compared to its individual components in vitro. Immunization with Angel-Vax provokes an efficient systemic cytotoxic T-cell immune response, contributing to the satisfied prophylactic and therapeutic efficacy in mice. Furthermore, when combined with immune checkpoint inhibitors (ICI), Angel-Vax effectively prevented postsurgical tumor recurrence, as evidenced by an increase in median survival of approximately 35% compared with ICI alone. Unlike the cumbersome preparation process of postoperative cancer vaccines, the simple and feasible approach herein may represent a general strategy for various kinds of tumor cell-based antigens in the inhibition of postsurgical tumor relapse by reinforced immunogenicity.

Polymeric nanoparticles for DNA vaccine-based cancer immunotherapy: a review.

Cancer is one of the leading causes of death and mortality in the world. There is an essential need to develop new drugs or therapeutic approaches to manage treatment-resistant cancers. Cancer immunotherapy is a type of cancer treatment that uses the power of the body's immune system to prevent, control, and eliminate cancer. One of the materials used as a vaccine in immunotherapy is DNA. The application of polymeric nanoparticles as carriers for DNA vaccines could be an effective therapeutic approach to activate immune responses and increase antigen presentation efficiency. Various materials have been used as polymeric nanoparticles, including: chitosan, poly (lactic-co-glycolic acid), Polyethylenimine, dendrimers, polypeptides, and polyesters. Application of these polymer nanoparticles has several advantages, including increased vaccine delivery, enhanced antigen presentation, adjuvant effects, and more sustainable induction of the immune system. Besides many clinical trials and commercial products that were developed based on polymer nanoparticles, there is still a need for more comprehensive studies to increase the DNA vaccine efficiency in cancer immunotherapy using this type of carrier.

Spleen-Targeted mRNA Delivery by Amphiphilic Carbon Dots for Tumor Immunotherapy

In recent years, the application of mRNA vaccine-based tumor immunotherapy invigorated anti-tumor therapy. However, the low efficiency of mRNA delivery and the lack of targeting ability in vivo are the major obstacles to achieving highly efficient immunotherapy. In this work, we report a chemical library of amphiphilic carbon dots (ACDs) and the synthesized ACDs were applied to mRNA delivery, bio-imaging, and tumor immunotherapy. The ACDs can smoothly bind with mRNA to form ACDs@mRNA nanocomplexes, and the fluorescent properties of the ACDs afforded the nanoparticles with bio-imaging ability. By screening of the ACDs, O12-Tta-CDs were found to have optimal mRNA transfection efficiency and the ability of spleen-targeted delivery. In addition, O12-Tta-CDs can well transfect the immune cells and promote the maturation and antigen presentation of bone marrow-derived dendritic cells (BMDCs). Furthermore, O12-Tta-CDs@OVA-mRNA was successfully applied to inhibit tumor growth, and more specific T-cell infiltration was observed in spleen and tumors of mice after treatment in the E.G7-OVA tumor model. Besides, O12-Tta-CDs@OVA-mRNA also achieved a good therapeutic effect in tumor recurrence inhibition and tumor prophylactic experiments. This study provided a new direction for the design of mRNA vectors, which is promising in tumor immunotherapy.

First-in-human, phase 1 study of PF-06753512, a vaccine-based immunotherapy regimen (VBIR), in non-metastatic hormone-sensitive biochemical recurrence and metastatic castration-resistant prostate cancer (mCRPC)

BackgroundThis phase 1 study evaluated PF-06753512, a vaccine-based immunotherapy regimen (PrCa VBIR), in two clinical states of prostate cancer (PC), metastatic castration-resistant PC (mCRPC) and biochemical recurrence (BCR).MethodsFor dose escalation,...

Leveraging β-Adrenergic Receptor Signaling Blockade for Improved Cancer Immunotherapy Through Biomimetic Nanovaccine.

The establishment of effective antitumor immune responses of vaccines is mainly limited by insufficient priming tumor infiltration of T cells and immunosuppressive tumor microenvironment (TME). Targeting β-adrenergic receptor (β-AR) signaling exerts promising benefits on reversing the suppressive effects directly on T cells, but it appears to have considerably limited antitumor performance when combined with vaccine-based immunotherapies. Herein, a tumor membrane-coated nanoplatform for codelivery of adjuvant CpG and propranolol (Pro), a β-AR inhibitor is designed. The biomimetic nanovaccine displayed an improved accumulation in lymph nodes and sufficient drug release, thereby inducing dendritic cell maturation and antigen presentation. Meanwhile, the integration of vaccination and blockade of β-AR signaling not only promoted the priming of the naive CD8+ T cells and effector T cell egress from lymph nodes, but also alleviated the immunosuppressive TME by decreasing the frequency of immunosuppressive cells and increasing the tumor infiltration of B cells and NK cells. Consequently, the biomimetic nanovaccines outperformed greater prophylactic and therapeutic efficacy than nanovaccines without Pro encapsulation in B16-F10 melanoma mice. Taken together, the work explored a biomimetic nanovaccine for priming tumor infiltration of T cells and immunosuppressive TME regulation, offering tremendous potential for a combined β-AR signaling-targeting strategy in cancer immunotherapy.

Ovalbumin-loaded paramagnetic nano-triangles for enhanced dendritic cell stimulation, T1-MR imaging, and antitumor immunity

Vaccine-based cancer immunotherapy has demonstrated a significant potential for cancer treatment in clinics. Although the efficiencies of vaccines are limited, they can be enhanced by a well-designed antigen delivery system that promotes sufficient antigen presentation of dendritic cells (DCs) for initiating high T cell immunity. Herein, antigen-loaded manganese oxide (Mn3O4) triangular-shaped ultrasmall nanoparticles were prepared to stimulate DC-based immunotherapy under the guidance of T1 magnetic resonance imaging. The FDA-approved triblock copolymer Pluronic® F-68 was used not only to transfer the phase from hydrophobic to hydrophilic but also to enrich antigen loading and improve the biocompatibility of the prepared nanoparticles. Ovalbumin (OVA), a model antigen, was adsorbed on the surface of polymer-coated nanoparticles through electrostatic interaction to form Mn3O4@PF68-OVA nanoparticle-antigen complexes to stimulate DC-based immunization and antigen-specific T cell immunity. The Mn3O4@PF68-OVA nanovaccine (NV) induces negligible toxicity effects against 4T1 and bone marrow-derived dendritic cells (BMDCs) by conventional methods supports the proliferation of intestine organoids, which are an innovative three-dimensional cytotoxicity evaluation system, thereby indicating their potential safety for in vivo cancer therapies. The designed paramagnetic nanovaccine possessed excellent OVA delivery to dendritic-regulated antigen-specific T cells in vitro by stimulating the maturation level of BMDCs. In addition, Mn3O4@PF68-OVA NVs enhance immunity in vivo by increasing the T-cells and M1 macrophages, which suggests improved immunity. Excitingly, vaccination with Mn3O4@PF68-OVA offer complete protection in the prophylactic group and significant tumor inhibition in the therapeutic group against B16-OVA tumor. In addition, the designed nanovaccine demonstrated high T1-MR imaging in the tumor, further justifying enhanced tumor accumulation and capability to real-time monitor the treatment procedure. This study presents a promising nanosystem to design an effective nanovaccine for T1-MR imaging-guided tumor immunotherapy.

Dual-responsive PEG-lipid polyester nanoparticles for siRNA and vaccine delivery elicit anti-cancer immune responses by modulating tumor microenvironment.

Cancer vaccine-based immunotherapy has great potential; however, the vaccines have been hindered by the immunosuppressive tumor microenvironment (TME). In this study, dual-responsive PEG-lipid polyester nanoparticles (PEG BR647-NPs) for tumor-targeted delivery were proposed. PEG BR647-NPs containing the model tumor-associated antigen (TAA) OVA and the signal transduction and activator of transcription 3 (STAT3) siRNA were delivered to the tumor. The PEG BR647-NPs were internalized by tumor-associated dendritic cells (TADCs), where the TAA and siRNA were released into the cytoplasm via the endo/lysosome escape effect. The released OVA was presented by the major histocompatibility complex class I to activate T cells, and the released STAT3 siRNA acted to relieve TADC dysfunction, promote TADC maturation, improve antigen-presenting ability, and enhance anticancer T cell immunity. Meanwhile, the PEG BR647-NPs were ingested by tumor cells, killing them by the pro-apoptosis effect of STAT3 siRNA. Moreover, PEG BR647-NPs could reduce the proportion of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in tumors and abrogate immunosuppression. The integration of relieved TADC dysfunction, promoted TADC maturation, enhanced antigen cross-presentation, abrogated immunosuppression, and improved pro-apoptosis effect boosted the vaccination for tumor immunotherapy. Thus, PEG BR647-NPs efficiently delivered the vaccine and STAT3 siRNA to the tumor and modulated immunosuppressive TME, thus providing better antitumor effects.

The main battlefield of mRNA vaccine - Tumor immune microenvironment.

With the increasing threat of tumors to humans, mRNA vaccine-based immunotherapy has received extensive attention; however, the killing effect is sometimes unsatisfactory. The occurrence of tumors is closely related to the abnormality of the tumor immune microenvironment, including the increase in the number of immunosuppressive cells, the anomaly of some cells with tumor-killing function, and the increase in the glycolysis pathway, all of which will affect the anti-tumor effect of mRNA vaccines. Furthermore, delivery in the body and successful escape from lysosome are also essential steps that involve the result of killing. Starting from inhibiting tumor growth and metastasis by mRNA vaccines, this paper summarizes the tumor microenvironment constructed by immunosuppressive cells and cytokines, which inhibit immune cells from exerting anti-tumor effects, emphasizing the increase of glycolytic pathway after tumor formation, which makes tumors have a high probability of metastasis. In the present study, mRNA vaccines adjust the number of immune cells by combining adjuvants or immune checkpoint inhibitors (ICIs), thereby improving the tumor immune microenvironment (TIME) and tilting the balance in favor of immune-potent cells can achieve better anti-tumor effects. All efforts to understand the relationship between TIME and mRNA vaccine will provide a basis for tumor treatment in the future.

Hydrogel-guided strategies to stimulate an effective immune response for vaccine-based cancer immunotherapy.

Cancer vaccines have attracted widespread interest in tumor therapy because of the potential to induce an effective antitumor immune response. However, many challenges including weak immunogenicity, off-target effects, and immunosuppressive microenvironments have prevented their broad clinical translation. To overcome these difficulties, effective delivery systems have been designed for cancer vaccines. As carriers in cancer vaccine delivery systems, hydrogels have gained substantial attention because they can encapsulate a variety of antigens/immunomodulators and protect them from degradation. This enables hydrogels to simultaneously reverse immunosuppression and stimulate the immune response. Meanwhile, the controlled release properties of hydrogels allow for precise temporal and spatial release of loads in situ to further enhance the immune response of cancer vaccines. Therefore, this review summarizes the classification of cancer vaccines, highlights the strategies of hydrogel-based cancer vaccines, and provides some insights into the future development of hydrogel-based cancer vaccines.

CTIM-33. SEXUAL DIMORPHISM OF HUMAN IMMUNE SYSTEM PREDICTS CLINICAL OUTCOMES IN GLIOBLASTOMA IMMUNOTHERAPY: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract Biological differences based on sex have been documented throughout scientific literature. Glioblastoma, the most common primary malignant brain tumor in adults, has a male sex incidence bias, however, no clinical trial data examining differential effects of treatment between sexes currently exist. We analyzed genomic data, as well as clinical trials, to delineate the effect of sex on the immune system and glioblastoma outcome following immunotherapy. We found that, in general females possess enriched immunological signatures on gene set enrichment analysis, that also stratified patient survival when delineated by sex. Female glioblastoma patients treated with immunotherapy had a statistically significant survival advantage at the 1-year compared to males (RR = 1.15; p = 0.0241). This effect was even more pronounced in vaccine-based immunotherapy, (RR = 1.29; p = 0.0158). Our study shows a meaningful difference in the immunobiology between males and females that also influences overall response to immunotherapy in the setting of glioblastoma. Our study adds to a growing body of literature examining sex differences in male and female immunology. We demonstrate both using large scale omic data sets, as well as clinical trials, that female sexually dimorphic genes are tied to immunological responses, and that females have better outcomes during GBM immunotherapy treatments. This data is critical to better inform treatment practices and further crystalizes the need for balanced trial design and prospective reporting of sex as a variable across all GBM clinical trials.

Preclinical development of a vaccine-based immunotherapy regimen (VBIR) that induces potent and durable T cell responses to tumor-associated self-antigens.

The development of therapeutic cancer vaccines remains an active area, although previous approaches have yielded disappointing results. We have built on lessons from previous cancer vaccine approaches and immune checkpoint inhibitor research to develop VBIR, a vaccine-based immunotherapy regimen. Assessment of various technologies led to selection of a heterologous vaccine using chimpanzee adenovirus (AdC68) for priming followed by boosts with electroporation of DNA plasmid to deliver T cell antigens to the immune system. We found that priming with AdC68 rapidly activates and expands antigen-specific T cells and does not encounter pre-existing immunity as occurs with the use of a human adenovirus vaccine. The AdC68 vector does, however, induce new anti-virus immune responses, limiting its use for boosting. To circumvent this, boosting with DNA encoding the same antigens can be done repetitively to augment and maintain vaccine responses. Using mouse and monkey models, we found that the activation of both CD4 and CD8 T cells was amplified by combination with anti-CTLA-4 and anti-PD-1 antibodies. These antibodies were administered subcutaneously to target their distribution to vaccination sites and to reduce systemic exposure which may improve their safety. VBIR can break tolerance and activate T cells recognizing tumor-associated self-antigens. This activation lasts more than a year after completing treatment in monkeys, and inhibits tumor growth to a greater degree than is observed using the individual components in mouse cancer models. These results have encouraged the testing of this combination regimen in cancer patients with the aim of increasing responses beyond current therapies.

Sexual dimorphism of the immune system predicts clinical outcomes in glioblastoma immunotherapy: A systematic review and meta-analysis.

BackgroundBiological differences based on sex have been documented throughout the scientific literature. Glioblastoma (GBM), the most common primary malignant brain tumor in adults, has a male sex incidence bias, however, no clinical trial data examining differential effects of treatment between sexes currently exists.MethodWe analyzed genomic data, as well as clinical trials, to delineate the effect of sex on the immune system and GBM outcome following immunotherapy.ResultsWe found that in general females possess enriched immunological signatures on gene set enrichment analysis, which also stratified patient survival when delineated by sex. Female GBM patients treated with immunotherapy had a statistically significant survival advantage at the 1-year compared to males (relative risk [RR] = 1.15; P = .0241). This effect was even more pronounced in vaccine-based immunotherapy (RR = 1.29; P = .0158).ConclusionsOur study shows a meaningful difference in the immunobiology between males and females that also influences the overall response to immunotherapy in the setting of GBM.

Immunotherapeutic Peptide Vaccine Approaches to Glioma

Heretofore, there are no FDA-approved immunotherapeutics for malignant gliomas despite many novel therapies currently in different stages of clinical trials. Malignant gliomas are immunosuppressive tumors and are difficult for immune effector cells to infiltrate the tumor sites in the central nervous system. This inefficiency results in median survival of about only two years with a few long-term survivors. Recent clinical trials of vaccine-based immunotherapies against malignant gliomas have demonstrated encouraging results in enhancing progression-free survival and overall survival of patients. The vaccine-based treatments include peptide and heat-shock proteins, dendritic cell-based vaccines, as well as viral-based immunotherapy. In this review, we will focus on recent clinical trials of neoantigen peptide vaccines on gliomas, the delivery routes of such peptide vaccines, their adjuvants, clinical challenges, and its future strategies, respectively

Vaccine-Based Immunotherapy for Head and Neck Cancers.

Simple SummaryTherapeutic vaccines are given to patients with cancer, as opposed to prophylactic vaccines given to a healthy population. The challenge for therapeutic oncological vaccines is to stimulate an immune T cell response against endogenous (or derived) antigens that is sufficiently potent to induce cytotoxic activity and broad enough to take tumor heterogeneity into account. The purpose of this article is to provide an updated review of the prophylactic and therapeutic vaccines that target viral or non-viral antigens, particularly in head and neck cancers.In 2019, the FDA approved pembrolizumab, a monoclonal antibody targeting PD-1, for the first-line treatment of recurrent or metastatic head and neck cancers, despite only a limited number of patients benefiting from the treatment. Promising effects of therapeutic vaccination led the FDA to approve the use of the first therapeutic vaccine in prostate cancer in 2010. Research in the field of therapeutic vaccination, including possible synergistic effects with anti-PD(L)1 treatments, is evolving each year, and many vaccines are in pre-clinical and clinical studies. The aim of this review article is to discuss vaccines as a new therapeutic strategy, particularly in the field of head and neck cancers. Different vaccination technologies are discussed, as well as the results of the first clinical trials in HPV-positive, HPV-negative, and EBV-induced head and neck cancers.

Neoantigen-Specific T-Cell Immune Responses: The Paradigm of NPM1-Mutated Acute Myeloid Leukemia

The C-terminal aminoacidic sequence from NPM1-mutated protein, absent in normal human tissues, may serve as a leukemia-specific antigen and can be considered an ideal target for NPM1-mutated acute myeloid leukemia (AML) immunotherapy. Different in silico instruments and in vitro/ex vivo immunological platforms have identified the most immunogenic epitopes from NPM1-mutated protein. Spontaneous development of endogenous NPM1-mutated-specific cytotoxic T cells has been observed in patients, potentially contributing to remission maintenance and prolonged survival. Genetically engineered T cells, namely CAR-T or TCR-transduced T cells, directed against NPM1-mutated peptides bound to HLA could prospectively represent a promising therapeutic approach. Although either adoptive or vaccine-based immunotherapies are unlikely to be highly effective in patients with full-blown leukemia, these strategies, potentially in combination with immune-checkpoint inhibitors, could be promising in maintaining remission or preemptively eradicating persistent measurable residual disease, mainly in patients ineligible for allogeneic hematopoietic stem cell transplant (HSCT). Alternatively, neoantigen-specific donor lymphocyte infusion derived from healthy donors and targeting NPM1-mutated protein to selectively elicit graft-versus-leukemia effect may represent an attractive option in subjects experiencing post-HSCT relapse. Future studies are warranted to further investigate dynamics of NPM1-mutated-specific immunity and explore whether novel individualized immunotherapies may have potential clinical utility in NPM1-mutated AML patients.

Helicobacter pylori infection has a detrimental impact on the efficacy of cancer immunotherapies

ObjectiveIn this study, we determined whether Helicobacter pylori (H. pylori) infection dampens the efficacy of cancer immunotherapies.DesignUsing mouse models, we evaluated whether immune checkpoint inhibitors or vaccine-based immunotherapies are effective...