Dendritic Cell-based Vaccines Research Articles

Irreversible Electroporation Combined With Dendritic Cell-based Vaccines for the Treatment of Osteosarcoma.

Osteosarcoma is the most common primary bone malignancy, and surgical resection combined with neoadjuvant chemotherapy is the gold-standard treatment for affected patients. Although the overall survival rates for patients with osteosarcoma currently range from 60% to 70%, outcomes remain disappointing for patients with recurrent, metastatic, or unresectable disease. Irreversible electroporation (IRE) is a novel ablation technique with the potential to elicit an immune response in solid tumors. Dendritic cell (DC)-based tumor vaccines have shown promising therapeutic efficacy in preclinical studies focused on osteosarcoma; however, only limited therapeutic efficacy has been observed in clinical trials. Thus, there is considerable potential therapeutic value in developing combination osteosarcoma treatments that involve IRE and DC-based tumor vaccines. In this review, we discuss recent advances in preclinical and clinical DC-based immunotherapies, as well as potential combinations of DC-based vaccines and IRE, that may improve therapeutic outcomes for patients with osteosarcoma.

Potential of Personalized Dendritic Cell-Based Immunohybridoma Vaccines to Treat Prostate Cancer.

Prostate cancer (PCa) is the most commonly diagnosed cancer and the second most common cause of death due to cancer. About 30% of patients with PCa who have been castrated develop a castration-resistant form of the disease (CRPC), which is incurable. In the last decade, new treatments that control the disease have emerged, slowing progression and spread and prolonging survival while maintaining the quality of life. These include immunotherapies; however, we do not yet know the optimal combination and sequence of these therapies with the standard ones. All therapies are not always suitable for every patient due to co-morbidities or adverse effects of therapies or both, so there is an urgent need for further work on new therapeutic options. Advances in cancer immunotherapy with an immune checkpoint inhibition mechanism (e.g., ipilimumab, an anti-CTLA-4 inhibitor) have not shown a survival benefit in patients with CRPC. Other immunological approaches have also not given clear results, which has indirectly prevented breakthrough for this type of therapeutic strategy into clinical use. Currently, the only approved form of immunotherapy for patients with CRPC is a cell-based medicine, but it is only available to patients in some parts of the world. Based on what was gained from recently completed clinical research on immunotherapy with dendritic cell-based immunohybridomas, the aHyC dendritic cell vaccine for patients with CRPC, we highlight the current status and possible alternatives that should be considered in the future.

825-P: Novel Autologous Dendritic Cell Therapy AVT001 for Type 1 Diabetes

Studies in several animal models and of humans with type 1 diabetes (T1D) have suggested that Qa-1/HLA-E restricted CD8+ T regulatory cells (Tregs) are important in maintaining self-tolerance and a defect thereof playing a key role in T1D pathogenesis. To evaluate the safety and efficacy of targeting this pathway in T1D we undertook a first in human, phase 1/2 study of AVT001, an investigational autologous dendritic cell-based vaccine designed to address this immunologic mechanism. This double-blind, randomized (2:1 treated vs placebo) trial enrolled individuals (n=25) who were 16 years and older, within 1 year of clinical diagnosis of T1D, and with an ex-vivo correctable defect in the function of HLA-E-restricted CD8+ Tregs. All participants underwent leukapheresis, the first step in the generation of AVT001. AVT001 treatment (n=16) or placebo (n=9) was delivered as a series of three-monthly intravenous infusions. The primary endpoint of the study was safety/tolerability at day 150. AVT001 was safe and well tolerated with all participants completing treatment, no peri-infusion reactions noted, and adverse events reported as being mild or moderate in the AVT001 treated group, with rates similar to placebo. A pre-specified efficacy endpoint was change from baseline in C-peptide area under the curve (AUC) during a 4-hour mixed meal tolerance test utilizing a mixed-effect model for repeated measurements (MMRM). The baseline mean (SD) AUCs were treated 0.531 (0.363) and placebo 0.611 (0.178) nmol/L. At day 150, the C-peptide AUCs were significantly different between groups, namely 0.518 (0.430) and 0.472 (0.134) respectively. Per MMRM, the least square mean difference between AVT001 and placebo at day 150, is estimated to be 0.172 (p=<.0001). There was an increase in AUC or no change for 6 (37.5%) in the AVT001 treated group and 1 (11.1%) in the placebo group. These results indicate that AVT001 treatment was safe and well tolerated with evidence of significant preservation of endogenous insulin secretion. Disclosure J.L.Gaglia: Advisory Panel; Dompé, Consultant; Vertex Pharmaceuticals Incorporated, Abata Therapeutics, Avotres Inc., Current Health, Research Support; Avotres Inc., Dompé, Imcyse, Stock/Shareholder; Vertex Pharmaceuticals Incorporated. J.Ritz: Advisory Panel; Novartis, Taleris, AvroBio, Clade Therapeutics, LifeVault Bio, Smart Immune, Garuda, Tscan, Research Support; Gilead Sciences, Inc., Novartis. H.Jiang: Employee; Avotres Inc. M.Mackey: None. H.L.Daley: None. N.Bryant: None. D.Y.Kim: None. T.Dong: Employee; Avotres Inc., Novartis. E.E.Fan: None. J.Vora: Other Relationship; Avotres Inc., Glyscend Inc. J.S.Skyler: Advisory Panel; Adocia, Altheia Sciences, Arecor, Avotres Inc., Bayer Inc., COUR Pharmaceuticals, Dance Biopharm/Aerami, Diasome, Enthera, Immnomolecular Therapeutics, Kriya Therapeutics, Oramed Pharmaceuticals, Orgenesis Inc., Precigen, Inc., ViaCyte, Inc., Board Member; Applied Therapeutics Inc., Dexcom, Inc., Consultant; Novo Nordisk, Sanofi, Signos, 4Immune, Other Relationship; Imcyse, Provention Bio, Inc. Funding Avotres Inc.

CAR T cells and dendritic cells: vaccinomics perspectives

Immunotherapy has revolutionized cancer treatment with Chimeric Antigen Receptor (CAR) T cells and dendritic cell-based vaccines showing remarkable efficacy in certain malignancies. This review provides an integrative overview of recent advances and future directions in vaccinomics. A critical aspect of improving efficacy is the integration of CAR T cells and dendritic cell-based therapies to leverage synergistic effects. Personalization of cancer treatment, facilitated by strategies such as HLA typing and antigen selection, is essential for targeting specific tumor antigens and evading immune resistance. The tumor microenvironment plays a crucial role in modulating immune responses and can be targeted to enhance therapy efficacy. Novel adjuvants and immune modulators, such as Toll-like receptor agonists and checkpoint inhibitors, can further improve efficacy and safety. Predictive biomarkers and patient stratification strategies are essential for optimizing candidate selection. Future research should focus on optimizing CAR T cell and dendritic cell-based therapies, developing novel combinational strategies, and advancing gene editing and manufacturing techniques. Expansion to non-cancerous diseases could greatly broaden the impact on public health. Addressing challenges and limitations associated with these therapies can unlock their full potential and revolutionize the treatment of various malignancies and other medical conditions.

Tubeimuside I improves the efficacy of a therapeutic Fusobacterium nucleatum dendritic cell-based vaccine against colorectal cancer.

Fusobacterium nucleatum (F. nucleatum) infection has been confirmed to be associated with the development, chemoresistance, and immune evasion of colorectal cancer (CRC). The complex relationship between the microorganism, host cells, and the immune system throughout all stages of CRC progression, which makes the development of new therapeutic methods difficult. We developed a new dendritic cell (DC) vaccine to investigate the antitumor efficacy of CRC immunotherapy strategies. By mediating a specific mode of interaction between the bacteria, tumor, and host, we found a new plant-derived adjuvant, tubeimuside I (TBI), which simultaneously improved the DC vaccine efficacy and inhibited the F. nucleatum infection. Encapsulating TBI in a nanoemulsion greatly improved the drug efficacy and reduced the drug dosage and administration times. The nanoemulsion encapsulated TBI DC vaccine exhibited an excellent antibacterial and antitumor effect and improved the survival rate of CRC mice by inhibiting tumor development and progression. In this study, we provide a effective strategy for developing a DC-based vaccine against CRC and underlies the importance of further understanding the mechanism of CRC processes caused by F. nucleatum.

Cancer vaccines based on whole-tumor lysate or neoepitopes with validated HLA binding outperform those with predicted HLA-binding affinity

Antigen selection and prioritization represent crucial determinants of vaccines' efficacy. Here, we compare two personalized dendritic cell-based vaccination strategies using whole-tumor lysate or neoantigens. Data in mouse and in cancer patients demonstrate that peptide vaccines using neoantigens predicted on the sole basis of in silico peptide-major histocompatibility complex (MHC) binding affinity underperform relative to whole-tumor-lysate vaccines. In contrast, effective invitro peptide-MHC binding affinity and peptide immunogenicity significantly improve the prioritization of tumor-rejecting neoepitopes and result in more efficacious vaccines.

ARE DENDRITIC CELLS A POTENTIAL TOOL FOR MASTITIS VACCINE DEVELOPMENT?

Mastitis is one of the main disease causing big economic losses to dairy farmers. This disease is caused mainly by bacteria. Because of not efficient vaccines, there are necessary to develop new immunotherapy of vaccination strategy to reduce this disease in dairy farms. Dendritic cells are antigen-presenting cells which are able to present antigen to lymphocytes. They are able to induce activation of T naïve lymphocytes. Dendritic cells were used for development of dendritic cell-based anti-tumor vaccines. Development of vaccines against bovine mastitis has many limitations as high number of various pathogens that are able to cause inflammation of mammary gland in cattle; absence of mucus barrier in mammary gland; reduced phagocytic efficiency because of casein and fat globules etc. To this day, it is not available vaccine against bovine mastitis with high efficiency. Development of new immunotherapy or vaccine against mastitis would be very desirable. In this mini review, we are considering possibilities for development of new dendritic cell-based vaccine against bovine mastitis.

IFNα and 5-Aza-2'-deoxycytidine combined with a dendritic-cell targeting DNA vaccine alter tumor immune cell infiltration in the B16F10 melanoma model.

DNA vaccines containing a fusion of the gene encoding chemokine MIP-3α (CCL20), the ligand for CCR6 on immature dendritic cells (DCs), to melanoma-associated antigen genes have enhanced anti-tumor immunity and efficacy compared to those lacking the chemokine gene. Previous work has shown that type-I interferon (IFNα or IFN) and 5-Aza-2'-deoxycytidine (5Aza) significantly enhance the therapeutic benefit of DNA vaccines as measured by reduced tumor burden and improved mouse survival. Here, we explored mouse intratumoral immune correlates underlying the therapeutic benefit of this combination regimen (vaccine, IFN, and 5Aza) as compared to vaccine alone and IFN and 5Aza without vaccine, focusing on chemokine mRNA expression by qRT-PCR and inflammatory cellular infiltration into the tumor microenvironment (TME) by flow cytometry and immunohistochemistry (IHC). The combination group significantly upregulated intratumoral mRNA expression of key immune infiltration chemokines XCL1 and CXCL10. Flow cytometric analyses of tumor suspensions exhibited greater tumor infiltration of CD8+ DCs, CCR7+ DCs, and NK cells in the combination group, as well as reduced levels of myeloid-derived suppressor cells (MDSCs) in vaccinated groups. The mice receiving combination therapy also had greater proportions of effector/memory T-cells (Tem), in addition to showing an enhanced infiltration of Tem and central memory CD8+ T-cells, (Tcm). Tem and Tcm populations both correlated with smaller tumor size. Immunohistochemical analysis of tumors confirmed that CD8+ cells were more abundant overall and especially in the tumor parenchyma with combination therapy. Efficient targeting of antigen to immature DCs with a chemokine-fusion vaccine offers a potential alternative approach to classic and dendritic cell-based vaccines. Combining this approach with IFNα and 5Aza treatments significantly improved vaccine efficacy. This treatment creates an environment of increased inflammatory chemokines that facilitates the trafficking of CD8+ DCs, NK cells, and CD8+ T-cells, especially memory cells, while reducing the number of MDSCs. Importantly, in the combination group, CD8+ cells were more able to penetrate the tumor mass in addition to being more numerous. Further analysis of the pathways engaged by our combination therapy is expected to provide additional insights into melanoma pathogenesis and facilitate the development of novel treatment strategies.

A New Plasmacytoid Dendritic Cell-Based Vaccine in Combination with Anti-PD-1 Expands the Tumor-Specific CD8+ T Cells of Lung Cancer Patients.

The purpose of immune checkpoint inhibitor (ICI)-based therapies is to help the patient's immune system to combat tumors by restoring the immune response mediated by CD8+ cytotoxic T cells. Despite impressive clinical responses, most patients do not respond to ICIs. Therapeutic vaccines with autologous professional antigen-presenting cells, including dendritic cells, do not show yet significant clinical benefit. To improve these approaches, we have developed a new therapeutic vaccine based on an allogeneic plasmacytoid dendritic cell line (PDC*line), which efficiently activates the CD8+ T-cell response in the context of melanoma. The goal of the study is to demonstrate the potential of this platform to activate circulating tumor-specific CD8+ T cells in patients with lung cancer, specifically non-small-cell lung cancer (NSCLC). PDC*line cells loaded with peptides derived from tumor antigens are used to stimulate the peripheral blood mononuclear cells of NSCLC patients. Very interestingly, we demonstrate an efficient activation of specific T cells for at least two tumor antigens in 69% of patients irrespective of tumor antigen mRNA overexpression and NSCLC subtype. We also show, for the first time, that the antitumor CD8+ T-cell expansion is considerably improved by clinical-grade anti-PD-1 antibodies. Using PDC*line cells as an antigen presentation platform, we show that circulating antitumor CD8+ T cells from lung cancer patients can be activated, and we demonstrate the synergistic effect of anti-PD-1 on this expansion. These results are encouraging for the development of a PDC*line-based vaccine in NSCLC patients, especially in combination with ICIs.

Neutrophils in Dendritic Cell-Based Cancer Vaccination: The Potential Roles of Neutrophil Extracellular Trap Formation.

Neutrophils have conflicting roles in the context of cancers, where they have been associated with contributing to both anti-tumor and pro-tumor responses. Their functional heterogenicity is plastic and can be manipulated by environmental stimuli, which has fueled an area of research investigating therapeutic strategies targeting neutrophils. Dendritic cell (DC)-based cancer vaccination is an immunotherapy that has exhibited clinical promise but has shown limited clinical efficacy. Enhancing our understanding of the communications occurring during DC cancer vaccination can uncover opportunities for enhancing the DC vaccine platform. There have been observed communications between neutrophils and DCs during natural immune responses. However, their crosstalk has been poorly studied in the context of DC vaccination. Here, we review the dual functionality of neutrophils in the context of cancers, describe the crosstalk between neutrophils and DCs during immune responses, and discuss their implications in DC cancer vaccination. This discussion will focus on how neutrophil extracellular traps can influence immune responses in the tumor microenvironment and what roles they may play in promoting or hindering DC vaccine-induced anti-tumor efficacy.

Dendritic Cell-Based Vaccines Recruit Neutrophils to the Local Draining Lymph Nodes to Prime Natural Killer Cell Responses

Dendritic cell (DC)-based cancer vaccines are a form of immunotherapy that activates the innate and adaptive immune systems to combat cancers. Neutrophils contribute to cancer biology and have the potential to be exploited by immunotherapeutic platforms to enhance anti-tumor immune responses. We previously showed that DC vaccines elicit the expansion of mouse interferon (IFN)γ-producing mature natural killer (NK) cells to elevate anti-tumor responses. Here, we demonstrate the rapid recruitment of neutrophils to the draining lymph nodes of DC-vaccinated mice. This was accompanied by an increase in the total number of NK cells producing IFNγ and expressing CD107a, a marker of degranulation that demonstrates NK cell functional activity. Furthermore, the depletion of neutrophils in DC-immunized mice resulted in decreased numbers of NK cells in draining lymph nodes compared to the controls. Interestingly, the increased number of IFNγ- and CD107a-expressing NK cells in DC-immunized mice was not detected in mice depleted of neutrophils. Further investigations showed that DC vaccines induced IFNγ- and TNFα-producing CD8+ T cells that also expressed CD107a, but depletion of neutrophils did not have any impact on the CD8+ T cell population. Our findings suggest that neutrophil-mediated anti-tumor immunity induced by a DC vaccine platform could be targeted to provide innovative strategies to enhance its clinical efficacy.

Evaluation of an Adoptive Cellular Therapy-Based Vaccine in a Transgenic Mouse Model of α-synucleinopathy.

Aggregated α-synuclein, a major constituent of Lewy bodies plays a crucial role in the pathogenesis of α-synucleinopathies (SPs) such as Parkinson's disease (PD). PD is affected by the innate and adaptive arms of the immune system, and recently both active and passive immunotherapies targeted against α-synuclein are being trialed as potential novel treatment strategies. Specifically, dendritic cell-based vaccines have shown to be an effective treatment for SPs in animal models. Here, we report on the development of adoptive cellular therapy (ACT) for SP and demonstrate that adoptive transfer of pre-activated T-cells generated from immunized mice can improve survival and behavior, reduce brain microstructural impairment via magnetic resonance imaging (MRI), and decrease α-synuclein pathology burden in a peripherally induced preclinical SP model (M83) when administered prior to disease onset. This study provides preclinical evidence for ACT as a potential immunotherapy for LBD, PD and other related SPs, and future work will provide necessary understanding of the mechanisms of its action.

Experience in the use of dendritic vaccines in the treatment of patients with recurrent gliomas

Purpose of the study. To substantiate the expediency of cellular immunotherapy in the treatment of patients with relapses of high-grade gliomas and evaluate the safety of injecting allogeneic cells directly into the cerebrospinal fluid.Materials and methods. Our study included 5 patients, median age 7,6 years (2–16). Three patients had anaplastic astrocytoma (AA) (1st recurrence – 1 patient, 2nd recurrence – 2 patients), 1 patient had glioblastoma multiforme (GBM) (3rd recurrence) and 1 had diffuse brainstem glioma (BSG). The median time to the first relapse was 12 months (4 to 16), to the second one was 5 months (1 to 8). The protocol of immunotherapy included combined administration of autologous dendritic cell-based vaccine (DV) and repeated intrathecal/intraventricular injections of donor allogenic immunocompetent cells (alloIC) for at least 2 years.Results. Two of 3 patients with AA experienced a progression-free interval of 67 and 71 months One patient with 3rd GBM relapse is alive without any therapy 13.3 years after immunotherapy start. The median time of follow-up was 67 months with the 2‑years overall survival was 58 %. Two patients died from disease progression within 6 and 7 months from the start of immunotherapy. Over the period of treatment the patients received a median of 20 (8 to 60) alloIC injections and 18 (8 to 44) DV administrations. No serious side-effect was observed.Conclusion. Immunotherapy could be an attractive option for treating patients with high-grade malignant gliomas irresponsible to conventional therapy and is worthy of further investigation.

Cellular Cancer Immunotherapy Development and Manufacturing in the Clinic.

The transfusion of naturally derived or modified cellular therapies, referred to as adoptive cell therapy (ACT), has demonstrated clinical efficacy in the treatment of hematologic malignancies and metastatic melanoma. In addition, cellular vaccination, such as dendritic cell-based cancer vaccines, continues to be actively explored. The manufacturing of these therapies presents a considerable challenge to expanding the use of ACT as a viable treatment modality, particularly at academic production facilities. Furthermore, the expanding commercial interest in ACT presents new opportunities as well as strategic challenges for the future vision of cellular manufacturing in academic centers. Current trends in the production of ACT at tertiary care centers and prospects for improved manufacturing practices that will foster further clinical benefit are reviewed herein.

The effects of dendritic cell-based vaccines in the tumor microenvironment: Impact on myeloid-derived suppressor cells.

Dendritic cells (DCs) are a heterogenous population of professional antigen presenting cells whose main role is diminished in a variety of malignancies, including cancer, leading to ineffective immune responses. Those mechanisms are inhibited due to the immunosuppressive conditions found in the tumor microenvironment (TME), where myeloid-derived suppressor cells (MDSCs), a heterogeneous population of immature myeloid cells known to play a key role in tumor immunoevasion by inhibiting T-cell responses, are extremely accumulated. In addition, it has been demonstrated that MDSCs not only suppress DC functions, but also their maturation and development within the myeloid linage. Considering that an increased number of DCs as well as the improvement in their functions boost antitumor immunity, DC-based vaccines were developed two decades ago, and promising results have been obtained throughout these years. Therefore, the remodeling of the TME promoted by DC vaccination has also been explored. Here, we aim to review the effectiveness of different DCs-based vaccines in murine models and cancer patients, either alone or synergistically combined with other treatments, being especially focused on their effect on the MDSC population.

EXTH-44. PERSONALIZED IMMUNOTHERAPY VACCINES FOR GLIOBLASTOMA AND THEIR TREATMENT EFFICACY

Abstract BACKGROUND Glioblastoma multiforme (GBM) remains a disease with debilitating survival outcomes. Cancer immunogenomics represents a complementary approach to the application of genomics in developing novel immunotherapies for brain malignancies. Using a cancer immunogenomics approach that we developed, called the Open Reading Frame Antigen Network (O.R.A.N.), we identified the immunogenic neoantigens and tumor-associated antigens (TAAs) including cancer-testis and developmental antigens, that are aberrantly overexpressed in murine models of GBM. The aim of this study is to evaluate the immunologic effects and safety of immunotherapy vaccines targeting neoantigens and TAAs in preclinical models of GBM. METHODS RNAseq and WES were performed for murine glioblastoma tumors- KR158-Luc and GL261, and the results were fed to the O.R.A.N pipeline for antigen prediction. A tumor antigen-specific RNA library was created for each tumor using a gene enrichment strategy and validated by RNAseq. Tumor-bearing animals were treated with adoptively transferred ex vivo expanded lymphocytes and dendritic cell vaccines loaded with the tumor antigen-specific RNA. Tumor volume, and thus progress, was determined using in vivo luciferase imaging technique and the survival outcomes were noted. We also evaluated the efficacy of the tumor vaccines in combination with checkpoint blockade therapy by treating tumor-bearing animals with dendritic cell vaccines loaded with the tumor antigen-specific RNA combined with an anti-PD-1 antibody. RESULTS The dendritic cell vaccines loaded with tumor antigen-specific RNA were significantly effective in slowing the progression of murine GBM tumors in combination with both the adoptive cellular therapy as well as checkpoint blockade therapy. Additionally, we identified antigen-specific T cells targeting several of our predicted antigens and an increase in tumor-infiltrating lymphocytes and memory T cells in the treated animals. CONCLUSION We developed a dendritic cell-based vaccination approach targeting neoantigens and TAAs identified as being tumor-specific and evaluated the efficacy of immunotherapy vaccines in preclinical models of GBM.

Developing dendritic cell for SARS-CoV-2 vaccine: Breakthrough in the pandemic.

Finding a vaccine that can last a long time and effective against viruses with high mutation rates such as SARS-CoV-2 is still a challenge today. The various vaccines that have been available have decreased in effectiveness and require booster administration. As the professional antigen presenting cell, Dendritic Cells can also activate the immune system, especially T cells. This ability makes dendritic cells have been developed as vaccines for some types of diseases. In SARS-CoV-2 infection, T cells play a vital role in eliminating the virus, and their presence can be detected in the long term. Hence, this condition shows that the formation of T cell immunity is essential to prevent and control the course of the disease. The construction of vaccines oriented to induce strong T cells response can be formed by utilizing dendritic cells. In this article, we discuss and illustrate the role of dendritic cells and T cells in the pathogenesis of SARS-CoV-2 infection and summarizing the crucial role of dendritic cells in the formation of T cell immunity. We arrange the basis concept of developing dendritic cells for SARS-CoV-2 vaccines. A dendritic cell-based vaccine for SARS-CoV-2 has the potential to be an effective vaccine that solves existing problems.

Vaccination Therapy for Acute Myeloid Leukemia: Where Do We Stand?

Simple SummaryImmunotherapy is changing the therapeutic landscape of many hematologic diseases. Nevertheless, in acute myeloid leukemia (AML) the anti CD33 antibody-drug conjugate gemtuzumab ozogamicin is the only approved drug. In this review, we aimed at reporting biological mechanisms and their clinical impact of vaccines in AML. The principal vaccination strategies have been analyzed and commented, highlighting advantages in terms of toxicity and possibility to apply in elderly patients. Nevertheless, the clinical results of this strategy in AML are still far from satisfactory. It is necessary to evaluate the best scenario for this approach, whether in a therapeutic, prophylactic, or preemptive setting, considering the poorer results in active or high-burden disease. Finally, we underlined the necessity in AML of further research to optimize immunotherapy-based strategies, among which vaccines might represent relevant actors to contribute to long-term disease control.Immunotherapy is changing the therapeutic landscape of many hematologic diseases, with immune checkpoint inhibitors, bispecific antibodies, and CAR-T therapies being its greatest expression. Unfortunately, immunotherapy in acute myeloid leukemia (AML) has given less brilliant results up to now, and the only approved drug is the antiCD33 antibody-drug conjugate gemtuzumab ozogamicin. A promising field of research in AML therapy relies on anti-leukemic vaccination to induce remission or prevent disease relapse. In this review, we analyze recent evidence on AML vaccines and their biological mechanisms. The principal proteins that have been exploited for vaccination strategies and have reached clinical experimental phases are Wilm’s tumor 1, proteinase 3, and RHAMM. the majority of data deals with WT1-base vaccines, given also the high expression and mutation rates of WT1 in AML cells. Stimulators of immune responses such as TLR7 agonist and interleukin-2 have also proven anti-leukemic activity both in vivo and in vitro. Lastly, cellular vaccines mainly based on autologous or allogeneic off-the-shelf dendritic cell-based vaccines showed positive results in terms of T-cell response and safety, also in elderly patients. Compared to other immunotherapeutic strategies, anti-AML vaccines have the advantage of being a less toxic and a more manageable approach, applicable also to elderly patients with poorer performance status, and may be used in combination with currently available therapies. As for the best scenario in which to use vaccination, whether in a therapeutic, prophylactic, or preemptive setting, further studies are needed, but available evidence points to poorer results in the presence of active or high-burden disease. Given the poor prognosis of relapsed/refractory or high-risk AML, further research is urgently needed to better understand the biological pathways that sustain its pathogenesis. In this setting, research on novel frontiers of immunotherapy-based agents, among which vaccines represent important actors, is warranted to develop new and efficacious strategies to obtain long-term disease control by immune patrolling.

Abstract LB531: The addition of IFNα and 5-Aza-2'deoxycytidine treatments to a dendritic cell-targeting DNA vaccine enhance the expression of Th1-related genes and the infiltration of CD11c+ CD8+ T-cells

Abstract Background: DNA vaccines fusing the chemokine MIP-3α (CCL20), which binds to CCR6 on immature dendritic cells (DCs), to melanoma-associated antigens have enhanced anti-tumor immunity and efficacy compared to vaccines lacking the chemokine. To further enhance the therapeutic effects of the vaccine, our laboratory has added type-I interferon (IFNα) and 5-Aza-2’-deoxycitidine (5Aza) to the therapy. Here, we report that the efficacy seen in this combination results in deeper intratumoral penetration of CD8+ cells, enhanced expression of Th1 t-cell related genes, and increased influx of CD11c+ CD8+ T-cells. Methods: Beginning on day five post-transplantation of B16F10 melanoma, the vaccine was administered intramuscularly (i.m.) by electroporation. CpG adjuvant was given two days later. 5Aza was given intraperitoneally at 1mg/kg and IFNα therapy intratumorally as noted. Tumor sizes over time were assessed. For immunohistochemistry (IHC), formalin-fixed tumors were processed, embedded, cut into slides, and stained for CD8 by on-site core facility. Stained slides were analyzed by a pathologist in a blinded fashion. Tumor lysate gene expression levels and tumor-infiltrating lymphocytes (TILs) were assessed by qRT-PCR and flow cytometry respectively. Results: Previous work has shown that the combination of IFNα, 5Aza, and vaccine led to significantly reduced tumor burden and overall increases in mouse survival dependent upon all three components. We have since discovered by IHC that CD8+ cells are more abundant and penetrate further into the tumor with the combination treatment compared to vaccine or therapeutics alone. The tumor immune genetic profile shows broad increases of expression for genes responsible for T-cell activation, efficacy, and trafficking. Of note, the combination therapy doubled the proportion of CD8+ T cells in the tumor microenvironment expressing CD11c (p = 0.027), and the proportions of these cells correlated more strongly to tumor size than do the proportions of CD11c- CD8+ T-cells (r2=0.51; p<0.0001 compared to r2=0.19; p = 0.02). Conclusions: Efficient targeting of antigen to immature dendritic cells with a chemokine-fusion vaccine offers a potential alternative approach to classic and dendritic cell-based vaccines. Combining this approach with IFNα and 5Aza treatments significantly improved vaccine efficacy. This treatment creates a complex intratumoral network that facilitates T-cell trafficking, Th1-associated gene expression, and an increase of CD11c+CD8+ T-cells, which have recently been shown in the literature to have greater anti-tumor activity than CD11c- T-cells. Further analysis of the pathways engaged by our treatment protocol should provide insights into how to more efficiently activate this recently described, highly effective T cell population. Citation Format: James T. Gordy, Kaitlyn Comstock, Avinaash K. Sandhu, Yinan Hui, Styliani Karanika, Joel Sunshine, Petros C. Karakousis, Richard B. Markham. The addition of IFNα and 5-Aza-2'deoxycytidine treatments to a dendritic cell-targeting DNA vaccine enhance the expression of Th1-related genes and the infiltration of CD11c+ CD8+ T-cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB531.

WT1-specific TCRs directed against newly identified peptides install antitumor reactivity against acute myeloid leukemia and ovarian carcinoma

BackgroundTranscription factor Wilms’ tumor gene 1 (WT1) is an ideal tumor target based on its expression in a wide range of tumors, low-level expression in normal tissues and promoting role...