Cell Vaccine Research Articles

Abstract 6519: Dendritic cell vaccine cell numbers and survival in patients with primary glioblastoma

Abstract Standard glioblastoma (GBM) treatment is associated with poor survival. A promising novel immunotherapy consists of autologous dendritic cells (DC) pulsed with autologous tumor antigens (ATA) from a lysate of irradiated self-renewing autologous cancer cells. An open-label, phase 2 trial was conducted in 57 patients with primary GBM. Here we report correlations between survival and DC-ATA doses. Two autologous intermediate products were manufactured for each patient: a tumor cell line established from resected GBM, and DC differentiated from cryopreserved peripheral blood monocytes (MC). Patients were enrolled prior to standard radiation therapy (RT) and temozolomide (TMZ) chemotherapy. DC-ATA were manufactured during RT/TMZ, divided into individual doses, then cryopreserved in liquid nitrogen. For each patient-specific vaccine batch, cell numbers were calculated using a hemocytometer; viability was determined before cryopreservation (cryo) using trypan blue and post-cryo using 7ADD per flow cytometry. After RT/TMZ, up to 8 doses were injected s.c. concurrent with TMZ over 6 months. Patients were grouped into tertiles based on DC-ATA cell numbers and survival. Prism 10.03 was used to generate survival curves and calculate correlation coefficients and log-rank and T-Test comparisons. As previously reported, cell line success rate was 71/73, sufficient MC numbers were collected by leukapheresis for 63/65; DC-ATA was successfully manufactured for 60/60; 57 patients were treated; median progression free survival (PFS) and overall survival (OS) were 10.4 and 16.0 months respectively. Correlations were strong between total and viable DC-ATA pre-cryo (0.97, p<0.0001) and post-cryo (0.95, p<0.0001), but weaker between DC-ATA pre- and post-cryo (0.30, p=0.02), and between viable DC-ATA pre- and post-cryo (0.37, p=0.004). When patients were grouped by OS tertiles, medians were 9.8, 18.1, and more than 36 months. There were no differences in the average millions (M) of DC-ATA pre-cryo (10.0, 9.7, 9.6), viable DC-ATA pre-cryo (8.5, 7.8, 7.9), DC-ATA post-cryo (9.0, 10.3, 10.8) or viable DC-ATA post-cryo (6.0, 7.3, 7.4). Similarly, when patients were grouped into tertiles by DC-ATA numbers, there were no differences in OS curves associated with DC-ATA pre-cryo, viable DC-ATA pre-cryo, DC-ATA post-cryo, or viable DC-ATA post-cryo. Pre-cryo viable DC-ATA numbers ranged from 0.27 to 27.0 M. An ineffective dose was not identified; pre-cryo viable DC-ATA doses of less than 2M were associated with OS of 10.4, 13.0, 13.3, and 36.4+ months. Also, there was no OS difference by number of MC used to manufacture DC or by number of DC manufactured. In conclusion, there was no evidence for a dose/response relationship between DC-ATA dose and OS for any of the parameters tested. This data supports that pre-cryo cell counts can be used to establish treatment doses. Pre-cryo viable cell counts of 2M DC-ATA per dose seem sufficient. Citation Format: Robert O. Dillman, Gabriel I. Nistor, Krystal Godding, Rockelle Robles, Hans S. Keirstead. Dendritic cell vaccine cell numbers and survival in patients with primary glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6519.

AN OVERVIEW OF CURRENT VACCCINES FOR THE PROPHYLAXIS OF BACTERICAL INFECTIONS

Antibacterial vaccines play a central role in modern medicine by providing an effective approach to combating infectious diseases caused by bacteria. The importance of these vaccines lies in their ability to stimulate the immune system to recognise and neutralise bacterial pathogens, or exotoxins produced by them, thereby preventing, or mitigating the severity of bacterial infections. The development and widespread use of antibacterial vaccines have contributed significantly to reducing the global burden of diseases such as pneumonia, meningitis, and sepsis. Today, the global increase in vaccine-preventable diseases is a worrying trend that is closely linked to the emergence and advocacy of anti-vaccination policies. According to the latest World Health Organisation report, vaccination coverage in Serbia has declined over the past decade, jeopardising the collective immunity and led to recent outbreaks of vaccine-preventable diseases such as whooping cough and measles. Understanding the significance of antibacterial vaccines underscores their importance in promoting individual and community immunity, which ultimately leads to a healthier population and the prevention of antibiotic resistance. This paper summarises the main characteristics of the different types of antibacterial vaccines, such as whole cell vaccines, subunit vaccines and toxoid vaccines, and provides an overview of the types of bacterial antigens contained in vaccines available for mandatory immunisation (vaccines against tuberculosis, diphtheria, tetanus, pertussis, Haemophilus influenzae and pneumoccus) or for non-mandatory immunisation (meningococcal vaccine, typhoid vaccine, cholera vaccine).

An Advanced Intrahepatic Cholangiocarcinoma Patient Benefits from Personalized Immunotherapy.

Advanced intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy characterized by limited response to standard therapeutic modalities, such as radiotherapy, chemotherapy, and targeted therapy. The prognosis for patients with advanced ICC is exceedingly bleak, with an overall survival of less than 1 year. In recent years, personalized neoantigen vaccines have emerged as a promising approach to augment the immune response against tumors. Clinical investigations are currently underway to evaluate the efficacy of neoantigen-based peptide, DNA, and dendritic cell vaccines. Herein, we present a noteworthy case of advanced ICC patients who experienced disease progression following relapse and subsequently received immunotherapy with a personalized neoantigen nanovaccine. This innovative treatment strategy involved the administration of a custom-designed neoantigen-based peptide nanovaccine tailored to the patient's specific gene mutation profile subsequent to failure of first-line therapy. The clinical efficacy and anti-tumor immune responses were evaluated using various methods, including imaging, interferon-γ ELISPOT assay, and intracellular cytokine staining. Notably, the neoantigen nanovaccine elicited a robust and specific tumor-killing effect mediated by T cells, resulting in a durable response lasting up to 25 months. These findings highlight the potential of neoantigen-based immunotherapy as a novel therapeutic avenue for the management of advanced ICC.

Immunogenicity and Safety of a Purified Vero Rabies Vaccine-Serum Free, Compared With 2 Licensed Vaccines, in a Simulated Rabies Post-Exposure Regimen in Healthy Adults in France: A Randomized, Controlled, Phase 3 Trial.

A next-generation Vero cell rabies vaccine (PVRV-NG2) was developed using the same Pitman-Moore strain as in the licensed purified Vero cell vaccine (PVRV; Verorab) and the human diploid cell vaccine (HDCV; Imovax Rabies®). This dual-center, modified, double-blind, phase 3 study evaluated the immunogenic non-inferiority and safety of PVRV-NG2 with and without concomitant intramuscular human rabies immunoglobulin (HRIG) versus PVRV + HRIG and HDCV + HRIG in a simulated post-exposure prophylaxis (PEP) regimen. Healthy adults ≥18 years old (N = 640) were randomized 3:1:1:1 to PVRV-NG2 + HRIG, PVRV + HRIG, HDCV + HRIG, or PVRV-NG2 alone (administered as single vaccine injections on days [D] 0, D3, D7, D14, and 28, with HRIG on D0 in applicable groups). Rabies virus neutralizing antibodies (RVNA) titers were assessed pre- (D0) and post-vaccination (D14, D28, and D42) using the rapid fluorescent focus inhibition test. Non-inferiority, based on the proportion of participants achieving RVNA titers ≥0.5 IU/mL (primary objective), was demonstrated if the lower limit of the 95% CI of the difference in proportions between PVRV-NG2 + HRIG and PVRV + HRIG/HDCV + HRIG was >-5% at D28. Safety was assessed up to 6 months after the last injection. Non-inferiority of PVRV-NG2 + HRIG compared with PVRV + HRIG and HDCV + HRIG was demonstrated. Nearly all participants (99.6%, PVRV-NG2 + HRIG; 100%, PVRV + HRIG; 98.7%, HDCV + HRIG; 100%, PVRV-NG2 alone) achieved RVNA titers ≥0.5 IU/mL at D28. Geometric mean titers were similar between groups with concomitant HRIG administration at all time points. Safety profiles were similar between PVRV-NG2 and comparator vaccines. In a simulated PEP setting, PVRV-NG2 + HRIG showed comparable immunogenicity and safety to current standard-of-care vaccines. NCT03965962.

Exploring the development prospects of TNBC and HER2+ BC treatment based on targeted therapy

Breast cancer (BC) is one of the most common cancers in women, and the number of patients is increasing year by year. TNBC (triple-negative breast cancer) and HER2+ BC, as the two most common subtypes, deserve more in-depth research. At present, there are many targeted therapies and immunotherapies for these two subtypes, using inhibitors or cancer vaccines to treat breast cancer more efficiently, and some research has achieved phased results. However, there are still many research gaps, such as the safety and immune mechanism of the vaccine are unclear, and only a few number of epitopes trigger an immune response. In this paper, three targeted therapies for TNBC (PARA inhibitors, CDK inhibitors and PI3K/AKT/mTOR signaling pathway inhibitors) were analyzed. Two types of immunotherapy (ICIs and CAR-T therapy), And four cancer vaccines for HER2+ BC (Peptide-based cancer vaccines, Protein-based cancer vaccines,DNA Based Anti-HER2 Vaccines and Dendritic Cell Vaccines), and summarized their respective advantages and disadvantages to provide more theories and case references for future studies. There are still many unanswered questions about drug resistance, and future research can focus on the immune microenvironment and drug resistance

Self-Metallized Whole Cell Vaccines Prepared by Microfluidics for Bioorthogonally Catalyzed Antitumor Immunotherapy.

Tumor whole cell, carrying a complete set of tumor-associated antigens and tumor-specific antigens, has shown great potential in the construction of tumor vaccines but is hindered by the complex engineering means and limited efficacy to cause immunity. Herein, we provided a strategy for the self-mineralization of autologous tumor cells with palladium ions in microfluidic droplets, which endowed the engineered cells with both immune and catalytic functions, to establish a bioorthogonally catalytic tumor whole-cell vaccine. This vaccine showed strong inhibition both in the occurrence and recurrence of tumor by invoking the immediate antitumor immunity and building a long-term immunity.

Nucleic acid-based vaccine for ovarian cancer cells; bench to bedside.

Ovarian cancer continues to be a difficult medical issue that affects millions of individuals worldwide. Important platforms for cancer immunotherapy include checkpoint inhibitors, chimeric antigen receptor T cells, bispecific antibodies, cancer vaccines, and other cell-based treatments. To avoid numerous infectious illnesses, conventional vaccinations based on synthetic peptides, recombinant subunit vaccines, and live attenuated and inactivated pathogens are frequently utilized. Vaccine manufacturing processes, however, are not entirely safe and carry a significant danger of contaminating living microorganisms. As a result, the creation of substitute vaccinations is required for both viral and noninfectious illnesses, including cancer. Recently, there has been testing of nucleic acid vaccines, or NAVs, as a cancer therapeutic. Tumor antigens (TAs) are genetically encoded by DNA and mRNA vaccines, which the host uses to trigger immune responses against ovarian cancer cells that exhibit the TAs. Despite being straightforward, safe, and easy to produce, NAVs are not currently thought to be an ideal replacement for peptide vaccines. Some obstacles to this strategy include selecting the appropriate therapeutic agents (TAs), inadequate immunogenicity, and the immunosuppressive characteristic of ovarian cancer. We focus on strategies that have been employed to increase NAVs' effectiveness in the fight against ovarian cancer in this review.

Structural insights into a functional unit from an immunogenic mollusk hemocyanin

Mollusk hemocyanins, among the largest known proteins, are used as immunostimulants in biomedical and clinical applications. The hemocyanin of the Chilean gastropod Concholepas concholepas (CCH) exhibits unique properties, which makes it safe and effective for human immunotherapy, as observed in animal models of bladder cancer and melanoma, and dendritical cell vaccine trials. Despite its potential, the structure and amino acid sequence of CCH remain unknown. This study reports two sequence fragments of CCH, representing three complete functional units (FUs). We also determined the high-resolution (1.5Å) X-ray crystal structure of an "FU-g type" from the CCHB subunit. This structure enables in-depth analysis of chemical interactions at the copper-binding center and unveils an unusual, truncated N-glycosylation pattern. These features are linked to eliciting more robust immunological responses in animals, offering insights into CCH's enhanced immunostimulatory properties and opening new avenues for its potential applications in biomedical research and therapies.

SARS-CoV-2 Vaccine-Elicited Immunity after B Cell Depletion in Multiple Sclerosis.

The impact of B cell deficiency on the humoral and cellular responses to SARS-CoV2 mRNA vaccination remains a challenging and significant clinical management question. We evaluated vaccine-elicited serological and cellular responses in 1) healthy individuals who were pre-exposed to SARS-CoV-2 (n = 21), 2) healthy individuals who received a homologous booster (mRNA, n = 19; or Novavax, n = 19), and 3) persons with multiple sclerosis on B cell depletion therapy (MS-αCD20) receiving mRNA homologous boosting (n = 36). Pre-exposure increased humoral and CD4 T cellular responses in immunocompetent individuals. Novavax homologous boosting induced a significantly more robust serological response than mRNA boosting. MS-α CD20 had an intact IgA mucosal response and an enhanced CD8 T cell response to mRNA boosting compared with immunocompetent individuals. This enhanced cellular response was characterized by the expansion of only effector, not memory, T cells. The enhancement of CD8 T cells in the setting of B cell depletion suggests a regulatory mechanism between B and CD8 T cell vaccine responses.

Development of Mannosylated Lipid Nanoparticles for mRNA Cancer Vaccine with High Antigen Presentation Efficiency and Immunomodulatory Capability.

Insufficient accumulation of lipid nanoparticles (LNPs)-based mRNA vaccines in antigen presenting cells remains a key barrier to eliciting potent antitumor immune responses. Herein, we develop dendritic cells (DCs) targeting LNPs by taking advantage of mannose receptor-mediated endocytosis. Efficient delivery of mRNA to DCs is achieved in vitro and in vivo utilizing the sweet LNPs (STLNPs-Man). Intramuscular injection of mRNA vaccine (STLNPs-Man@mRNAOVA ) results in a four-fold higher uptake by DCs in comparison with commercially used LNPs. Benefiting from its DCs targeting ability, STLNPs-Man@mRNAOVA significantly promotes the antitumor performances, showing a comparable therapeutic efficacy by using one-fifth of the injection dosage as the vaccine prepared from normal LNPs, thus remarkably avoiding the side effects brought by conventional mRNA vaccines. More intriguingly, STLNPs-Man@mRNAOVA exhibits the ability to downregulate the expression of cytotoxic T-lymphocyte-associated protein 4 on T cells due to the blockade of CD206/CD45 axis, showing brilliant potentials in promoting antitumor efficacy combined with immune checkpoint blockade therapy.

Development of Mannosylated Lipid Nanoparticles for mRNA Cancer Vaccine with High Antigen Presentation Efficiency and Immunomodulatory Capability

AbstractInsufficient accumulation of lipid nanoparticles (LNPs)‐based mRNA vaccines in antigen presenting cells remains a key barrier to eliciting potent antitumor immune responses. Herein, we develop dendritic cells (DCs) targeting LNPs by taking advantage of mannose receptor‐mediated endocytosis. Efficient delivery of mRNA to DCs is achieved in vitro and in vivo utilizing the sweet LNPs (STLNPs‐Man). Intramuscular injection of mRNA vaccine (STLNPs‐Man@mRNAOVA) results in a four‐fold higher uptake by DCs in comparison with commercially used LNPs. Benefiting from its DCs targeting ability, STLNPs‐Man@mRNAOVA significantly promotes the antitumor performances, showing a comparable therapeutic efficacy by using one‐fifth of the injection dosage as the vaccine prepared from normal LNPs, thus remarkably avoiding the side effects brought by conventional mRNA vaccines. More intriguingly, STLNPs‐Man@mRNAOVA exhibits the ability to downregulate the expression of cytotoxic T‐lymphocyte‐associated protein 4 on T cells due to the blockade of CD206/CD45 axis, showing brilliant potentials in promoting antitumor efficacy combined with immune checkpoint blockade therapy.

Enhanced production yields of rVSV-SARS-CoV-2 vaccine using Fibra-Cel® macrocarriers.

The COVID-19 pandemic has led to high global demand for vaccines to safeguard public health. To that end, our institute has developed a recombinant viral vector vaccine utilizing a modified vesicular stomatitis virus (VSV) construct, wherein the G protein of VSV is replaced with the spike protein of SARS-CoV-2 (rVSV-ΔG-spike). Previous studies have demonstrated the production of a VSV-based vaccine in Vero cells adsorbed on Cytodex 1 microcarriers or in suspension. However, the titers were limited by both the carrier surface area and shear forces. Here, we describe the development of a bioprocess for rVSV-ΔG-spike production in serum-free Vero cells using porous Fibra-Cel® macrocarriers in fixed-bed BioBLU®320 5p bioreactors, leading to high-end titers. We identified core factors that significantly improved virus production, such as the kinetics of virus production, the use of macrospargers for oxygen supply, and medium replenishment. Implementing these parameters, among others, in a series of GMP production processes improved the titer yields by at least two orders of magnitude (2e9 PFU/mL) over previously reported values. The developed process was highly effective, repeatable, and robust, creating potent and genetically stable vaccine viruses and introducing new opportunities for application in other viral vaccine platforms.

Metal-Phenolic Nanocloaks on Cancer Cells Potentiate STING Pathway Activation for Synergistic Cancer Immunotherapy.

Due to the presence of natural neoantigens, autologous tumor cells hold great promise as personalized therapeutic vaccines. Yet autologous tumor cell vaccines require multi-step production that frequently leads to the loss of immunoreactive antigens, causing insufficient immune activation and significantly hampering their clinical applications. Herein, we introduce a novel whole-cell cancer vaccine by cloaking cancer cells with lipopolysaccharide-decorated manganese(II)-phenolic networks (MnTA nanocloaks) to evoke tumor-specific immune response for highly efficacious synergistic cancer immunotherapy. The natural polyphenols coordinate with Mn2+ and immediately adhere to the surface of individual cancer cells, thereby forming a nanocloak and encapsulating tumor neoantigens. Subsequent decoration with lipopolysaccharide induces internalization by dendritic cells, where Mn2+ ions are released in the cytosol, further facilitating the activation of the stimulator of the interferon genes (STING) pathway. Highly effective tumor suppression was observed by combining the nanocloaked cancer cell treatment with anti-programmed cell death ligand 1 (anti-PD-L1) antibodies-mediated immune checkpoint blockade therapy. Our work demonstrates a universal yet simple strategy to engineer a cell-based nanobiohybrid system for enhanced cancer immunotherapy.

Metal‐Phenolic Nanocloaks on Cancer Cells Potentiate STING Pathway Activation for Synergistic Cancer Immunotherapy

AbstractDue to the presence of natural neoantigens, autologous tumor cells hold great promise as personalized therapeutic vaccines. Yet autologous tumor cell vaccines require multi‐step production that frequently leads to the loss of immunoreactive antigens, causing insufficient immune activation and significantly hampering their clinical applications. Herein, we introduce a novel whole‐cell cancer vaccine by cloaking cancer cells with lipopolysaccharide‐decorated manganese(II)‐phenolic networks (MnTA nanocloaks) to evoke tumor‐specific immune response for highly efficacious synergistic cancer immunotherapy. The natural polyphenols coordinate with Mn2+ and immediately adhere to the surface of individual cancer cells, thereby forming a nanocloak and encapsulating tumor neoantigens. Subsequent decoration with lipopolysaccharide induces internalization by dendritic cells, where Mn2+ ions are released in the cytosol, further facilitating the activation of the stimulator of the interferon genes (STING) pathway. Highly effective tumor suppression was observed by combining the nanocloaked cancer cell treatment with anti‐programmed cell death ligand 1 (anti‐PD‐L1) antibodies‐mediated immune checkpoint blockade therapy. Our work demonstrates a universal yet simple strategy to engineer a cell‐based nanobiohybrid system for enhanced cancer immunotherapy.

Safety, immunogenicity and protective effectiveness of heterologous boost with a recombinant COVID-19 vaccine (Sf9 cells) in adult recipients of inactivated vaccines

Vaccines have proven effective in protecting populations against COVID-19, including the recombinant COVID-19 vaccine (Sf9 cells), the first approved recombinant protein vaccine in China. In this positive-controlled trial with 85 adult participants (Sf9 cells group: n = 44; CoronaVac group: n = 41), we evaluated the safety, immunogenicity, and protective effectiveness of a heterologous boost with the Sf9 cells vaccine in adults who had been vaccinated with the inactivated vaccine, and found a post-booster adverse events rate of 20.45% in the Sf9 cells group and 31.71% in the CoronaVac group (p = 0.279), within 28 days after booster injection. Neither group reported any severe adverse events. Following the Sf9 cells vaccine booster, the geometric mean titer (GMT) of binding antibodies to the receptor-binding domain of prototype SARS-CoV-2 on day 28 post-booster was significantly higher than that induced by the CoronaVac vaccine booster (100,683.37 vs. 9,451.69, p < 0.001). In the Sf9 cells group, GMTs of neutralizing antibodies against pseudo SARS-CoV-2 viruses (prototype and diverse variants of concern [VOCs]) increased by 22.23–75.93 folds from baseline to day 28 post-booster, while the CoronaVac group showed increases of only 3.29–10.70 folds. Similarly, neutralizing antibodies against live SARS-CoV-2 viruses (prototype and diverse VOCs) increased by 68.18–192.67 folds on day 14 post-booster compared with the baseline level, significantly greater than the CoronaVac group (19.67–37.67 folds). A more robust Th1 cellular response was observed with the Sf9 cells booster on day 14 post-booster (mean IFN-γ+ spot-forming cells per 2 × 105 peripheral blood mononuclear cells: 26.66 vs. 13.59). Protective effectiveness against symptomatic COVID-19 was approximately twice as high in the Sf9 cells group compared to the CoronaVac group (68.18% vs. 36.59%, p = 0.004). Our study findings support the high protective effectiveness of heterologous boosting with the recombinant COVID-19 vaccine (Sf9 cells) against symptomatic COVID-19 of diverse SARS-CoV-2 variants of concern, while causing no apparent safety concerns.

Contrasting roles for IgM and B-cell MHCII expression in Brucella abortus S19 vaccine-mediated efficacy against B. melitensis infection.

Brucella is a neglected zoonotic pathogen with a worldwide distribution. Our study delves into B-cell effector functions in live vaccine-mediated immunity against brucellosis. Notably, we found antibody production, particularly secretory IgM, confers protection against virulent Brucella melitensis in vaccinated mice, which was associated with complement activation. By contrast, B-cell MHCII expression negatively impacted vaccine efficacy. In addition, B-cell depletion after vaccination, but before the B. melitensis challenge, enhanced protection against infection, suggesting a detrimental B-cell role during the challenge phase. Interestingly, deficiency of T follicular helper cells, which are crucial for aiding germinal center B cells, dampened vaccine efficacy at later stages of challenge independent of antibody production. This study underscores contrasting and phase-dependent roles of B-cell effector functions in vaccine-mediated immunity against Brucella.

Dendritic cell vaccination in combination with erlotinib in a patient with inoperable lung adenocarcinoma: a case report

BackgroundSatisfactory treatment for patients with unresectable advanced lung cancer has not yet been established. We report a case of unresectable advanced lung cancer (stage IIIb: T2aN3M0) treated with a total of 15 doses of dendritic cells pulsed with a Wilms’ tumor 1 and mucin 1 vaccine in combination with erlotinib, a small molecule epidermal growth factor receptor tyrosine kinase inhibitor, for more than 699 days without recurrence or metastasis.Case presentationA 63-year-old Korean woman was diagnosed with lung adenocarcinoma by pathology and computed tomography. The adenocarcinoma showed an epidermal growth factor receptor (EGFR) mutation, no anaplastic lymphoma kinase expression, and less than 1% expression of programmed death ligand 1. She received erlotinib alone for approximately 1 month. She then received erlotinib and the dendritic cells pulsed with Wilms’ tumor 1 and mucin 1 vaccine. The diameter of the erythema at the vaccinated sites was 30 mm at 48 hours after the first vaccination. Moreover, it was maintained at more than 20 mm during the periods of vaccination. These results suggested the induction of antitumor immunity by the vaccine. Remarkably, the tumor size decreased significantly to 12 mm, a 65.7% reduction, after combined therapy with eight doses of the dendritic cells pulsed with Wilms’ tumor 1 and mucin 1 vaccine and erlotinib for 237 days based on fluorodeoxyglucose uptake by positron emission tomography/computed tomography and computed tomography. Interestingly, after 321 days of combination therapy, the clinical findings improved, and no tumor was detected based on computed tomography. Validation of the tumor’s disappearance persisted for at least 587 days after treatment initiation, without any indication of recurrence or metastasis.ConclusionStandard anticancer therapy combined with the dendritic cells pulsed with Wilms’ tumor 1 and mucin 1 vaccine may have therapeutic effects for such patients with unresectable lung adenocarcinoma.

Myeloid Cell-Triggered In Situ Cell Engineering for Robust Vaccine-Based Cancer Treatment.

Following the success of the dendritic cell (DC) vaccine, the cell-based tumor vaccine shows its promise as a vaccination strategy. Except for DC cells, targeting other immune cells, especially myeloid cells, is expected to address currently unmet clinical needs (e.g., tumor types, safety issues such as cytokine storms, and therapeutic benefits). Here, it is shown that an in situ injected macroporous myeloid cell adoptive scaffold (MAS) not only actively delivers antigens (Ags) that are triggered by scaffold-infiltrating cell surface thiol groups but also releases granulocyte-macrophage colony-stimulating factor and other adjuvant combos. Consequently, this promotes cell differentiation, activation, and migration from the produced monocyte and DC vaccines (MASVax) to stimulate antitumor T-cell immunity. Neoantigen-based MASVax combined with immune checkpoint blockade induces rejection of established tumors and long-term immune protection. The combined depletion of immunosuppressive myeloid cells further enhances the efficacy of MASVax, indicating the potential of myeloid cell-based therapies for immune enhancement and normalization treatment of cancer.

A systematic review of immunotherapy in high-grade glioma: learning from the past to shape future perspectives.

High-grade gliomas (HGGs) constitute the most common malignant primary brain tumor with a poor prognosis despite the standard multimodal therapy. In recent years, immunotherapy has changed the prognosis of many cancers, increasing the hope for HGG therapy. We conducted a comprehensive search on PubMed, Scopus, Embase, and Web of Science databases to include relevant studies. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Fifty-two papers were finally included (44 phase II and eight phase III clinical trials) and further divided into four different subgroups: 14 peptide vaccine trials, 15 dendritic cell vaccination (DCV) trials, six immune checkpoint inhibitor (ICI) trials, and 17 miscellaneous group trials that included both "active" and "passive" immunotherapies. In the last decade, immunotherapy created great hope to increase the survival of patients affected by HGGs; however, it has yielded mostly dismal results in the setting of phase III clinical trials. An in-depth analysis of these clinical results provides clues about common patterns that have led to failures at the clinical level and helps shape the perspective for the next generation of immunotherapies in neuro-oncology.

Abstract B026: Targeting wild type and ESR1 mutations as neoantigens in hormone receptor positive breast cancer

Abstract Hormone receptor positive (HR+) metastatic breast cancer remains a difficult clinical problem. Endocrine Therapies (ET) have remained the mainstay of therapy for decades. However, a large percent of these patients become resistant to the therapies and succumb to the disease. One of the most common resistance mechanisms is the ER alpha type I (ESR1) point mutations with amino acid substitutions such that they become constitutively active. About 40-50% of metastatic HR+ patients develop these mutations. Hence, there is a need to develop strategies that target WT and mutant ESR1 in order to achieve robust anti-tumor immune responses. Type I polarized dendritic cell (DC1) vaccine developed by our group has shown to be a powerful immunotherapeutic tool to treat breast cancer by boosting the CD4 Th1 responses against oncodrivers like HER2 and HER3. This is facilitated by identification of immunogenic human peptides using a novel peptide screening method targeting these oncodrivers and breaching the tolerance. Having strong evidence of the effectiveness of DC1 vaccines, our study focusses on testing efficacy of DC1 pulsed WT ESR1 peptides (DC1-WT ESR1) and clinically prevalent ESR1 mutations/neoantigens (DC1-Mutant ESR1) in pre-clinical mouse model. In this study, we tested the homology between human and murine WT and mutated ESR1 peptides and also assessed the efficacy of DC1-WT ESR1 and DC1-Mutant ESR1 vaccines in mice to generate CD4 Th1 response (IFNγ production). To develop pre-clinical ESR1 mouse tumor models, two different cell lines were validated for nuclear ESR1 expression. We tested the efficacy of DC1-WT ESR1 vaccine in orthotopic ESR1+ tumor bearing mice by administrating six DC1 vaccines intratumorally. Our results show around 90% and above homology between human and murine WT and mutated ESR1 peptides generating immunogenic responses in mice. In vitro treatment of ESR1+ mouse cell lines with IFNγ resulted in reduced proliferation. This effect was in line with the mouse tumor model, wherein we observed reduced tumor burden post administration of six DC1-WT ESR1 vaccines intratumorally in ESR1+ pre-clinical mouse models. In addition, we observed about a 12% of complete regression in these mice. Upon using combinatorial approaches such as fulvestrant and DC1-WT ESR1, we observed about a 14% of complete regression, however, the DC1 alone mice showed 62% responders and did a lot better than the fulvestrant alone. Overall, these findings suggest that DC1 vaccines targeting ESR1 could be a promising tool to treat aggressive ESR1+ breast cancer. We now aim to use combinatorial approaches such as CDK4/6 inhibitors and DC1-WT ESR1 to boost the anti-tumor responses and further test the efficacy of DC1-Mutant ESR1 vaccines using pre-clinical ESR1+ mouse models. Citation Format: Namrata Gautam, Gabriella Albert, Colin Synder, Brian Czerniecki. Targeting wild type and ESR1 mutations as neoantigens in hormone receptor positive breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B026.