Tumor-specific Immune Responses Research Articles

Glucosylated Nanovaccines for Dendritic Cell-Targeted Antigen Delivery and Amplified Cancer Immunotherapy.

Engineering nanovaccines capable of targeting dendritic cells (DCs) is desperately required to maximize antigen cross-presentation to effector immune cells, elicit strong immune responses, and avoid adverse reactions. Here, we showed that glucose transporter 1 (Glut-1) on DCs is a reliable target for delivering antigens to DCs, and thus, a versatile antigen delivery strategy using glucosylated nanovaccines was developed for DC-targeted antigen delivery and tumor immunotherapy. The developed glucosylated ovalbumin-loaded nanovaccines highly accumulated in lymph nodes and efficiently engaged with Glut-1 on DCs to accelerate intracellular antigen delivery and promote DC maturation and antigen presentation, which elicited potent antitumor immunity to prevent and inhibit ovalbumin-expressing melanoma. Moreover, immunotherapeutic experiments in DC- and macrophage-depleted animal models confirmed that the glucosylated nanovaccines functioned mainly through DCs. In addition, the neoantigen-delivering glucosylated nanovaccines were further engineered to elicit tumor-specific immune responses against MC38 tumors. This study offers a DC-targeted antigen delivery strategy for cancer immunotherapy.

Minimally Invasive Injectable Gel for Local Immunotherapy of Liver and Gastric Cancer.

Local immunotherapy represents a promising solution for preventing tumor recurrence and metastasis post tumor surgical resection by eliminating residue tumor cells as well as eliciting tumor-specific immune responses. Minimally invasive surgery has become a mainstream surgical method worldwide due to its advantages of aesthetics and rapid postoperative recovery. Unfortunately, the currently reported local immunotherapy strategies are mostly designed to be used after open laparotomy, which go against the current surgical philosophy of minimally invasive therapy and is not suitable for clinical translation. Aiming at this problem, a minimally invasive injectable gel (MIGel) is herein reported loaded with immunotherapeutic agents for gastric and liver cancer postoperative treatment. The MIGel is formed by crosslinking between oxidized dextran (ODEX) and 4-arm polyethylene glycol hydroxylamine (4-arm PEG-ONH2) through oxime bonds, which can be injected through a clinic-used minimally invasive drainage tube and adhered tightly to the tissue. The loaded oxaliplatin (OxP) and resiquimod (R848) can be released constantly over two weeks and resulted in over 75% cure rate in orthotopic mouse gastric and liver cancer model. Collectively, a concept of minimally invasive local immunotherapy is proposed and MIGel is designed for local intraperitoneal cancer immunotherapy through minimally invasive surgery, with good clinical translation potential.

Neoadjuvant lutetium PSMA, the TIME and immune response in high-risk localized prostate cancer.

High-risk localized prostate cancer remains a lethal disease with high rates of recurrence, metastases and death, despite attempts at curative local treatment including surgery. Disease recurrence is thought to be a result of failure of local control and occult micrometastases. Neoadjuvant strategies before surgery have been effective in many cancers, but, to date, none has worked in this setting for prostate cancer. Prostate-specific membrane antigen (PSMA)-based theranostics is an exciting and rapidly evolving field in prostate cancer. The novel intravenous radionuclide therapy, [177Lu]Lu-PSMA-617 (lutetium PSMA) has been shown to be effective in treating men with metastatic castration-resistant prostate cancer, targeting cells expressing PSMA throughout the body. When given in a neoadjuvant setting, lutetium PSMA might also improve long-term oncological outcomes in men with high-risk localized disease. A component of radiotherapy is potentially an immunogenic form of cancer cell death. Lutetium PSMA could cause cancer cell death, resulting in release of tumour antigens and induction of a tumour-specific systemic immune response. This targeted radioligand treatment has the potential to treat local and systemic tumour sites by directly targeting cells that express PSMA, but might also act indirectly via this systemic immune response. In selected patients, lutetium PSMA could potentially be combined with systemic immunotherapies to augment the antitumour T cell response, and this might produce long-lasting immunity in prostate cancer.

Bio-orthogonal click chemistry strategy for PD-L1-targeted imaging and pyroptosis-mediated chemo-immunotherapy of triple-negative breast cancer

BackgroundThe combination of programmed cell death ligand-1 (PD-L1) immune checkpoint blockade (ICB) and immunogenic cell death (ICD)-inducing chemotherapy has shown promise in cancer immunotherapy. However, triple-negative breast cancer (TNBC) patients undergoing this treatment often face obstacles such as systemic toxicity and low response rates, primarily attributed to the immunosuppressive tumor microenvironment (TME).Methods and resultsIn this study, PD-L1-targeted theranostic systems were developed utilizing anti-PD-L1 peptide (APP) conjugated with a bio-orthogonal click chemistry group. Initially, TNBC was treated with azide-modified sugar to introduce azide groups onto tumor cell surfaces through metabolic glycoengineering. A PD-L1-targeted probe was developed to evaluate the PD-L1 status of TNBC using magnetic resonance/near-infrared fluorescence imaging. Subsequently, an acidic pH-responsive prodrug was employed to enhance tumor accumulation via bio-orthogonal click chemistry, which enhances PD-L1-targeted ICB, the pH-responsive DOX release and induction of pyroptosis-mediated ICD of TNBC. Combined PD-L1-targeted chemo-immunotherapy effectively reversed the immune-tolerant TME and elicited robust tumor-specific immune responses, resulting in significant inhibition of tumor progression.ConclusionsOur study has successfully engineered a bio-orthogonal multifunctional theranostic system, which employs bio-orthogonal click chemistry in conjunction with a PD-L1 targeting strategy. This innovative approach has been demonstrated to exhibit significant promise for both the targeted imaging and therapeutic intervention of TNBC.Graphical abstract

Advances and challenges in anti-cancer vaccines for multiple myeloma.

Multiple myeloma (MM) is a hematological cancer marked by plasma cell accumulation in the bone marrow. Despite treatment advancements, MM remains incurable in most patients. MM-associated immune dysregulation fosters disease progression, prompting research into immunotherapy to combat the disease. An area of immunotherapy investigation is the design of myeloma vaccine therapy to reverse tumor-associated immune suppression and elicit tumor-specific immune responses to effectively target MM cells. This article reviews vaccine immunotherapy for MM, categorizing findings by antigen type and delivery method. Antigens include idiotype (Id), tumor-associated (TAA), tumor-specific (TSA), and whole tumor lysate. Myeloma vaccination has so far shown limited clinical efficacy. However, further studies are essential to optimize various aspects, including antigen and patient selection, vaccine timing and sequencing, and rational combinations with emerging MM treatments.

S-Sulfenylation Driven Antigen Capture Boosted by Radiation for Enhanced Cancer Immunotherapy.

Radiotherapy (RT)-induced in situ vaccination greatly promotes the development of personalized cancer vaccines owing to the massive release of antigens initiated by tumor-localized RT eliciting the tumor-specific immune response. However, its broad application in cancer treatment is seriously impeded by poor antigen cross-presentation, low response rate, and short duration of efficacy. Herein, the tumor-antigen-capturing nanosystem dAuNPs@CpG consisting of gold nanoparticles, 3,5-cyclohexanedione (CHD), and immunoadjuvant CpG were fabricated to enhance RT-induced vaccination. Taking advantage of the specific covalent binding between CHD and sulfenic acids of antigen proteins, we show that this nanoplatform has an unexpected potential to capture the sulfenylated tumor-derived protein antigens (TDPAs) induced by RT to in situ generate a vaccination effect, achieving significant growth suppression of both primary and distant tumors in combination with PD-1 blockade. We thus believe that our work presents a powerful and effective means to improve the synergistic tumor radioimmunotherapy.

Extracellular Vesicle-Inspired Minimalist Flexible Nanocapsules Assembled with Whole Active Ingredients for Highly Efficient Enhancement of DC-Mediated Tumor Immunotherapy.

The development of nanovaccines capable of eliciting tumor-specific immune responses holds significant promise for tumor immunotherapy. However, many nanovaccine designs rely heavily on incorporating multiple adjuvants and carriers, increasing the biological hazards associated with these additional components. Here, this work introduces novel flexible nanocapsules (OVAnano) designed to mimic extracellular vesicles, primarily using the ovalbumin antigen and minimal polyethylenimine adjuvant components. These results show that the biomimetic flexible structure of OVAnano facilitates enhanced antigen uptake by dendritic cells (DCs), leading to efficient antigen and adjuvant release into the cytosol via endosomal escape, and ultimately, successful antigen cross-presentation by DCs. Furthermore, OVAnano modulates the intracellular nuclear factor kappa-B (NF-κB) signaling pathway, promoting DC maturation. The highly purified antigens in OVAnano demonstrate remarkable antigen-specific immunogenicity, triggering strong antitumor immune responses mediated by DCs. Therapeutic tumor vaccination studies have also shown that OVAnano administration effectively suppresses tumor growth in mice by inducing immune responses from CD8+ and CD4+ T cells targeting specific antigens, reducing immunosuppression by regulatory T cells, and boosting the populations of effector memory T cells. These findings underscore that the simple yet potent strategy of employing minimal flexible nanocapsules markedly enhances DC-mediated antitumor immunotherapy, offering promising avenues for future clinical applications.

Radioactive Hydroxyapatite Microspheres Empower Sustainable In Situ Tumor Vaccination.

Tumor in situ vaccination (ISV) strategies have emerged in clinical trials as promising approaches, involving the release of tumor antigens through local radiotherapy and intratumorally adjuvant injections. However, the current fabrication strategy for achieving a sustainable immune response to ISV remains a pressing challenge. In this study, we present an empowered sustainable ISV method for antitumor therapy using 177Lu-labeled manganese-doped mesoporous hydroxyapatite (177Lu/Mn-HAP) microspheres. The ISV enables the sustained utilization of tumor antigens, leading to the activation of dendritic cells and polarization of macrophages toward the M1 subtype. Consequently, it facilitates the generation of potent CD8+ T-cell responses, enhancing the antitumor effects of internal radiation in both primary and distant tumors. Importantly, this approach achieves complete remission in all tumor-bearing mice and stimulates immune memory to prevent tumor recurrence. Our study highlights a universal and safe ISV strategy capable of inducing potent tumor-specific and sustainable immune response.

Enhancing in situ cancer vaccines using delivery technologies.

In situ cancer vaccination refers to any approach that exploits tumour antigens available at a tumour site to induce tumour-specific adaptive immune responses. These approaches hold great promise for the treatment of many solid tumours, with numerous candidate drugs under preclinical or clinical evaluation and several products already approved. However, there are challenges in the development of effective in situ cancer vaccines. For example, inadequate release of tumour antigens from tumour cells limits antigen uptake by immune cells; insufficient antigen processing by antigen-presenting cells restricts the generation of antigen-specific T cell responses; and the suppressive immune microenvironment of the tumour leads to exhaustion and death of effector cells. Rationally designed delivery technologies such as lipid nanoparticles, hydrogels, scaffolds and polymeric nanoparticles are uniquely suited to overcome these challenges through the targeted delivery of therapeutics to tumour cells, immune cells or the extracellular matrix. Here, we discuss delivery technologies that have the potential to reduce various clinical barriers for in situ cancer vaccines. We also provide our perspective on this emerging field that lies at the interface of cancer vaccine biology and delivery technologies.

Liposome-based in situ antigen-modification strategy for "universal" T-cell-receptor engineered T cell in cancer immunotherapy.

T-cell receptor (TCR) engineered T-cell therapy, unlike chimeric antigen receptor T-cell therapy, relies on the inherent ability of TCRs to detect a wider variety of antigenic epitopes, such as protein fragments found internally or externally on cells. Hence, TCR-T-cell therapy offers broader possibilities for treating solid tumors. However, because of the complicated process of identifying specific antigenic peptides, their clinical application still encounters significant challenges. Thus, we aimed to establish a novel "universal" TCR-T "artificial antigen expression" technique that involves the delivery of the antigen to tumor cells using DSPE-PEG-NY-ESO-1157-165 liposomes (NY-ESO-1 Lips) to express TCR-T-cell-specific recognition targets. In vitro as well as in vivo studies revealed that they could accumulate efficiently in the tumor area and deliver target antigens to activate the tumor-specific cytotoxic T-cell immune response. NY-ESO-1 TCR-T therapy, when used in combination, dramatically curbed tumor progression and extended the longevity of mice. Additionally, PD-1 blockage enhanced the therapeutic effect of the aforementioned therapy. In conclusion, NY-ESO-1 Lips "cursed" tumor cells by enabling antigenic target expression on their surface. This innovative technique presents a groundbreaking approach for the widespread utilization of TCR-T in solid tumor treatment.

CD40 agonist engineered immunosomes modulated tumor microenvironment and showed pro-immunogenic response, reduced toxicity, and tumor free survival in mice bearing glioblastoma

CD40 agonist antibodies (αCD40) have shown promising anti-tumor response in both preclinical and early clinical studies. However, its systemic administration is associated with immune- and hepato-toxicities which hampers its clinical usage. In addition, αCD40 showed low tumor retention and induced PD-L1 expression which makes tumor microenvironment (TME) immunosuppressive. To overcome these issues, in this study, we have developed a multifunctional Immunosome where αCD40 is conjugated on the surface and RRX-001, a small molecule immunomodulator was encapsulated inside it. Immunosomes showed higher tumor accumulation till 96 h of administration and displayed sustained release of αCD40 in vivo. Immunosomes significantly delayed tumor growth and showed tumor free survival in mice bearing GL-261 glioblastoma by increasing the population of CD45+CD8+ T cells, CD45+CD20+ B cells, CD45+CD11c+ DCs and F4/80+CD86+ cells in TME. Immunosome significantly reduced the population of T-regulatory cells, M2 macrophage, and MDSCs and lowered the PD-L1 expression. Moreover, Immunosomes significantly enhanced the levels of Th1 cytokines (IFN-γ, IL-6, IL-2) over Th2 cytokines (IL-4 and IL-10) which supported anti-tumor response. Most interestingly, Immunosomes averted the in vivo toxicities associated with free αCD40 by lowering the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), IL-6, IL-1α and reduced the degree of liver damage. In addition, Immunosomes treated long-term surviving mice showed tumor specific immune memory response which prevented tumor growth upon rechallenge. Our results suggested that this novel formulation can be further explored in clinics to improve in vivo anti-tumor efficacy of αCD40 with long-lasting tumor specific immunity while reducing the associated toxicities.

Self-Illuminating Nanoagonist Simultaneously Induces Dual Cell Death Pathways via Death Receptor Clustering for Cancer Therapy.

Inducing death receptor 5 (DR5) clustering holds particular promise in tumor-specific therapeutics because it could trigger an apoptotic cascade in cancerous cells. Herein, we present a tumor microenvironment H2O2-responsive self-illuminating nanoagonist, which could induce dual tumor cell death pathways through enhancing DR5 clustering. By conjugating DR5 ligand peptides onto the surfaces of self-illuminating nanoparticles with cross-linking capacity, this strategy not only provides scaffolds for ligands to bind receptors but also cross-links them through photo-cross-linking. This strategy allows for efficient activation of DR5 downstream signaling, initiating the extrinsic apoptosis pathway and immunogenic cell death of tumor cells, and contributes to improved tumor-specific immune responses, resulting in enhanced antitumor efficacy and minimized systemic adverse effects.

The Oncolytic virus VT1092M and an Anti-PD-L1 antibody synergize to induce systemic antitumor immunity in a murine bilateral tumor model

This study investigated the synergistic potential of an oncolytic herpes simplex virus armed with interleukin 12 (VT1092M) in combination with immune checkpoint inhibitors for enhancing antitumor responses. The potential of this combination treatment to induce systemic antitumor immunity was assessed using bilateral subcutaneous tumor and tumor re-challenge mouse models. The antitumor efficacy of various OV and ICI treatment combinations and the underlying mechanisms were explored through diverse analytical techniques, including flow cytometry and RNA sequencing. Using VT1092M, either alone or in combination with an anti-PD-L1 antibody, significantly reduced the sizes of both the injected and untreated abscopal tumors in a bilateral tumor mouse model. The combination therapy demonstrated superior antitumor efficacy to the other treatment conditions tested, which was accompanied by an increase in T cell numbers and CD8+T cell activation. Results from the survival and tumor re-challenge experiments showed that the combination therapy elicited long-term, tumor-specific immune responses, which were associated with tumor clearance and prolonged survival. Immune cell depletion assays identified CD8+T cells as the crucial mediators of systemic antitumor immunity during combination therapy. In conclusion, the combination of VT1092M and PD-L1 blockade emerged as a potent inducer of antitumor immune responses, surpassing the efficacy of each monotherapy. This synergistic approach holds promise for achieving robust and sustained antitumor immunity, with potential implications for preventing tumor metastasis in patients with cancer.

Black TiO2-based nanoparticles as Toll-like receptor stimulator delivery system for enhanced photothermal-immunotherapy of pancreatic cancer

BackgroundThe tumor-specific immune responses, essential for removing residual lesions and preventing tumor metastases, can be stimulated by tumor-associated antigens (TAAs) released following photothermal therapy (PTT). However, due to the immunosuppressed microenvironment of pancreatic ductal adenocarcinoma (PDAC), the TAAs released by PTT are difficult to induce an effective immune response. In this work, we prepared the mesoporous silica (mSiO2) coated black titanium dioxide (bTiO2) photothermal nanoparticles (NPs) for enhanced photothermal-immunotherapy toward PDAC, in which resiquimod (R848) was loaded and DOTA-Gd was conjugated. The NPs are specified as bTiO2@mSiO2@Gd/R848 and abbreviated to NPs/R848. R848 as a kind of Toll-like receptor 7/8 agonist can remodel the tumor microenvironment (TME) in PDAC and induce a strong immune response. Furthermore, DOTA-Gd serves as a magnetic resonance imaging (MRI) contrast agent to improve the T1-weighted MRI performance of the NPs.ResultsIn vitro results of this study show that NPs/R848 could thermally ablate tumor cells and efficiently trigger dendritic cell (DC) maturation. The results of in vivo investigations demonstrate that the combined use of photothermal-immunotherapy exhibits a significant inhibitory effect on tumor growth. Besides, it promoted maturation of DCs and enhanced infiltration of CD8 + , CD4 + T cells to improve the TME in PDAC.ConclusionsOur study anticipates that by encouraging the maturation of DCs, this strategy will improve the TME and enable the successful photothermal-immunotherapy of PDAC.

In situ tumor vaccine with optimized nanoadjuvants and lymph node targeting capacity to treat ovarian cancer and metastases

Tumor vaccine, a promising modality of tumor immunotherapy, needs to go through the process of tumor antigen generation and loading, antigen drainage to lymph nodes (LNs), antigen internalization by dendritic cells (DCs), DC maturation, and antigen cross-presentation to activate T-cells. However, tumor vaccines are often unable to satisfy all the steps, leading to the limitation of their application and efficacy. Herein, based on a smart nanogel system, an in situ nano-vaccine (CpG@Man-P/Tra/Gel) targeting LNs was constructed to induce potent anti-tumor immune effects and inhibit the recurrence and metastasis of ovarian cancer. The CpG@Man-P/Tra/Gel exhibited MMP-2-sensitive release of trametinib (Tra) and nano-adjuvant CPG@Man-P, which generated abundant in situ depot of whole-cell tumor antigens and formed in situ nano-vaccines with CpG@Man-P. Benefiting from mannose (Man) modification, the nano-vaccines targeted to LNs, promoted the uptake of antigens by DCs, further inducing the maturation of DCs and activation of T cells. Moreover, CpG@Man-P with different particle sizes were prepared and the effective size was selected to evaluate the antitumor effect and immune response in vivo. Notably, combined with PD-1 blocking, the vaccine effectively inhibited primary tumor growth and induced tumor-specific immune response against tumor recurrence and metastasis of ovarian cancer.

Tumor microenvironment-modulating oncolytic adenovirus combined with GSK-3β inhibitor enhances antitumor immune response against bladder cancer.

Bladder cancer is a common type of cancer around the world, and the majority of patients are diagnosed with non-muscle-invasive bladder cancer (NMIBC). Although low-risk NMIBC has a good prognosis, the disease recurrence rate and development of treatment-refractory disease remain high in intermediate- to high-risk NMIBC patients. To address these challenges for the treatment of NMIBC, a novel combination therapy composed of an oncolytic adenovirus (oAd) co-expressing interleukin (IL)-12, granulocyte-macrophage colony-stimulating factor (GM-CSF), and relaxin (RLX; HY-oAd) and a clinical-stage glycogen synthase kinase (GSK)-3β inhibitor (9-ING-41; elraglusib) was investigated in the present report. Our findings demonstrate that HY-oAd and 9-ING-41 combination therapy (HY-oAd+9-ING-41) exerted superior inhibition of tumor growth compared with respective monotherapy in a syngeneic NMIBC tumor model. HY-oAd+9-ING-41 induced high-level tumor extracellular matrix (ECM) degradation and a more potent antitumor immune response than the respective monotherapy. In detail, HY-oAd+9-ING-41 induced superior accumulation of intratumoral T cells, prevention of immune cell exhaustion, and induction of tumor-specific adaptive immune response compared to either monotherapy. Collectively, these results demonstrate that the combination of HY-oAd and 9-ING-41 may be a promising approach to elicit a potent antitumor immune response against bladder cancer.

Emerging role of immunogenic cell death in cancer immunotherapy.

Cancer immunotherapy, such as immune checkpoint blockade (ICB), has emerged as a groundbreaking approach for effective cancer treatment. Despite its considerable potential, clinical studies have indicated that the current response rate to cancer immunotherapy is suboptimal, primarily attributed to low immunogenicity in certain types of malignant tumors. Immunogenic cell death (ICD) represents a form of regulated cell death (RCD) capable of enhancing tumor immunogenicity and activating tumor-specific innate and adaptive immune responses in immunocompetent hosts. Therefore, gaining a deeper understanding of ICD and its evolution is crucial for developing more effective cancer therapeutic strategies. This review focuses exclusively on both historical and recent discoveries related to ICD modes and their mechanistic insights, particularly within the context of cancer immunotherapy. Our recent findings are also highlighted, revealing a mode of ICD induction facilitated by atypical interferon (IFN)-stimulated genes (ISGs), including polo-like kinase 2 (PLK2), during hyperactive type I IFN signaling. The review concludes by discussing the therapeutic potential of ICD, with special attention to its relevance in both preclinical and clinical settings within the field of cancer immunotherapy.

Abstract PO5-19-07: A Single Arm Phase 2 Study of Peri-Operative Immune Checkpoint Inhibition and Cryoablation in Women With Hormone Receptor-Negative, HER2-Negative Early Stage/Resectable Breast Cancer

Abstract Background: Triple negative breast cancer (TNBC) is a biologically distinct subtype with a high risk of early relapse. Patients not achieving a pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) have a 3-year event free survival (EFS) of < 60%. Approximately 1/3 of patients receiving NAC with pembrolizumab-mediated immune therapy will not achieve a pCR and of those, approximately 1/3 will experience a recurrence within 3 years. Physical disruption of tumors with local strategies such as cryoablation (cryo) induces inflammation and releases antigens that can activate tumor-specific immune responses. The combination of cryo with immune checkpoint inhibition (ICI) has been shown to induce tumor regression and prevented tumor re-challenge in pre-clinical models. Clinical studies have also demonstrated that the combination of pre-operative cryo with ICI is safe in women with operable, early-stage breast cancer and generates intra-tumoral and systemic immune responses (NCT01502592, NCT02833233). This multi-center, single arm, phase 2 study is currently evaluating the impact of cryo with standard-of-care pembrolizumab (pembro) in women with residual TNBC after taxane-based NAC, a group at high risk of early relapse (NCT03546686). Methods: Eligible women are ≥18y, with ER < 10%, PR < 10%, HER2 negative (per ASCO/CAP definition), ≥ 1.0 cm, residual operable disease after taxane-based NAC. Pts undergo percutaneous, image-guided cryo with concurrent research core biopsy 7-10 days prior to surgery and receive peri-operative pembro per standard-of-care. Adjuvant capecitabine or olaparib is recommended for all patients per local standard-of-care. Patients are stratified by NAC platinum administration, NAC anthracycline administration, and clinical nodal status (positive versus negative). The primary endpoint is 3-year Event Free Survival (EFS). Secondary endpoints include Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS), overall survival (OS) and safety. Exploratory correlative studies will be performed on tumor and serum to characterize the immunologic impact of the intervention and to explore predictors of efficacy and toxicity. Funding sources: Conquer Cancer Foundation, Breast Cancer Research Foundation, Boston Scientific Citation Format: Heather McArthur, Elizabeth Comen, Yolanda Bryce, Stephen Solomon, Sangeetha Reddy, Isaac Chan, Baṣak Dogan, Dawn Klemow, Nisha Unni, Jorge Henrique Santos Leal, Cristal Martinez, Reva Basho, Dorothy Park, Philomena McAndrew, Brigid Larkin, David Page, William Mills, Staci Mellinger, Nicole Fredrich, Nicole Moxon, Lynette Currie, Meredith Carter, Melissa Ramos, Stephanie Rice, Sujata Patil, Margaret Gatti-Mays, Larry Norton. A Single Arm Phase 2 Study of Peri-Operative Immune Checkpoint Inhibition and Cryoablation in Women With Hormone Receptor-Negative, HER2-Negative Early Stage/Resectable Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-19-07.

The Impact of High Intensity Focused Ultrasound (HIFU) on Tumor-Specific Immune Responses of Prostate Cancer.

High intensity focused ultrasound (HIFU), also referred to as focused ultrasound surgery (FUS), has garnered recent attention as a non-invasive therapeutic strategy for prostate cancer. It utilizes focused acoustic energy to achieve localized thermal ablation, while also potentially exerting immunomodulatory effects. This review aims to elucidate the mechanisms underlying how HIFU influences tumor-specific immune responses in prostate cancer. These mechanisms include the release of tumor-associated antigens and damage-associated molecular patterns, the activation of innate immune cells, the facilitation of antigen presentation to adaptive immune cells, the enhancement of activation and proliferation of tumor-specific cytotoxic T lymphocytes, and the attenuation of the immunosuppressive tumor microenvironment by reducing the activity of regulatory T cells and myeloid-derived suppressor cells. Both preclinical investigations and emerging clinical data in prostate cancer models highlight HIFU's potential to modulate the immune system, as evidenced by increased infiltration of effector immune cells, elevated levels of pro-inflammatory cytokines, and improved responsiveness to immune checkpoint inhibitors. HIFU induces immunogenic cell death, leading to the release of tumor antigens and danger signals that activate dendritic cells and facilitate cross-presentation to cytotoxic T cells. Additionally, FUS ablation reduces immunosuppressive cells and increases infiltration of CD8+ T cells into the tumor, reshaping the tumor microenvironment. By priming the immune system while overcoming immunosuppression, combining FUS with other immunotherapies like checkpoint inhibitors and cancer vaccines holds promise for synergistic anti-tumor effects. Despite challenges in optimizing parameters and identifying suitable patients, FUS represents a novel frontier by modulating the tumor microenvironment and enhancing anti-tumor immunity through a non-invasive approach.

Expanding the Potential of Neoantigen Vaccines: Harnessing Bacille Calmette-Guérin Cell-Wall-Based Nanoscale Adjuvants for Enhanced Cancer Immunotherapy.

Personalized antitumor immunotherapy utilizing neoantigen vaccines holds great promise. However, the limited immunogenicity of existing recognized neoantigens and the inadequate stimulation of antitumor immune responses by conventional adjuvants pose significant challenges. To address these limitations, we developed a nanovaccine that combines a BCG bacterial cell wall skeleton (BCG-CWS) based nanoscale adjuvant (BCNA) with peptide neoantigens (M27 and M30). This integrated approach provides an efficient translational strategy for cancer immunotherapy. The BCNA nanovaccine, formulated with PLGA as an emulsifier, exhibits excellent biocompatibility and superior antigen presentation compared with conventional BCG-CWS adjuvants. Subcutaneous immunization with the BCNA-based nanovaccine effectively targets lymph nodes, eliciting robust innate and tumor-specific immune responses. Importantly, our findings demonstrate that BCNAs significantly enhance neoantigen immunogenicity while minimizing acute systemic toxicity. Furthermore, when combined with a mouse PD-L1 antibody, our strategy achieves complete tumor elimination in 60% of cases and prevents 25% of tumor growth in a melanoma mouse model. In conclusion, our BCNA-based nanovaccine represents a promising avenue for advancing personalized therapeutic neoantigen vaccines and holds significant implications for enhancing personalized immunotherapy and improving patient outcomes in the field of cancer treatment.