Cell Cancer Vaccines Research Articles

Combinatory Immunotherapy for Glioblastoma Treatment

AbstractDespite advancements in the treatment of glioblastoma, it faces challenges due to tumor heterogeneity, the blood‐brain barrier, recurrence, immune evasion, and conventional strategies, leading to low survival and a poor prognosis. Therefore, it is crucial to develop novel, useful treatment strategies for improving brain distribution to overcome blood‐brain barriers (BBB) and help the treatment of glioblastoma. Conventional immunotherapy like checkpoint inhibitors, CAR‐T cell therapy, monoclonal antibodies, cancer vaccines, and adoptive cell transfer often suffers from low therapeutic outcomes because the singular therapy generally has shortcomings, such as the cold immune microenvironment of brain tumors. In contrast, the emerging combinatory immunotherapy integrated with chemo‐immunotherapy, photothermal‐immunotherapy, and radio‐immunotherapy has shown great promise to modulate tumoral immune microenvironment and boost treatment outcomes. This review discusses the immune microenvironment of GBM, its impact on immunological effects, current immunotherapy methods, and advanced studies. It also introduces combinational GBM immunotherapy with traditional cancer therapies like chemo‐immunotherapy, surgery‐immunotherapy, photothermal‐immunotherapy, and radiotherapy‐immunotherapy. In the future, it is anticipated that this article will provide beneficial information and a path for the strategy of innovative, efficient combination immunotherapy in the treatment of glioblastoma.

Photocatalytic Carbon Dots-Triggered Pyroptosis for Whole Cancer Cell Vaccines.

Manufacturing whole cancer cell vaccines (WCCV) with both biosafety and efficacy is crucial for tumor immunotherapy. Pyroptotic cancer cells, due to their highly immunogenic properties, present a promising avenue for the development of WCCV. However, the successful development of WCCV based on pyroptotic cancer cells is yet to be accomplished. Here, a facile strategy that utilized photocatalytic carbon dots (CDs) to induce pyroptosis of cancer cells for fabricating WCCV is reported. Photocatalytic CDs are capable of generating substantial amounts of hydroxyl radicals and can effectively decrease cytoplasmic pH values under white light irradiation. This process efficiently triggers cancer cell pyroptosis through the reactive oxygen species (ROS)-mitochondria-caspase 3-gasdermin E pathway and the proton motive force-driven mitochondrial ATP synthesis pathway. Moreover, in vitro, these photocatalytic CDs-induced pyroptotic cancer cells (PCIP) can hyperactivate macrophage (M0-M1) with upregulation of major histocompatibility complex class II expression. In vivo, PCIP induced specific immune-preventive effects in melanoma and breast cancer mouse models through anticancer immune memory, demonstrating effective WCCV. This work provides novel insights for inducing cancer cell pyroptosis and bridges the gap in the fabrication of WCCV based on pyroptotic cancer cells.

Feasibility Study for the Use of Gene Electrotransfer and Cell Electrofusion as a Single-Step Technique for the Generation of Activated Cancer Cell Vaccines.

Cell-based therapies hold great potential for cancer immunotherapy. This approach is based on manipulation of dendritic cells to activate immune system against specific cancer antigens. For the development of an effective cell vaccine platform, gene transfer, and cell fusion have been used for modification of dendritic or tumor cells to express immune (co)stimulatory signals and to load dendritic cells with tumor antigens. Both, gene transfer and cell fusion can be achieved by single technique, a cell membrane electroporation. The cell membrane exposed to external electric field becomes temporarily permeable, enabling introduction of genetic material, and also fusogenic, enabling the fusion of cells in the close contact. We tested the feasability of combining gene electrotransfer and electrofusion into a single-step technique and evaluated the effects of electroporation buffer, pulse parameters, and cell membrane fluidity for single or combined method of gene delivery or cell fusdion. We determined the percentage of fused cells expressing green fluorescence protein (GFP) in a murine cell model of melanoma B16F1, cell line used in our previous studies. Our results suggest that gene electrotransfer and cell electrofusion can be applied in a single step. The percentage of viable hybrid cells expressing GFP depends on electric pulse parameters and the composition of the electroporation buffer. Furthermore, our results suggest that cell membrane fluidity is not related to the efficiency of the gene electrotransfer and electrofusion. The protocol is compatible with microfluidic devices, however further optimization of electric pulse parameters and buffers is still needed.

Immunocyte membrane-derived biomimetic nano-drug delivery system: a pioneering platform for tumour immunotherapy.

Tumor immunotherapy characterized by its high specificity and minimal side effects has achieved revolutionary progress in the field of cancer treatment. However, the complex mechanisms of tumor immune microenvironment (TIME) and the individual variability of patients' immune system still present significant challenges to its clinical application. Immunocyte membrane-coated nanocarrier systems, as an innovative biomimetic drug delivery platform, exhibit remarkable advantages in tumor immunotherapy due to their high targeting capability, good biocompatibility and low immunogenicity. In this review we summarize the latest research advances in biomimetic delivery systems based on immune cells for tumor immunotherapy. We outline the existing methods of tumor immunotherapy including immune checkpoint therapy, adoptive cell transfer therapy and cancer vaccines etc. with a focus on the application of various immunocyte membranes in tumor immunotherapy and their prospects and challenges in drug delivery and immune modulation. We look forward to further exploring the application of biomimetic delivery systems based on immunocyte membrane-coated nanoparticles, aiming to provide a new framework for the clinical treatment of tumor immunity.

Developments and applications of therapeutic tumor vaccines

The incidence and mortality rates of malignant tumors have rapidly increased. Cancer has become the leading cause of death worldwide. Traditional treatment methods such as surgery, chemotherapy, and radiation have limited effectiveness, with poor prognosis, drug resistance, and low specificity. As a result, cancer immunotherapy has emerged as a promising approach in biotechnology. The development and application of tumor vaccines in tumor immunotherapy have garnered significant attention. These vaccines employ TAA or TSA to activate the bodys specific immune response against tumor cells. This review provides an overview of the tumor microenvironment, tumor immunotherapy, and various types of therapeutic cancer vaccines, including peptide, cell, DC, nucleic acid (DNA and mRNA), and neoantigen vaccines. In conclusion, this review summarizes the current progress and future prospects of tumor vaccines.

Current Trends and Innovative Approaches in Cancer Immunotherapy.

Immunotherapy is one of the most promising therapeutic approaches in the field of cancer treatment. As a tumor progresses, tumor cells employ an array of immune-regulatory mechanisms to suppress immune responses within the tumor microenvironment. Using our understanding of these mechanisms, cancer immunotherapy has been developed to enhance the immune system's effectiveness in treating cancer. Numerous cancer immunotherapies are currently in clinical use, yet many others are either in different stages of development or undergoing clinical studies. In this paper, we briefly discuss the features and current status of cancer immunotherapies. This includes the application of monoclonal antibodies, immune checkpoint inhibitors, adoptive cell therapy, cytokine therapy, cancer vaccines, and gene therapy, all of which have gained significant recognition in clinical practice. Additionally, we discuss limitations that may hinder successful clinical utilization and promising strategies, such as combining immunotherapy with nanotechnology.

Enhancing Dendritic Cell Cancer Vaccination: The Synergy of Immune Checkpoint Inhibitors in Combined Therapies.

Dendritic cell (DC) cancer vaccines are a promising therapeutic approach, leveraging the immune system to fight tumors. These vaccines utilize DCs' ability to present tumor-associated antigens to T cells, triggering a robust immune response. DC vaccine development has progressed through three generations. The first generation involved priming DCs with tumor-associated antigens or messenger RNA outside the body, showing limited clinical success. The second generation improved efficacy by using cytokine mixtures and specialized DC subsets to enhance immunogenicity. The third generation used blood-derived DCs to elicit a stronger immune response. Clinical trials indicate that cancer vaccines have lower toxicity than traditional cytotoxic treatments. However, achieving significant clinical responses with DC immunotherapy remains challenging. Combining DC vaccines with immune checkpoint inhibitors (ICIs), such as anticytotoxic T-lymphocyte Antigen 4 and antiprogrammed death-1 antibodies, has shown promise by enhancing T-cell responses and improving clinical outcomes. These combinations can transform non-inflamed tumors into inflamed ones, boosting ICIs' efficacy. Current research is exploring new checkpoint targets like LAG-3, TIM-3, and TIGIT, considering their potential with DC vaccines. Additionally, engineering T cells with chimeric antigen receptors or T-cell receptors could further augment the antitumor response. This comprehensive strategy aims to enhance cancer immunotherapy, focusing on increased efficacy and improved patient survival rates.

Outcomes of advanced/metastatic breast cancer (aMBC) treated with BRIA-IMT, an allogeneic whole cell immunotherapy.

1022 Background: The Bria-IMT regimen is a combination immunotherapy using an allogeneic whole cell cancer vaccine combined with checkpoint inhibitors (CPIs). Intradermally administered irradiated SV-BR-1-GM breast cancer cells secrete GM-CSF and present tumor associated antigens (TAAs) on HLA-I and –II molecules to directly stimulate anti-tumor immunity. Anti-PD1 CPI further stimulates T-cells and synergizes with SV-BR-1-GM. Here we report the results of the phase 1/2 trial (NCT03328026) of Bria-IMT in metastatic/advanced breast cancer evaluating sequencing of SV-BR-1-GM inoculation and CPI. Methods: Analysis of the phase 1 with expansion phase 2 cohort randomized by sequence using SV-BR-1-GM, checkpoint inhibitor (pembrolizumab or retifanlimab), low dose cyclophosphamide (Day –2) and post-dose local pegylated interferon α, with cycles every 3 weeks. In the 1:1 randomized cohort, CPI is either dosed at C1 prior to SV-BR-1-GM (original sequence) or delayed to C2 post-SV-BR-1-GM (alternative sequence). Cancer-associated macrophage-like cells (CAMLs) and circulating tumor cells (CTCs) were monitored as biomarkers. Results: A total of 54 patients were dosed: 11 with pembrolizumab, 44 with retifanlimab (1 patient received pembrolizumab and later retifanlimab). Median age=61 (38-81); Median prior regimen=6 (2-13); 72% ER+/PR+/HER2-; 6% HER2+ and 22% triple negative. Bria-IMT regimen was well tolerated with only 9% drop-out rate due to AE. AEs related to IPs were seen in 74% of patients; the majority (91%) being grade 1-2, and few (1.7%) grade 4 cases including pulmonary embolism, dehydration and increased lipase. Among 30 patients with post-dose CAML/CTC data and evaluable outcome, CAML count <5 associates with disease control (p=0.06, Chi square test). Patients who developed DTH to SV-BR-1-GM had significantly better PFS and higher OS. Patients treated with phase III formulation had an increase in PFS. Quality of life improvement correlates with disease outcome and survival. Among the patients treated with the phase III formulation of SV-BR-1-GM (n=23 with evaluable outcomes), objective response rate (ORR) is 13% and disease control rate (DCR) is 61%, with median PFS and OS are 4.1 and 13.3 months, respectively. In the randomized portion, the original sequence cohort had higher DCR (43% vs 36%) and OS (P=0.08, HR 0.30, 95%CI 0.08-1.17) compared to the alternative sequence cohort. Conclusions: BRIA-IMT has shown a favorable safety profile while providing benefits to heavily treated aMBC patients. Superior outcomes and survival were seen in patients treated with the phase III formulation and regimen now being used in the ongoing Ph3 trial, confirming the improvement in efficacy of the novel regimen. The results from this randomized phase 2 study informed the study design of the ongoing Ph3 trial comparing BRIA-IMT to standard of care physician choice treatments (NCT06072612). Clinical trial information: NCT03328026 .

State-of-the-art and upcoming trends in RAS-directed therapies in gastrointestinal malignancies.

Overall, the review underscores the evolving landscape of KRAS-targeted therapy and the potential for these approaches to improve outcomes for patients with gastrointestinal malignancies. It highlights the importance of ongoing research and clinical trials in advancing precision medicine strategies for KRAS-driven cancers. This review provides a comprehensive overview of the RAS signaling pathway and its significance in gastrointestinal malignancies. The introduction of KRAS inhibitor represents a significant advancement in the treatment landscape for KRAS-mutant cancers. In this review, we discuss upcoming trends in KRAS-targeted therapy, including the development of mutant-specific direct KRAS inhibitors like MRTX1133 and pan-RAS inhibitors such as RMC-6236. It also explores indirect RAS inhibitors targeting upstream and downstream components of the RAS pathway. Additionally, the review examines other upcoming strategies like combination therapies, such as CDK4/6 and ERK MAPK inhibitors, as well as adoptive cell therapy and cancer vaccines targeting KRAS-mutant cancers. Targeting RAS has become an important strategy in treating gastrointestinal cancer. These findings in this review underscore the importance of a multidisciplinary approach, integrating advances in molecular profiling, targeted therapy, immunotherapy, and clinical research to optimize treatment strategies for patients with KRAS-mutant gastrointestinal malignancies.

Revolutionizing Oral Cancer Treatment: Immunotherapeutic Approaches

Background: Immunotherapy is a promising addition to the cancer treatment arsenal, with the potential to be an effective adjuvant therapy. In the ever-changing landscape of cancer care, it appears as a potential fourth pillar, supplementing surgery, chemotherapy, and radiation. The key to effective immunotherapy is cautious patient selection, which is based on a thorough study of the unique immune makeup of each patient. Aim: This review article aims to provide a comprehensive understanding of the fundamental principles of tumor immunity and immunotherapy, with a specific focus on oral squamous cell carcinoma. Methods: The review involved a thorough investigation of scientific databases and relevant publications, including studies conducted up to the present date obtained from PubMed, Science Direct, and Google Scholar Key. The selected studies underwent careful evaluation for methodological rigor and the significance of their findings. Results: Checkpoint inhibitors, targeted monoclonal antibodies, adoptive cell transfer, cancer vaccines, biomarkers and prediction tools, and cytokine immunotherapy are all promising treatments for oral cancer. Conclusion: In recent decades, there has been a substantial increase in interest and study in cancer immunotherapy, indicating a turning point in our approach to cancer treatment. While significant progress has been made, major hurdles remain across a range of cancers.

Tumor cell membrane‐based vaccines: A potential boost for cancer immunotherapy

AbstractBecause therapeutic cancer vaccines can, in theory, eliminate tumor cells specifically with relatively low toxicity, they have long been considered for application in repressing cancer progression. Traditional cancer vaccines containing a single or a few discrete tumor epitopes have failed in the clinic, possibly due to challenges in epitope selection, target downregulation, cancer cell heterogeneity, tumor microenvironment immunosuppression, or a lack of vaccine immunogenicity. Whole cancer cell or cancer membrane vaccines, which provide a rich source of antigens, are emerging as viable alternatives. Autologous and allogenic cellular cancer vaccines have been evaluated as clinical treatments. Tumor cell membranes (TCMs) are an intriguing antigen source, as they provide membrane‐accessible targets and, at the same time, serve as integrated carriers of vaccine adjuvants and other therapeutic agents. This review provides a summary of the properties and technologies for TCM cancer vaccines. Characteristics, categories, mechanisms, and preparation methods are discussed, as are the demonstrable additional benefits derived from combining TCM vaccines with chemotherapy, sonodynamic therapy, phototherapy, and oncolytic viruses. Further research in chemistry, biomedicine, cancer immunology, and bioinformatics to address current drawbacks could facilitate the clinical adoption of TCM vaccines.

Abstract 2471: State-of-the-art Specific T cell Activating Modulator on ePENDY platform (STAM.eP) activates specific CD8+ T cell by stimulating TCR signal

Abstract After decades of research, therapeutic cancer vaccine approach now sheds light on developing efficient cancer therapy treating patients who have resistance to other cancer immunotherapy. However, cancer vaccine approach using conventional modalities such as protein, peptide, and mRNA is considered a powerful cancer treatment only when the patients have healthy immune systems. In addition, dendritic cell (DC) cancer vaccine can be a great alternative therapy, but manufacture of DC vaccines in vitro is a labor-intensive, time- and money-consuming procedure. Here, we developed Specific T cell Activating Modulator (STAM) on our engineered IgM backbone, ePENDY (engineered PENtamer boDY), with high avidity based on multivalent binding sites to overcome the disadvantages of other therapeutic cancer vaccines. STAM on ePENDY (STAM.eP) consists of ten peptide-loaded-HLAs linked to ePENDY to simulate priming signal of CD8+ T cell by TCR cluster and a costimulatory signal molecule is linked to J chain of ePENDY to prevent CD8+ T cell from becoming anergic status. With these features, STAM.eP mimics cognately licensed DC that can present tumor peptide-loaded MHC class I molecule to CD8+ T cell and promote its priming. Thus, one of the greatest advantages of STAM.eP is to be a potential treatment for immunosuppressive cancer patients with DCs that do not respond appropriately. Another advantage is that any tumor specific antigen (TSA), including from intracellular proteins, can be applied to STAM.eP concept to activate specific CD8+ T cells for targeting cancer cells. In this study, we used Human Papillomavirus (HPV) E7-derived peptide which is an oncoprotein associated with cervical and head/neck cancers. We observed that HPV E7-derived peptide loaded STAM.eP, named IMB-401, increases antigen-specific CD8+ T cell population and shows cytotoxicity activity against cancer cells expressing HPV E7 protein in vitro test model. In vivo test model, it was also observed that population of specific CD8+ T cells and memory T cells were increased in the blood and spleens of transgenic mice treated with IMB-401. Furthermore, we confirmed that IMB-401 shows anti-tumor efficacy due to an increase of antigen-specific CD8+ T cell in vivo humanized mouse model. These results suggest that IMB-401 can be a new therapeutic cancer vaccine technology that replaces DC function and is expected to have robust anti-tumor activity in combination with immune checkpoint inhibitors. Citation Format: Kyung-gi Hyun, Sungmuk Kang, Yongjun Kang, Jihye Koo, Suho Park, Sunghyun Byun, Sunghyun Yoon, Jaebeom Lee, Hong Jai Lee, Hong Kyu Lee, Eunyoung Cho, Chungmin Lee, Kyung-Chul Choi, Gyongsik Ha. State-of-the-art Specific T cell Activating Modulator on ePENDY platform (STAM.eP) activates specific CD8+ T cell by stimulating TCR signal [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 2471.

Abstract 5296: Enhancing the strength and durability of vaccine-induced anti-tumor immunity with CD27 agonism of CD4+ T cells

Abstract Despite encouraging early phase clinical trials, decades of research have yet to yield effective cancer vaccine immunotherapies. To determine potential markers for success, we performed a follow-up study of a HER2-pulsed dendritic cell cancer vaccine Phase I trial performed in advanced HER2+ cancer patients. Surprisingly, we found that all treated patients were alive at over 18 years post-treatment. These patients still possessed significant HER2-specific memory T cell responses, typified by CD27 expression. The expansion of HER2-specific CD27+ memory T cells was also observed in patients from a separate clinical trial, who received a HER2-expressing viral vaccine. To validate these clinical responses, we vaccinated human CD27 transgenic mice with a HER2 viral vector again observing HER2-specific CD27+ memory T cells, suggesting the significance of this axis in eliciting and maintaining effective vaccine-specific memory T cell responses. We hypothesized that CD27 expression was not just a marker of memory T cells, but represented a critical activation pathway during memory formation. To determine the potential impact of CD27 agonism in vaccination, we combined HER2 vaccination with an anti-CD27 agonist antibody (Varlilumab). The combination treatment elicited a robust increase in HER2-specific CD4+ memory T cell responses that was maintained for at least 300 days post-vaccination. Using therapeutic HER2 vaccination in combination with anti-CD27 of HER2+ tumor bearing mice, we show significantly increased anti-tumor efficacy and further enhancement in combination with PD1 inhibition. The anti-tumor response was triggered by anti-CD27 antibody during the vaccine priming phase, which enhanced HER2-specific CD4+ T cells. Critically, we found that HER2 specific CD4+ T cell responses allowed for anti-tumor responses that persisted after CD8+ T cell depletion, indicating a direct role for antigen-specific CD4+ T cells independent of CD8+ T cells. Collectively, our results support a central role for antigen-specific CD27+ CD4+ T cells in cancer vaccination. These data support the addition of CD27 agonism to improve the therapeutic index of cancer vaccines and potentially enhance responses to immune checkpoint blockade in refractory cancers. Citation Format: Bin-Jin Hwang, Erika Crosby, Timothy Trotter, Li-Chung Tsao, Tao Wang, Congxiao Liu, Xiao Yang, Gangjun Lei, Junping Wei, Xingru Ma, Bushanqing Liu, Amy Hobeika, Michael Morse, Tibor Keler, Li-Zhen He, Herbert Kim Lyerly, Zachary Hartman. Enhancing the strength and durability of vaccine-induced anti-tumor immunity with CD27 agonism of CD4+ T cells [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 5296.

Abstract 2966: Senescent cancer cell vaccines induce cytotoxic T cell responses targeting primary tumors and disseminated tumor cells

Abstract Diverse conventional cancer therapies, including genotoxic agents and cell cycle or cell division-targeting drugs, can trigger cancer cell senescence. Senescent cells (SnCs) induced by cancer therapy often display unrepaired chromosomal damage but persist indefinitely. SnCs remain metabolically active and display distinct alterations in transcription, secretion, and membrane protein expression/presentation. While initially viewed as a favorable outcome and likely tumor-suppressive mechanism, therapy-induced senescence has more recently been recognized as contributing to resistance, recurrence and metastasis. Adverse effects may be mediated in part by release of inflammatory mediators as components of the senescence-associated secretory phenotype (SASP). Recent studies have argued for reconsidering the potential benefits of therapy-induced senescence, especially in modulating the tumor microenvironment to potentiate anti-tumor immunity and potentiate immunotherapy. We have explored the potential for SnCs to serve as vaccines, building upon prior findings where we demonstrated the immunogenic senescence triggered by the combination of ionizing radiation (IR) and the PARP1/2 inhibitor veliparib. We find that SnCs are avidly taken up by type I conventional, CD11c+/CD103+ dendritic cells (DCs), promoting their activation and maturation. Thereby, SnCs promote DC function in T cell priming and stimulation. The capacity of SnCs to activate DCs depends on how the SnCs are formed, with our results confirming IR+veliparib induces high immunogenicity and implicating a distinct SASP in these effects. On the other hand, blocking STING signaling limits SnC activation of DCs. In vivo experiments with the murine tumor models CT26 and 4T1 suggest that both SnCs and SnC-pulsed DCs serve as effective anti-tumor vaccines. They not only confer protective immunity against tumor engraftment but also act as therapeutic vaccines, inhibiting both primary and disseminated tumor growth, and synergize with radiotherapy and immune checkpoint blockade. While direct administration of tumor-derived SnCs to patients may raise safety concerns, pulsing autologous DCs with tumor SnCs may help drive anti-tumor immune response, offering a promising path toward personalized cancer immunotherapy. Citation Format: Yue Liu, Joanna Pagacz, Donald J. Wolfgeher, Stephen J. Kron. Senescent cancer cell vaccines induce cytotoxic T cell responses targeting primary tumors and disseminated tumor cells [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 2966.

Emerging potential of immunopeptidomics by mass spectrometry in cancer immunotherapy.

With significant advances in analytical technologies, research in the field of cancer immunotherapy, such as adoptive T cell therapy, cancer vaccine, and immune checkpoint blockade (ICB), is currently gaining tremendous momentum. Since the efficacy of cancer immunotherapy is recognized only by a minority of patients, more potent tumor-specific antigens (TSAs, also known as neoantigens) and predictive markers for treatment response are of great interest. In cancer immunity, immunopeptides, presented by human leukocyte antigen (HLA) class I, play a role as initiating mediators of immunogenicity. The latest advancement in the interdisciplinary multiomics approach has rapidly enlightened us about the identity of the "dark matter" of cancer and the associated immunopeptides. In this field, mass spectrometry (MS) is a viable option to select because of the naturally processed and actually presented TSA candidates in order to grasp the whole picture of the immunopeptidome. In the past few years the search space has been enlarged by the multiomics approach, the sensitivity of mass spectrometers has been improved, and deep/machine-learning-supported peptide search algorithms have taken immunopeptidomics to the next level. In this review, along with the introduction of key technical advancements in immunopeptidomics, the potential and further directions of immunopeptidomics will be reviewed from the perspective of cancer immunotherapy.

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

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

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

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

IMMUNOTHERAPY OF CANCER: IMMUNE CHECKPOINT BLOCKERS, VACCINES AND ADOPTIVE T CELL THERAPIES

The clinical effectiveness of the three dominant forms of cancer immunotherapy (ITx): Immune checkpoint inhibition (ICI), adoptive cell therapies (ACT) and cancer vaccines (Vx) all require the ability of cancer tissues to attract tumor specific cytotoxic T cells (CTLs) and support their local effector function. For this reason, “cold” tumors, which lack CTL infiltration are uniformly nonresponsive to immune therapies and are less responsive to chemo- and radiotherapy, which effectiveness also involves immune phenomena. Our group has developed three groups of strategies to eliminate the “cold” tumor phenotype and to enhance allow effectiveness of the above forms of therapy of solid tumors: 1) Cell-based immunotherapies of cancer with dendritic cells (DC), used as live vaccines or intratumorally injected live adjuvants; 2) DC-induced multi-epitope-specific CTLs; and 3) Combinatorial reprograming of tumor microenvironments (TME), using different classes of adjuvants to enhance local infiltration of immune cells. Preclinical data and the results of the recently completed clinical trials will be discussed.

Blockade of SIRPα-CD47 axis by anti-SIRPα antibody enhances anti-tumor activity of DXd antibody-drug conjugates.

Signal regulatory protein alpha (SIRPα) is an immune inhibitory receptor on myeloid cells including macrophages and dendritic cells, which binds to CD47, a ubiquitous self-associated molecule. SIRPα-CD47 interaction is exploited by cancer cells to suppress anti-tumor activity of myeloid cells, therefore emerging as a novel immune checkpoint for cancer immunotherapy. In blood cancer, several SIRPα-CD47 blockers have shown encouraging monotherapy activity. However, the anti-tumor activity of SIRPα-CD47 blockers in solid tumors seems limited, suggesting the need for combination therapies to fully exploit the myeloid immune checkpoint in solid tumors. Here we tested whether combination of SIRPα-CD47 blocker with antibody-drug conjugate bearing a topoisomerase I inhibitor DXd (DXd-ADC) would enhance anti-tumor activity in solid tumors. To this end, DS-1103a, a newly developed anti-human SIRPα antibody (Ab), was assessed for the potential combination benefit with datopotamab deruxtecan (Dato-DXd) and trastuzumab deruxtecan (T-DXd), DXd-ADCs targeting human trophoblast cell-surface antigen 2 and human epidermal growth factor receptor 2, respectively. DS-1103a inhibited SIRPα-CD47 interaction and enhanced antibody-dependent cellular phagocytosis of Dato-DXd and T-DXd against human cancer cells. In a whole cancer cell vaccination model, vaccination with DXd-treated cancer cells led to activation of tumor-specific T cells when combined with an anti-mouse SIRPα (anti-mSIRPα) Ab, implying the benefit of combining DXd-ADCs with anti-SIRPα Ab on anti-tumor immunity. Furthermore, in syngeneic mouse models, both Dato-DXd and T-DXd combination with anti-mSIRPα Ab showed stronger anti-tumor activity over the monotherapies. Taken together, this study provides a preclinical rationale of novel therapies for solid tumors combining SIRPα-CD47 blockers with DXd-ADCs.

A mitochondria-targeting dihydroartemisinin derivative as a reactive oxygen species -based immunogenic cell death inducer

Immunogenic cell death (ICD) can activate the anticancer immune response and its occurrence requires high reliance on oxidative stress. Inducing mitochondrial reactive oxygen species (ROS) is a desirable capability for ICD inducers. However, in the category of ICD-associated drugs, numerous reported ICD inducers are a series of anthracyclines and weak in ICD induction. Herein, a mitochondria-targeting dihydroartemisinin derivative (T-D) was synthesized by conjugating triphenylphosphonium (TPP) to dihydroartemisinin (DHA). T-D can selectively accumulate in mitochondria to trigger ROS generation, leading to the loss of mitochondrial membrane potential (ΔΨm) and ER stress. Notably, T-D exhibits far more potent ICD-inducing properties than its parent compound. Invivo, T-D-treated breast cancer cell vaccine inhibits metastasis to the lungs and tumor growth. These results indicate that T-D is an excellent ROS-based ICD inducer with the specific function of trigging vigorous ROS in mitochondria and sets an example for incorporating artemisinin-based drugs into the ICD field.