Adoptive Cell Transfer Therapy Research Articles

Immune Checkpoint Inhibitors in HBV-Caused Hepatocellular Carcinoma Therapy

Hepatitis B virus (HBV) infection is the main risk factor for the development of hepatocellular carcinoma (HCC), the most common type of liver cancer, with high incidence and mortality worldwide. Surgery, liver transplantation, and ablation therapies have been used to treat early HBV-caused HCC (HBV-HCC); meanwhile, in the advanced stage, chemoradiotherapy and drug-targeted therapy are regularly considered, but with limited efficacy. Recently, immunotherapies, such as tumor vaccine therapy, adoptive cell transfer therapy, and immune checkpoint inhibitor therapy, have demonstrated promising efficacy in cancer treatment. In particular, immune checkpoint inhibitors can successfully prevent tumors from achieving immune escape and promote an anti-tumor response, thereby boosting the therapeutic effect in HBV-HCC. However, the advantages of immune checkpoint inhibitors in the treatment of HBV-HCC remain to be exploited. Here, we describe the basic characteristics and development of HBV-HCC and introduce current treatment strategies for HBV-HCC. Of note, we review the principles of immune checkpoint molecules, such as programmed cell death protein 1(PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in HBV-HCC, as well as related inhibitors being considered in the clinic. We also discuss the benefits of immune checkpoint inhibitors in the treatment of HBV-HCC and the efficacy of those inhibitors in HCC with various etiologies, aiming to provide insights into the use of immune checkpoint inhibitors for the treatment of HBV-HCC.

Chimeric antigen receptor-based therapies beyond cancer.

Adoptive cell transfer (ACT) therapies have gained renewed interest in the field of immunotherapy following the advent of chimeric antigen receptor (CAR) technology. This immunological breakthrough requires immune cell engineering with an artificial surface protein receptor for antigen-specific recognition coupled to an intracellular protein domain for cell activating functions. CAR-based ACT has successfully solved some hematological malignancies, and it is expected that other tumors may soon benefit from this approach. However, the potential of CAR technology is such that other immune-mediated disorders are beginning to profit from it. This review will focus on CAR-based ACT therapeutic areas other than oncology such as infection, allergy, autoimmunity, transplantation, and fibrotic repair. Herein, we discuss the results and limitations of preclinical and clinical studies in that regard.

Immunotherapy: Recent Advances and Its Future as a Neoadjuvant, Adjuvant, and Primary Treatment in Colorectal Cancer.

Immunotherapy in colorectal cancer (CRC) has made great strides within the past decade. Immune checkpoint inhibitors are a class of immunotherapy and have been shown to greatly improve patient outcomes in mismatch repair-deficient (dMMR) CRC. Now, they are part of the standard of care for this subset of CRC. Because of this, there has been a growing interest in the efficacy and timing of immunotherapy for other subsets of CRC, including locally advanced, metastatic, and microsatellite stable (MSS). In this review, we aim to examine the three main classes of immunotherapy for CRC-immune checkpoint inhibitors (ICIs), adoptive cell transfer therapy (ACT), and tumor vaccines-and discuss the most recent advances and future directions for each.

Regulatory T cell profiles in patients with N-methyl-ᴅ-aspartate receptor-antibody encephalitis.

Purpose Regulatory T cells (Tregs) have been implicated in the pathogenesis of several autoimmune disorders and used in adoptive cell transfer therapies. Neither have been explored in patients with autoimmune encephalitis where treated patient outcomes remain suboptimal with frequent relapses. Here, to identify new treatment strategies for autoimmune encephalitis, we sought to evaluate the proportion of circulating Tregs and Treg subpopulations in peripheral blood of patients with N-methyl-ᴅ-aspartate receptor-antibody encephalitis (NMDAR-Ab-E) and compared this with healthy controls. We compared the phenotype of peripheral blood Tregs in four adult NMDAR-Ab-E patients and four age- and sex-matched healthy controls using an 11-color flow cytometry assay panel for characterization of Tregs (CD4+ CD25+ FoxP3+) cells into naïve (chemokine receptor [CCR] 7+ CD45RA+), central memory (CCR7+ CD45RA-), and effector memory (CCR7- CD45RA-) cells. We also examined and compared the expression of the CCR6 by circulating Tregs and the respective Treg subpopulations between the study groups. The proportion of circulating Tregs was similar between patients with NMDAR-Ab-E and healthy controls but the proportion of naïve Tregs was lower in NMDAR-Ab-E patients (p = 0.0026). Additionally, the frequency of circulating effector memory Tregs was higher, and the proportion of circulating effector memory Tregs expressing CCR6 was lower, in NMDAR-Ab-E patients compared with healthy controls (p = 0.0026). Altered Treg homeostasis may be a feature of patients with NMDAR-Ab-E. Future studies with larger samples are warranted to validate these findings.

Towards next‐generation TIL therapy: TILs enriched in neoepitope‐specific T cells

Towards next‐generation TIL therapy: TILs enriched in neoepitope‐specific T cells

Cancer immunotherapeutics: transforming T-cells to superior cancer killers

The evolution of cancer treatment has marked a significant shift from traditional therapies such as surgery, chemotherapy, and radiation to more targeted T-cell-based therapies. The emergence of immune checkpoint inhibitors (ICIs) and gene-editing techniques like CRISPR/Cas9 has revolutionized cancer immunotherapy. Currently, adoptive cell transfer (ACT) therapies, such as tumor-infiltrating lymphocyte (TIL) therapy and chimeric antigen receptor (CAR) T-cell therapy, are giving promising results in melanoma and leukemia, respectively. Challenges occur to infiltrating solid tumors due to their dense stromal network, and abnormal vasculature has become a barrier. Hence, focusing on these strategies to modify cancer vasculature, immune suppression, and chemokines are major goals of current ACTs. The present review provides insight into the emerging cancer immune therapeutics, their advantages, and limitations. Emphasis is given to the recently discovered “superior” T-cells. These cells exhibit a unique ability to recognize multiple cancer-associated proteins effectively, making TIL therapy the future of cancer management.

Development of CAR-T cells specifically targeting cancer stem cell antigen DNAJB8 against solid tumours.

As therapy for solid tumours, various tumour antigens have been selected as targets, but CAR-T cells targeting these antigens have shown limited efficacy, in contrast to the effectiveness of CAR-T cells targeting haematological malignancies. In a previous report, we identified a cancer-testis antigen, DNAJB8. DNAJB8 plays a major role in tumorigenicity in cancer stem-like cells/cancer-initiating cells (CSCs/CICs). Here, we report a DNAJB8-reactive CAR yielding anti-tumour effects against renal cell carcinoma (RCC) and osteosarcoma. We constructed a second-generation chimeric antigen receptor (CAR) against HLA-A*24:02/DNAJB8-derived peptide (DNAJB_143) complex (B10 CAR). The reactivity of B10-CAR T cells against T2-A24 cells pulsed with the cognate peptide and an RCC and osteosarcoma cell lines were quantified. The effects of adoptive cell transfer (ACT) therapy were assessed using in vivo xenografted mice models. B10 CAR-T cells recognised DNAJB8_143-pulsed T2-A24 cells and HLA-A*24:02(+)/DNAJB8(+) renal cell carcinoma and osteosarcoma cell lines. Moreover, ACT using B10 CAR-T cells showed anti-tumour effects against RCC and osteosarcoma cells. B10 CAR-T cells could show specific cytotoxicity against RCC and osteosarcoma cells in vitro and in vivo. B10 CAR-T cells targeting the CSC/CIC antigen DNAJB8 might be a candidate immunotherapy for carcinoma and sarcoma.

Adoptive cell transfer therapy for melanoma.

Adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TILs) for melanoma is an example of the most successful cancer immune therapy. It achieves a durable complete response about ~20% of patients, and they might be cured. However, the ratio of patients with durable benefits is not high, and its complicated procedure prevents its diffusion. Therefore, many efforts to enhance the effect and simplify the protocol of TIL therapy have been made so far, resulting in the establishment of a simple and effective current TIL therapy that has been propagated to other institutes and countries. Moreover, TIL therapy and translational research using clinical samples derived from durable responders elucidate the important element for developing more effective cancer immune therapies in the future. This review introduced the brief history, attempts for the improvement and important findings elucidated by translational research of ACT for melanoma.

OR22-4 Homing of Antigen-specific Engineered Regulatory T Cells To Human Pancreatic Islets

Abstract The therapeutic application of regulatory T cells (Tregs) for the treatment of autoimmune disorders, although efficacious, has been limited by the scarcity of antigen-specific Tregs. If antigen-specific Tregs, capable of reaching the desired autoimmune target, could be produced on demand, antigen-specific immune suppression of autoimmune diseases would be achievable. One approach to endow T cells with a desired antigen-specificity uses chimeric T cell antigen-receptors (CAR) with antibody-type specificity. Adoptive cell transfer therapies with CAR-re-directed cytotoxic T cells, have shown impressive efficacy in the treatment of hematologic malignancies. Accordingly, employing such technology to re-direct Tregs to sites of autoimmune attack may be a useful therapeutic approach to alleviate a broad spectrum of diseases in which uncontrolled auto and alloimmune responses play a major role. We recently developed pancreatic beta-cell, antigen-specific, CAR Tregs (1) and explored their therapeutic potential against T1D in our humanized mouse model (2). Ours is the first successful, antigen-specific CAR-Treg treatment of T1D in a humanized mouse model that closely resembles the human disease. Based on our mice data, we believe treatment with pancreatic beta-cell, antigen-specific CAR-Tregs will allow for recovery and reconstitution of beta cells in human T1D patients as well. The purpose of this study was to determine if antigen-specific human CAR Tregs could also identify target and home to human pancreatic islets in culture as they do in mice. The study involved drawing 10 cc of blood 1-2 weeks prior to pancreas surgery; followed by collection of a small piece of pancreas (5 cc wedge) once the pancreas was removed for a clinical indication (cancer, pancreatitis). We first isolated Tregs from peripheral blood of these human donors and expanded them in vitro. Treg cells were genetically modified to express either a beta-cell antigen-specific (GAD65) CAR or an irrelevant (EPCAM) CAR construct together with GFP marker. CAR Tregs were selectively expanded in the presence of rhGAD65 antigen. Once pancreas tissue became available, it was processed for islet separation using the collagenase method. Pancreatic islets were then co-cultured with syngeneic CAR Tregs for 7 days. IncuCyte S3 Live-cell System (Sartorius) is a real-time system that automatically acquires and analyzes HD, phase and fluorescent images of cell cultures, around the clock, for 7 days, while cells remain undisturbed. Live immunofluorescence microscopy demonstrated the distinct homing of GAD65 CAR Tregs to islets as compared to control EPCAM CAR Tregs as early as 24 hours of co-culture. Importantly, proliferation of GAD65 CAR Tregs was clearly demonstrated within 72 hours. GAD65 CAR Treg cytokine profile from co-culture supernatant was characteristic of activated Tregs. 1 PATENT #WO2020097546 2 PATENT #US20200037586 Presentation: Monday, June 13, 2022 11:45 a.m. - 12:00 p.m.

Review Article: Immune Landscape and Immunotherapy Options in Cervical Carcinoma.

Simple SummaryCervical cancer is one of the most common cancers with a high mortality rate, especially in women of reproductive age. A lot of treatment modalities are being used in clinical practice but they come with a wide range of toxic side effects, the relapse of cancer, and a low disease-free survival rate. Immunotherapy has revolutionized the treatment landscape of cervical cancer as it focuses majorly on agents that stimulate the body’s own immune system against tumor cells. A deeper understanding of immune system players and immune perturbations in the onset and progression of cervical cancer can pave the way to better treatment with zero relapse. Immunotherapy holds the key to a cancer-free future. This review summarizes the immune players that are perturbed in cervical cancer, and immunotherapy options that are being exploited, alone or in combination, for the treatment of cervical carcinoma in women.Carcinoma of the cervix is one of the most common cancers that claims women’s lives every year. Despite preventive HPV vaccines and conventional cancer treatments, approximately 273,000 women succumb to cervical carcinoma every year. Immune system perturbations help malignant cells in immune evasion, tumor establishment, invasion, and metastasis. An insight into immune system players that promote or suppress cervical cancer is important for the development of more targeted therapies with the fewest side effects. Immunotherapy has emerged as the most compliant approach to target cancer because it utilizes a natural course of action to stimulate the immune system against cancer cells. The major immunotherapy approaches for cervical carcinoma include monoclonal antibodies, immune checkpoint blockade therapy, adoptive cell transfer therapies, and oncolytic viruses. In October 2021 the FDA approved pembrolizumab in combination with chemotherapy or bevacizumab as a first-line treatment for cervical cancer. A recent breakthrough has been made in the cancer immunotherapy regimen in which a monoclonal antibody dostarlimab was able to completely cure all colorectal cancer patients, with disease-free progression after 6 months and counting. This creates hope that immunotherapy may prove to be the final nail in the coffin of this centuries-long prevalent disease of “cancer”.

Research Progress in Alpha-fetoprotein-induced Immunosuppression of Liver Cancer.

Liver cancer is one of the most common malignant tumors, with limited treatment and 8.2% mortality. Liver cancer is the fourth leading cause of cancer-related deaths, which seriously endangers human life and health. Approximately 70% of liver cancer patients show increased serum Alpha- Fetoprotein (AFP) levels. AFP is the main diagnostic and prognostic indicator of liver cancer. AFP, a key marker of liver cancer, plays a crucial role in regulating the proliferation of tumor cells, apoptosis, and induction of cellular immune escape. High levels of AFP during embryonic development protect the embryos from maternal immune attack. AFP also promotes immune escape of liver cancer cells by inhibiting Tumor-Infiltrating Lymphocytes (TILs), Natural Killer cells (NK), Dendritic Cells (DC), and macrophages; thus, it is also used as a target antigen in immunotherapy for liver cancer. AFP is highly expressed in liver cancer cells. In addition to being used in the diagnosis of liver cancer, it has become a target of immunotherapy for liver cancer as a tumor-associated antigen. In immunotherapy, it was also confirmed that early AFP response was positively correlated with the efficacy of immunotherapy. Early AFP responders had longer PFS and OS than non-responders. At present, the methods of immunotherapy for liver cancer mainly include Adoptive Cell Transfer Therapy (ACT), tumor vaccine therapy, immune checkpoint inhibitors (ICIs) therapy, etc. A large number of studies have shown that AFP mainly plays a role in ACT and liver cancer vaccines. This review presents the research progress of AFP and immunosuppression of liver cancer.

Good and Bad Stroma in Pancreatic Cancer: Relevance of Functional States of Cancer-Associated Fibroblasts.

Simple SummaryRecent progress in research on the biology of cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDAC) indicates their diverse states and plasticity, which may lead to good and bad stroma, suppressing and promoting cancer progression, respectively. The characteristics of the stroma differ spatially, even within the same tumors, based on the balance between cancer-restraining CAF and cancer-promoting CAF proliferation at the site. These heterogeneous CAFs also influence the sensitivity of PDAC to anticancer therapeutics. Further preclinical and clinical studies will advance our understanding of the roles of CAFs in disease progression and aid the development of therapeutics that modulate or ameliorate the tumor microenvironment in PDAC.A well-known feature of human pancreatic ductal adenocarcinoma (PDAC) is the extensive proliferation of cancer-associated fibroblasts (CAFs) and highly fibrotic stroma. Recent evidence, based mainly on single-cell analyses, has identified various subsets of CAFs in PDAC mouse models. However, we do not know how these CAF subsets are involved in the progression and drug resistance of human PDAC. Additionally, it remains unclear whether these diverse CAFs have distinct origins and are indicators of genuinely distinct CAF lineages or reflect different states of the same CAFs depending on the tumor microenvironment. Interestingly, recent preclinical studies have started to characterize the nature of cancer-restraining CAFs and have identified their markers Meflin and collagen type I alpha 1. These studies have led to the development of strategies to induce changes in CAF phenotypes using chemical reagents or recombinant viruses, and some of them have been tested in clinical studies. These strategies have the unique potential to convert the so-called bad stroma to good stroma and may also have therapeutic implications for non-cancer diseases such as fibrotic diseases. Together with recently developed sophisticated strategies that specifically target distinct CAF subsets via adoptive cell transfer therapy, vaccination, and antibody–drug conjugates, any future findings arising from these clinical efforts may expand our understanding of the significance of CAF diversity in human PDAC.

Mouse pulmonary interstitial macrophages mediate the pro-tumorigenic effects of IL-9

Although IL-9 has potent anti-tumor activity in adoptive cell transfer therapy, some models suggest that it can promote tumor growth. Here, we show that IL-9 signaling is associated with poor outcomes in patients with various forms of lung cancer, and is required for lung tumor growth in multiple mouse models. CD4+ T cell-derived IL-9 promotes the expansion of both CD11c+ and CD11c− interstitial macrophage populations in lung tumor models. Mechanistically, the IL-9/macrophage axis requires arginase 1 (Arg1) to mediate tumor growth. Indeed, adoptive transfer of Arg1+ but not Arg1- lung macrophages to Il9r−/− mice promotes tumor growth. Moreover, targeting IL-9 signaling using macrophage-specific nanoparticles restricts lung tumor growth in mice. Lastly, elevated expression of IL-9R and Arg1 in tumor lesions is associated with poor prognosis in lung cancer patients. Thus, our study suggests the IL-9/macrophage/Arg1 axis is a potential therapeutic target for lung cancer therapy.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

TCR-induced FOXP3 expression by CD8+ T cells impairs their anti-tumor activity

Adoptive cell transfer therapy using CD8+ T lymphocytes showed promising results eradicating metastatic malignancies. However, several regulatory mechanisms limit its efficacy. We studied the role of the expression of the transcription factor FOXP3 on CD8+ T cell function and anti-tumor immunity. Here we show that suboptimal T cell receptor stimulation of CD8+ T cells upregulates FOXP3 in vitro. Similarly, CD8 T cells transferred into tumor-bearing mice upregulate FOXP3 in vivo. Cell-intrinsic loss of FOXP3 by CD8+ T cells resulted in improved functionality after TCR stimulation and better antitumor responses in vivo. Inhibition of the FOXP3/NFAT interaction likewise improved CD8+ T cell functionality. Transcriptomic analysis of cells after TCR stimulation revealed an enrichment of genes implicated in the response to IFN-γ, IFN-α, inflammatory response, IL-6/JAK/STAT, G2M checkpoint and IL-2/STAT signaling in FOXP3-deficient CD8+ T cells with respect to FOXP3-wt CD8+ T cells. Our results suggest that transient expression of FOXP3 by CD8+ T cells in the tumor microenvironment restrains their anti-tumor activity, with clear implications for improving T cell responses during immunotherapy.

Targets of immunotherapy for hepatocellular carcinoma: An update.

Hepatocellular carcinoma, the most common primary liver cancer, in an immunogenic tumor with a poor prognosis because these tumors are diagnosed at late stages. Although, surgical resection, ablation, liver transplant, and locoregional therapies are available for early stages; however, there are yet no effective treatment for advanced and recurrent tumors. Immune checkpoint inhibitor therapy and adoptive cell transfer therapy has gained the popularity with some positive results because these therapies overcome anergy and systemic immune suppression. However, still there is a lack of an effective treatment and thus there is an unmet need of a novel treatment. At present, the focus of the research is on oncolytic viral therapy and combination therapy where therapies including radiotherapy, immune checkpoint therapy, adoptive cell transfer therapy, and vaccines are combined to get an additive or synergistic effect enhancing the immune response of the liver with a cytotoxic effect on tumor cells. This review discusses the recent key development, the basis of drug resistance, immune evasion, immune tolerance, the available therapies based on stage of the tumor, and the ongoing clinical trials on immune checkpoint inhibitor therapy, adoptive cell transfer therapy, oncolytic viral vaccine therapy, and combination therapy.

Efficacy and Safety of Immunotherapy for Cervical Cancer-A Systematic Review of Clinical Trials.

Simple SummaryCervical cancer is the 4th leading cause of cancer deaths in women worldwide. Surgery, chemotherapy, radiotherapy and chemoradiation therapy are routinely used in the treatment of cervical cancer, while immunotherapy remains a novelty. The aim of our systematic review was to provide an extensive overview of the efficacy and safety of immunotherapy in cervical cancer patients. A total of 50 clinical trials assessed immune checkpoint inhibitors, therapeutic vaccines and adaptive cell transfer therapy. Overall, immunotherapy showed an acceptable safety profile. While the level of evidence on efficacy is still low, promising results, including few complete remissions in heavily pretreated women with metastatic disease, have been observed. Furthermore, a recent phase III trial assessing pembrolizumab in combination with chemotherapy (±bevacizumab) demonstrated a prolonged overall survival and has now led to a new standard of care for first-line systemic treatment in persistent, metastatic or recurrent cervical cancer patients.Purpose: To systematically review the current body of evidence on the efficacy and safety of immunotherapy for cervical cancer (CC). Material and Methods: Medline, the Cochrane Central Register of Controlled Trials and Web of Science were searched for prospective trials assessing immunotherapy in CC patients in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Full-text articles in English and German reporting outcomes of survival, response rates or safety were eligible. Results: Of 4655 screened studies, 51 were included (immune checkpoint inhibitors (ICI) n=20; therapeutic vaccines n = 25; adoptive cell transfer therapy n=9). Of these, one qualified as a phase III randomized controlled trial and demonstrated increased overall survival following treatment with pembrolizumab, chemotherapy and bevacizumab. A minority of studies included a control group (n = 7) or more than 50 patients (n = 15). Overall, response rates were low to moderate. No response to ICIs was seen in PD-L1 negative patients. However, few remarkable results were achieved in heavily pretreated patients. There were no safety concerns in any of the included studies. Conclusion: Strong evidence on the efficacy of strategies to treat recurrent or metastatic cervical cancer is currently limited to pembrolizumab in combination with chemotherapy and bevacizumab, which substantiates an urgent need for large confirmatory trials on alternative immunotherapies. Overall, there is sound evidence on the safety of immunotherapy in CC.

Immunotherapy in liver transplantation for hepatocellular carcinoma: Pros and cons.

Liver transplantation (LT) has emerged as a curative strategy for hepatocellular carcinoma (HCC), but contributes to a higher predisposition to HCC recurrence in the immunosuppression context, especially for tumors beyond the Milan criteria. Although immunotherapy has dramatically improved survival for immunocompetent patients and has become the standard of care for a variety of tumors, including HCC, it is mainly used outside the scope of organ transplantation owing to potentially fatal allograft rejection. Nevertheless, accumulative evidence has expanded the therapeutic paradigms of immunotherapy for HCC, from downstaging or bridging management in the pretransplant setting to the salvage or adjuvant strategy in the posttransplant setting. Generally, immunotherapy mainly includes immune checkpoint inhibitors (ICIs), adoptive cell transfer (ACT) and vaccine therapy. ICIs, followed by ACT, have been most investigated in LT, with some promising results. Because of the complex tumor microenvironment and immunoreactivity when immunosuppressants are combined with immunotherapy, it is difficult to reach formulations for immunosuppressant adjustment and the optimal selection of immunotherapy as well as patients. In addition, the absence of effective biomarkers for identifying rejection and tumor response is still an unresolved barrier to successful clinical immunotherapy applications for LT. In this review, we comprehensively summarize the available evidence of immunotherapy used in LT that is specific to HCC. Moreover, we discuss clinically concerning issues regarding the concurrent goals of graft protection and antitumor response.

Ruthenium complexes boost NK cell immunotherapy via sensitizing triple-negative breast cancer and shaping immuno-microenvironment

Discovery of effective chemical sensitizers to synergize with natural killer cells immunotherapy is urgently desired to overcome its unsatisfactory efficacy in clinic. Herein, we design a series of ruthenium (Ru) polypyridyl complex to systematically explore their potentials in facilitating NK cells treatment. Intriguingly, the chemical structure greatly determines the activity of Ru complexes, while only RuPOP effectively regulates the immuno-suppressors and target proteins within tumor cells. This unique property contributes to its good capability in enhancing the sensitivity of MDA-MB-231 cells to NK cells from cancer patients. Furthermore, besides directly damaging tumor cells, RuPOP pretreatment together with NK cells can also induce robust ROS generation, activate multiple apoptosis-related receptors like TNF-R1, DR5, Fas and maximize the interactions between NK and tumor cells via up-regulating NKG2D and its multiple ligands to trigger caspase 3-dependent apoptosis. Moreover, the combination treatment exhibits high in vivo therapeutic efficacy against breast tumor through boosting the infiltration of NK cells and reducing the protumoral capability of myeloid-derived suppressor cells (MDSC). This study sheds lights for designing metal complexes to potentiate NK cells immunotherapy with clear action mechanisms and provides important information for developing more effective adoptive cell transfer therapy in clinic.

Circular RNA cancer vaccines drive immunity in hard-to-treat malignancies.

Rationale: Messenger RNA (mRNA) vaccine outperforms other kinds of cancer immunotherapy due to its high response rates, easy preparation, and wide applicability, which is considered as one of the most promising forms of next-generation cancer therapies. However, the inherent instability and insufficient protein expression duration of mRNA limit the efficacy and widespread application of the vaccine.Methods: Here, we first tested the possibility of a novel circular RNA (circRNA) platform for protein expression and compare its duration with linear RNA. Then, we developed a lipid nanoparticle (LNP) system for circRNA delivery in vitro and in vivo. Next, the innate and adaptive immune response of circRNA-LNP complex was evaluated in vivo. The anti-tumor efficacy of circRNA-LNP was further confirmed in three tumor models. Finally, the possibility of combination therapy with circRNA-LNP and adoptive cell transfer therapy was further investigated in a late-stage tumor model.Results: We successfully increased the stability of the RNA vaccine by circularizing the linear RNA molecules to form highly stable circRNA molecules which exhibited durable protein expression ability. By encapsulating the antigen-coding circRNA in LNP enabling in vivo expression, we established a novel circRNA vaccine platform, which was capable of triggering robust innate and adaptive immune activation and showed superior anti-tumor efficacy in multiple mouse tumor models.Conclusions: Overall, our circRNA vaccine platform provides a novel prospect for the development of cancer RNA vaccines in a wide range of hard-to-treat malignancies.