Field Of Cancer Immunotherapy Research Articles

Neoadjuvant immune checkpoint inhibition in the management of glioblastoma: Exploring a new frontier.

Brain tumors are one of the leading causes of cancer related death in both the adult and pediatric patient population. Gliomas represent a cohort of brain tumors derived from glial cell lineages which include astrocytomas, oligodendrogliomas and glioblastomas (GBMs). These tumors are known to grow aggressively and have a high lethality with GBM being the most aggressive tumor in this group. Currently, few treatment options exist for GBM outside of surgical resection, radiation therapy and chemotherapy. While these measures have been shown to marginally improve patient survival, patients, especially those diagnosed with GBM, often experience a recurrence of their disease. Following disease recurrence, treatment options become more limited as additional surgical resections can pose life threatening risk to the patient, patients may be ineligible for additional radiation, and the recurrent tumor may be resistant to chemotherapy. Immune checkpoint inhibitors (ICIs) have revolutionized the field of cancer immunotherapy as many patients with cancers residing outside the central nervous system (CNS) have experienced a survival benefit from this treatment modality. It has often been observed that this survival benefit is increased following neoadjuvant administration of immune checkpoint inhibitors as tumor antigen is still present in the patient which enables a more robust anti-tumor immune response. Interestingly, results for ICI-based studies for patients with GBM have been largely disappointing which is a stark contrast from the success this treatment modality has had in non-central nervous system cancers. In this review, we will discuss the various benefits of neoadjuvant immune checkpoint inhibition such as how this approach reduces tumor burden and allows for a greater induction of an anti-tumor immune response. Additionally, we will discuss several non-CNS cancers where neoadjuvant immune checkpoint inhibition has been successful and discuss why we believe this approach may provide a survival benefit for GBM patients. We hope this manuscript will foster future studies aimed at exploring whether this approach may be beneficial for patients diagnosed with GBM.

Head and Neck Cancer Immunotherapy: Molecular Biological Aspects of Preclinical and Clinical Research.

Breakthrough research in the field of immune checkpoint inhibitors and the development of a human papilloma virus vaccine triggered a plethora of research in the field of cancer immunotherapy. Both had significant effects on the treatment of head and neck squamous cell carcinoma. The advent of preclinical models and multidisciplinary approaches including bioinformatics, genetic engineering, clinical oncology, and immunology helped in the development of tumour-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T-cell therapy. Here, we discuss different immunotherapies such as adoptive T-cell transfer, immune checkpoint inhibitors, interleukins, and cancer vaccines for the treatment of head and neck cancer. This review showcases the intrinsic relation between the understanding and implementation of basic biology and clinical practice. We also address potential limitations of each immunotherapy approach and the advantages of personalized immunotherapy. Overall, the aim of this review is to encourage further research in the field of immunotherapy for head and neck cancer.

Exosomes: A potential tool for immunotherapy of ovarian cancer.

Ovarian cancer is a malignant tumor of the female reproductive system, with a very poor prognosis and high mortality rates. Chemotherapy and radiotherapy are the most common treatments for ovarian cancer, with unsatisfactory results. Exosomes are a subpopulation of extracellular vesicles, which have a diameter of approximately 30-100 nm and are secreted by many different types of cells in various body fluids. Exosomes are highly stable and are effective carriers of immunotherapeutic drugs. Recent studies have shown that exosomes are involved in various cellular responses in the tumor microenvironment, influencing the development and therapeutic efficacy of ovarian cancer, and exhibiting dual roles in inhibiting and promoting tumor development. Exosomes also contain a variety of genes related to ovarian cancer immunotherapy that could be potential biomarkers for ovarian cancer diagnosis and prognosis. Undoubtedly, exosomes have great therapeutic potential in the field of ovarian cancer immunotherapy. However, translation of this idea to the clinic has not occurred. Therefore, it is important to understand how exosomes could be used in ovarian cancer immunotherapy to regulate tumor progression. In this review, we summarize the biomarkers of exosomes in different body fluids related to immunotherapy in ovarian cancer and the potential mechanisms by which exosomes influence immunotherapeutic response. We also discuss the prospects for clinical application of exosome-based immunotherapy in ovarian cancer.

WT1 Pulsed Human CD141+ Dendritic Cell Vaccine Has High Potential in Solid Tumor-Targeted Immunotherapy.

Dendritic cells (DC) are powerful cells that play critical roles in anti-tumor immunity, and their use in cancer immunotherapy unlocks hidden capabilities as an effective therapeutic. In order to maximize the full potential of DC, we developed a DC vaccine named CellgramDC-WT1 (CDW). CDW was pulsed with WT1, an antigen commonly expressed in solid tumors, and induced with zoledronate to aid DC maturation. Although our previous study focused on using Rg3 as an inducer of DC maturation, problems with quality control and access led us to choose zoledronate as a better alternative. Furthermore, CDW secreted IL-12 and IFN-γ, which induced the differentiation of naïve T cells to active CD8+ T cells and elicited cytotoxic T lymphocyte (CTL) response against cancer cells with WT1 antigens. By confirming the identity and function of CDW, we believe CDW is an improved DC vaccine and holds promising potential in the field of cancer immunotherapy.

The role of extratumoral and intratumoral microorganisms in cancer immunotherapy

<p>Microbiome is ubiquitous in human and distributed in not only normal organs such as gut, but also in tumor tissues of the host. Numerous studies have proven that the extratumoral microbiota (mainly gut microbiota) has a close relationship with the local and systemic immune systems of the host. The bacteria, viruses and fungi in gut can influence the activity of innate and adaptive immune cells, affecting the outcomes of immunotherapy. In addition to microbiota in the gut, special microbiota (intratumoral microbiota) exists in the tumor microenvironment (TME), which provides a critical niche for anaerobic or facultative anaerobic bacteria to colonize and proliferate. Intratumoral microorganisms or their metabolites can substantially improve the immunosuppressive of the TME, reactivate immune cells, or recruit activated immune cells, indicating a potential effect on immunotherapy. Furthermore, with the development of synthetic biology, some tumor-targeting bacteria can be used as a biological chassis for the accurate delivery of different immunotherapeutic agents to tumor core through genetic programming technologies, enriching immunotherapy paradigms. In this review, we summarize the recent developments in effect of human microbiota, especially microorganisms in the TME, on immunoregulation, and discuss their potential application in the field of cancer immunotherapy. We also describe the ways to take advantage of genetically engineered bacteria targeting the TME to strengthen the efficacy of immunotherapy against cancer. Additionally, the remaining questions and further directions for microbiota application in immunotherapy are also discussed.</p>

Cell membrane-specific self-assembly of peptide nanomedicine induces tumor immunogenic death to enhance cancer therapy.

Immunogenic cell death (ICD), as an unusual cell death pattern, mediates cancer cells to release a series of damage-associated molecular patterns (DAMPs), and is widely used in the field of cancer immunotherapy. Injuring the cell membrane can serve as a novel ICD initiation strategy. In this study, a peptide nanomedicine (PNpC) is designed using the fragment CM11 of cecropin, which is effective in disrupting cell membranes because of its α-helical structure. PNpC self-assembles in situ in the presence of high levels of alkaline phosphatase (ALP) on the tumor cell membrane, transforming from nanoparticles to nanofibers, which reduces the cellular internalization of the nanomedicine and increases the interaction between CM11 and tumor cell membranes. Both in vitro and in vivo results indicate that PNpC plays a significant role in killing tumor cells by triggering ICD. The ICD induced by the destruction of the cancer cell membrane is accompanied by the release of DAMPs, which promotes the maturation of DCs and facilitates the presentation of tumor-associated antigens (TAA), resulting in the infiltration of CD8+ T cells. We believe that PNpC can trigger ICD while killing cancer cells, providing a new reference for cancer immunotherapy.

The 21st International Conference on Progress in Vaccination against Cancer (PIVAC-22), September 26-28, 2022, Turin, Italy.

The 21st international congress on Progress in Vaccination against Cancer (PIVAC-22, https://www.pivac22.it/) was held from September 26 to September 28, 2022, at the Molecular Biotechnology Center "Guido Tarone" in Turin, Italy. The meeting covered the most recent advances in the field of cancer immunotherapy, with a focus on the tumor microenvironment, and addressed how alterations to the microenvironment's molecular and metabolic features and the microbiota impact upon the response to immunotherapy.

The Role of Immune Checkpoint Inhibitors in Cancer Therapy

Over the years, immune checkpoint inhibitors (CPIs) have become a powerful treatment strategy in the field of cancer immunotherapy. In the last decade, the number of FDA-approved CPIs has been increasing prominently, opening new horizons for the treatment of a wide range of tumor types. Pointedly, three immune checkpoint molecules have been under extensive research, which include cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1) and its ligand-1 (PD-L1). Despite remarkable success, not all patients respond positively to therapy, which highlights the complexity of the tumor microenvironment (TME) and immune system. This has led to the identification of molecular biomarkers to predict response and toxicity. In addition, there has been an emerging focus on developing new delivery and targeting approaches for better drug efficacy and potency. In this review, we highlight the mechanism of action of major CPIs, their clinical impact, variation in effectiveness, response prediction, updated clinical indications, current challenges and limitations, promising novel approaches, and future directions.

Targeting Co-Stimulatory Receptors of the TNF Superfamily for Cancer Immunotherapy.

The clinical approval of immune checkpoint inhibitors is an important advancement in the field of cancer immunotherapy. However, the percentage of beneficiaries is still limited and it is becoming clear that combination therapies are required to further enhance the treatment efficacy. The potential of strategies targeting the immunoregulatory network by "hitting the gas pedal" as opposed to "blocking the brakes" is being recognized and intensively investigated. Hence, next to immune checkpoint inhibitors, agonists of co-stimulatory receptors of the tumor necrosis factor superfamily (TNF-SF) are emerging as promising options to expand the immunomodulatory toolbox. In this review the development of different categories of recombinant antibody and ligand-based agonists of 4-1BB, OX40, and GITR is summarized and discussed in the context of the challenges presented by the structural and mechanistical features of the TNFR-SF. An overview of current formats, trends, and clinical studies is provided.

CAR Triggered Release of Type-1 Interferon Limits CAR T-Cell Activities by an Artificial Negative Autocrine Loop

The advent of chimeric antigen receptor (CAR) T cells expedited the field of cancer immunotherapy enabling durable remissions in patients with refractory hematological malignancies. T cells redirected for universal cytokine-mediated killing (TRUCKs), commonly referred to as "fourth generation" CAR T-cells, are designed to release engineered payloads upon CAR-induced T-cell activation. Building on the TRUCK technology, we aimed to generate CAR T-cells with a CAR-inducible artificial, self-limiting autocrine loop. To this end, we engineered CAR T-cells with CAR triggered secretion of type-1 interferons (IFNs). At baseline, IFNα and IFNβ CAR T-cells showed similar capacities in cytotoxicity and cytokine secretion compared to conventional CAR T-cells. However, under "stress" conditions of repetitive rounds of antigen stimulation using BxPC-3 pancreas carcinoma cells as targets, anti-tumor activity faded in later rounds while being fully active in destructing carcinoma cells during first rounds of stimulation. Mechanistically, the decline in activity was primarily based on type-1 IFN augmented CAR T-cell apoptosis, which was far less the case for CAR T-cells without IFN release. Such autocrine self-limiting loops can be used for applications where transient CAR T-cell activity and persistence upon target recognition is desired to avoid lasting toxicities.

Emerging Sonodynamic Therapy-Based Nanomedicines for Cancer Immunotherapy.

Cancer immunotherapy effect can be greatly enhanced by other methods to induce immunogenic cell death (ICD), which has profoundly affected immunotherapy as a highly efficient paradigm. However, these treatments have significant limitations, either by causing damage of the immune system or limited to superficial tumors. Sonodynamic therapy (SDT) can induce ICD to promote immunotherapy without affecting the immune system because of its excellent spatiotemporal selectivity and low side effects. Nevertheless, SDT is still limited by low reactive oxygen species yield and the complex tumor microenvironment. Recently, some emerging SDT-based nanomedicines have made numerous attractive and encouraging achievements in the field of cancer immunotherapy due to high immunotherapeutic efficiency. However, this cross-cutting field of research is still far from being widely explored due to huge professional barriers. Herein, the characteristics of the tumor immune microenvironment and the mechanisms of ICD are firstly systematically summarized. Subsequently, the therapeutic mechanism of SDT is fully summarized, and the advantages and limitations of SDT are discussed. The representative advances of SDT-based nanomedicines for cancer immunotherapy are further highlighted. Finally, the application prospects and challenges of SDT-based immunotherapy in future clinical translation are discussed.

Use of a Foamy-Virus Vector System to Produce an 'Off-the-Shelf' Fcγ-CR-T Cell Product for the Treatment of Hematological and Solid Tumour Malignancies

Introduction Chimeric antigen receptor (CAR) T cells have transformed the field of cancer immunotherapy. Other approaches, such as the use of Fc gamma chimeric receptor (Fcγ-CR)-T cells have further expanded the applicability of such therapies in both solid and liquid tumours with the added benefit of tackling some of the hurdles associated with CAR-T therapies (such as loss or down-regulation of the target antigen). Previous studies have generated Fcγ-CR-T cells from autologous cells, which carry several limitations (prolonged production time, costly, manufacturing failure), whereas the use of Lentiviral vectors (LV) is endowed with extra limitations (packaging limits and mutagenesis risk). Our group has developed an in-house Fcγ-CR-T cell product, using a safer to LV, foamy virus (FV) vector and T cells from healthy donors. Materials We constructed FV vectors expressing the CD16 V158, which has higher Fc binding and is associated with higher tumour killing, the T cell stimulatory molecule CD3ζ and the costimulatory molecule CD28 and an EFP1a promoter. 2nd generation LV vector backbones were purchased from a commercial vendor. Peripheral blood from healthy individuals were used as T cell sources. T cells were activated by anti-CD3/CD28 beads and transduced with CD16-CR, LV or FV vectors. Transduction efficiency was assayed by flow cytometry (FCM) using an anti-CD16 antibody (Ab), on day 3. The human cell lines Raji, Panc01 and DLD-1 were used for functional assays, in the presence of the Abs Rituximab (anti-CD20) and Cetuximab (anti-EGFR), respectively, at a concentration of 0.1 ug/ml. The CR's Ab-binding capacity was assessed by incubating the CD16-CRs with the Abs for 30mins, followed by an anti-human Ig PE antibody and the related fluorescence intensity was assessed. To determine whether Ab binding to CD16-CR can promote aggregation of effector and target cells, CFSE-labelled target cells were mixed with Ab-coated CD16-CRs for 60 mins and the formation of CFSE-PE doublets was assessed by FCM. Their cytotoxic effect was evaluated against the CFSE-labelled Raji or DLD-1 or Panc01 cells at different ratios (5:1, 10:1) for 18 hours, in the presence of Rituximab (0.1ug/ml) or Cetuximab (0.1ug/ml), respectively. The % of live cells was assessed by flow cytometry and calculated as: [1-live targets (sample)/live targets (control)]x100. Results LV and FV vector titers were between 3-5x10^6 TU/ml and 4-5x10^6 TU/ml, respectively. Transduction efficiency ranged from 58.3-69.2% with FV vectors (MOI 3-5) and 85.2-85.9% with LV vectors (MOI 10-20). The Ab-binding capacity of FV-CD16-CRs was determined to be 68.7% (SEM 2.3) and 71.3% (SEM 3.1), (n=3) for Rituximab and Cetuximab, respectively, whereas that of LV-CD16-CRs was 72.1 (SEM 3.3) and 76.5 (SEM 2.8), (n=3), respectively. Cell aggregation of effector and target cells, assessed as doublets, was: (i) 32%, 39% and 36% for FV-CD16-CRs and (ii) 26%, 31% and 29% for LV-CD16-CRs, coated with Rituximab and Cetuximab, respectively, and it was specific for the Raji, DLD-1 and Panc01 cells, respectively. Next, we assessed whether CD16-CR T cells were able to kill target cells in the presence of specific antibodies. Results showed that the FV-CD16-CR-induced % cell lysis was: (i) 26.3% and 51.5% at 5:1 and 10:1 ratio, respectively, in the presence of Rituximab and Raji cells, (ii) 41.5% and 57.7% at 5:1 and 10:1 ratio, respectively, in the presence of Cetuximab and DLD1 cells and (iii) 39.4% and 57.3% at 5:1 and 10:1 ratio, respectively, in the presence of Cetuximab and Panc01 cells. For LV-CD16-CRs the respective % lysis was comparable. More importantly, this lysis was shown to be specific (no lysis noted with untransduced T cells) and significantly lower in the absence of the antibodies. Conclusion Our group has developed for the first time a FV vector for the generation of CD16-CR T cells, with an efficient gene transfer to human T cells and with potent in vitro cytotoxic properties, similar to their LV-derived counterpart. Overall, we provide a proof of concept that allogeneic, in-house Fcγ-CR-T cells derived from a non-pathogenic viral backbone such as the FV, could be a safe, efficient and affordable alternative to LV-derived vectors for immunotherapy. Our future aim is to further modify these Fcγ-CR-T cells, by interfering with immune checkpoint molecules, in order to achieve better tumour penetration and tackle the anergy induced by the tumour microenvironment.

IMMU-02. STANDARDIZATION OF THERAPY AND MANUFACTURING USING TUMOR-ASSOCIATED ANTIGEN-STIMULATED AUTOLOGOUS DENDRITIC CELLS CO-CULTURED WITH CYTOKINE-INDUCED KILLER CELLS IN CANCER IMMUNOTHERAPY

Abstract BACKGROUND The application of DC-CIK in the field of cancer immunotherapy has been shown to be an effective treatment. However, the cost of DC-CIK treatment is prohibitive for many patients, and the lack of standard manufacturing processes and treatment strategies are the main limitations. METHODS Our experiments used tumor lysate instead of tumor cell line as tumor-associated antigen source with DCs co-culture. We provide the most efficient method for obtaining autologous DC-CIK cells from peripheral blood. Flow cytometry was used to evaluate DCs activation, CBA assay was used to quantify cytokines secreted by CIK cells, and the antitumor activity of DC-CIK was evaluated in vitro by K562 cell line. RESULTS We demonstrate that the manufacturing process of employing frozen Peripheral Blood Mononuclear Cells (PBMCs) can balance patient’s comfort and economic benefits. DC-CIK can effectively upgrade the immunological specificity of CIK cells to tumors in the presence of tumor-associated antigen. In vitro experiments showed that when the number of DC: CIK cells was co-cultured in 1:20 ratio on the 14th day, the amount of cytokine secreted by CIK cells was the largest, and the anti-tumor immune effect was the most potent. When the number of CIK: K562 cells was in 25:1 ratio, the cytotoxic activity of CIK on K562 cells was the highest. CONCLUSION We developed an efficient activated fashion of DC:CIK, established the optimal ratio of DC-CIK immunologic activity and the best cytotoxic model of CIK to K562 cells.

Recruiting Immunity for the Fight against Colorectal Cancer: Current Status and Challenges.

Cancer immunotherapies have changed the landscape of cancer management and improved the standard treatment protocols used in multiple tumors. This has led to significant improvements in progression-free survival and overall survival rates. In this review article, we provide an insight into the major immunotherapeutic methods that are currently under investigation for colorectal cancer (CRC) and their clinical implementations. We emphasize therapies that are based on monoclonal antibodies (mAbs) and adoptive cell therapy, their mechanisms of action, their advantages, and their potential in combination therapy. We also highlight the clinical trials that have demonstrated both the therapeutic efficacy and the toxicities associated with each method. In addition, we summarize emerging targets that are now being evaluated as potential interventions for CRC. Finally, we discuss current challenges and future direction for the cancer immunotherapy field.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

The AACR Journals: Advancing Progress Toward the AACR's 115-Year Mission.

MatchTope: A tool to predict the cross reactivity of peptides complexed with Major Histocompatibility Complex I.

The therapeutic targeting of the immune system, for example in vaccinology and cancer treatment, is a challenging task and the subject of active research. Several in silico tools used for predicting immunogenicity are based on the analysis of peptide sequences binding to the Major Histocompatibility Complex (pMHC). However, few of these bioinformatics tools take into account the pMHC three-dimensional structure. Here, we describe a new bioinformatics tool, MatchTope, developed for predicting peptide similarity, which can trigger cross-reactivity events, by computing and analyzing the electrostatic potentials of pMHC complexes. We validated MatchTope by using previously published data from in vitro assays. We thereby demonstrate the strength of MatchTope for similarity prediction between targets derived from several pathogens as well as for indicating possible cross responses between self and tumor peptides. Our results suggest that MatchTope can enhance and speed up future studies in the fields of vaccinology and cancer immunotherapy.