Myeloid-derived suppressor cells MDSCs are both immature and immunosuppressive cells increasing in inflammatory diseases, particularly tumors. They can produce inhibitory factors such as IL and arginase to inhibit T cells and promote Tregs and detrimental M2 macrophages, and thus suppressing anti-tumor immunity [ 47 , 48 ].
Cancer immunoediting has been considered for relying on three phases: an early elimination phase with the activation of an innate and adoptive immune response, an equilibrium phase where the sporadic tumor cells may survive immune attacks, and an immune escape phase that the cancer cell variants survive in the immunosuppressive microenvironment by altering geno- or antigenic phenotype or under the control of immunoregulatory phenomena [ 61 ]. In this process, the immune system plays contradicting roles for both protecting body from tumor development however also promoting tumor progression [ 61 ].
At present, new strategies aiming at blocking of immune checkpoint regulators, overcoming immune tolerance such as engineered T cell therapy, or the identification of novel tumor antigens through next-generation sequencing opened a new era of cancer immunotherapy [ 62 - 64 ]. Cancer immunotherapy includes passive or active immunotherapy Table 1 [ 65 , 66 ]. Passive immunotherapy is administration of agents such as mAbs, lymphocytes or cytokines that enhance existing anti-tumor response [ 34 ]; active immunotherapy attempts to stimulate self-immune system to attack tumor cells via vaccination, non-specific immunomodulation, or targeting specific antigen receptors [ 34 ].
Promising methods were discussed below. Antibodies are modified proteins aimed at to target a specific part of deregulated signals transduction pathways in cancer or interfere with immunological processes [ 57 , 67 ]. FDA has already approved more than a dozen mAbs for the treatment of both solid and hematological malignancies, and also more new mAbs clinical trials are now being investigated [ 67 , 68 ].
Monoclonal antibody and gene transfer technologies have promoted further exploitation of our fundamental knowledge on antigen recognition, T cell activation as well as T cell co-stimulation, thus leading to the invention and also the success of checkpoint blockade and CAR T cell therapy [ 69 ]. Several types of mAbs are being used in cancer treatment now, including naked, conjugated and bipecific mAbs [ 70 , 71 ].
Naked mAbs are the most common type of mAbs for treating cancer, and it can work via boosting the immune response against cancer cells and acting as a marker for the immune system's destroying them.
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Alemtuzumab is an example of naked mAb which can bind to the CD52 antigen on lymphocytes attacking them which is used to treat chronic lymphocytic leukemia CLL [ 72 , 73 ]. Other naked mAbs work mainly by attaching to and blocking antigens on tumor cells helping cancer cells grow and spread, like trastuzumab , an antibody against the HER2 on breast and stomach cancer cells [ 74 ]. Conjugated mAbs are those mAbs joining to a chemotherapy agent or a radioactive particle taking one of these substances directly to the cancer cells [ 75 ].
Chemolabled antibodies are those antibodies with powerful chemotherapy attached to them, such as brentuximab vedotin an antibody that targets CD30 antigen found on lymphocytes, attaching to a chemotherapy drug and thus treating Hodgkin lymphoma and anaplastic large cell lymphoma [ 76 - 78 ]. Radiolabeled antibodies have radioactive particles attached to them [ 79 ].
Possible side effects of mAbs may include fever, chills, headache, weakness, nausea, diarrhea, rashes and hypotension [ 82 ]. Cancer vaccines are the response modifiers working by stimulating or restoring the ability of immune system to fight cancer [ 83 ]. It consists of preventive vaccines and therapeutic vaccines [ 84 ]. The goal of preventive vaccine is preventing cancer from developing. They are based on antigens carried by infectious agents and easy for the immune system to recognize as foreign invaders [ 85 ]. It stimulates the immune system with tumor antigens, peptides, or whole cancer cells [ 88 ].
The mechanism involves activating the immune system with targeted T cells to destroy target cancer cells. Therapeutic vaccines first directly target the immune system and expand the immune system's attack on cancer cells. A broadening of the immune response may also be observed as it might attack additional tumor-specific antigens antigen spread [ 57 , 89 ]. In this therapy, peripheral blood mononuclear cells are isolated from the patient and ex vivo activated with a recombinant fusion protein consisting of a prostate antigen prostatic acid phosphatase PAP conjugated with granulocyte-macrophage colony-stimulating factor GM-CSF , and the cells are then re-infused into the patient to activate PAP-specific T cells [ 90 ].
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T-VEC can trigger an antitumor immune response in non-injected lesions. The side effects of cancer vaccines vary from different vaccine formation and person, and the most commonly reported side effect of cancer vaccines is inflammation at the site of injection [ 91 ]. Adoptive cell transfer ACT of tumor-associated antigen-specific T cells is a very attractive form of immunotherapy for hematologic malignancies as well as solid cancers [ 92 ]. Initial studies of ACT utilizing tumor-infiltrating lymphocytes TILs have promising clinical results in metastatic melanoma patients to some degree [ 17 , 93 ].
But later on this approach had been limited by the difficulty in expanding viable TILs and only showing specific effector functions [ 94 ].
In order to overcome this problem, strategy of CAR- and T-cell receptor TCR -engineered T cells have been developed based on various approaches by genetic modifications, and inspiring efficacy in various clinical trials for particular cancers have been observed [ 95 , 96 ]. Traditionally, two major sources of T cells for ACT are the tumor itself and the peripheral blood of the cancer patient [ 92 ]. Transferring of antigen-specific TCR genes into lymphocytes isolated from the patient's peripheral blood becomes an alternative approach [ 95 , 97 ].
It is via T cell transductions with retroviruses or lentiviruses, thus they can express TCRs targeting specific cancer antigens and eradicate those cancer cells [ 97 ]. Although promising results have been achieved in metastatic melanoma patients, TCR technology seems less attractive because it is MHC-restricted which limited its further development [ 98 ]. CAR modified T cells are a second class of engineered T cells [ 99 ].
Compared to TCRs, CARs have antibody-like specificities which can recognize major histocompatibility complex MHC -non-restricted structures on the surfaces of target cells, thereby allowing for cancer cell recognition in the MHC-unrestricted manner [ ]. ScFv is designed to target a specific surface molecule on B cells [ ]. By altering the changeable components of a CAR like the epitope-recognition part, cell function could be improved [ ]. CAR constructs also differ in flexibility and length of the hinge region conjoining the scFv to the transmembrane region [ ].
Once modified, CAR T cells are expanded and infused back to lymphodepleted cancer patients where they can eradicate the cancer [ 89 ]. However, this therapy's widespread to solid tumors is one of the major future goals of ACT because of the difficulties to find suitable target antigens and also for the tumor immunosuppression and complex tumor microenvironment [ 90 , ]. In addition, ACT needs to be optimized to reduce toxicity and to enhance anti-tumor efficacy [ , ]. Methods of immunotherapy.
Immune checkpoint inhibitors are a class of drugs aimed to increase immune response against cancer cells [ - ]. The immune system consists of various checkpoint pathways focusing on T-cell activation that play an important role in modulating anti-tumor immunity [ ].
Molecules that play a crucial role in checkpoint regulation include the T-cell surface molecules CTLA-4, PD-1, T-cell immunoglobulin and mucin domain containing protein 3 Tim-3 , and lymphocyte activation gene-3 LAG-3 [ 88 ]. Tumor expressions of these markers will results in hyporesponsiveness or even exhaustion of the immune system [ ]. As a result, these molecules are highly attractive as targets for removing the inhibition and enable cytotoxic T cells to attack cancer cell for destruction [ 34 , 57 ]. In , FDA approved anti-CTLA-4 antibodies ipilimumab for the treatment of metastatic melanoma, which marked the beginning of a new era for cancer immunotherapy [ 89 , ].
Subsequently, antibodies against PD-1 pembrolizumab and nivolumab have been approved in , also for the metastatic melanoma [ ]. Nivolumab has also been approved in for previously treated advanced or metastatic squamous lung cancer, an approval later expanded also to small cell lung cancer [ ]. In , anti-PD-L1 atezolizumab was approved for bladder cancer [ ] and nivolumab was approved for Hodgkin lymphoma [ ]. At present, more than clinical trials are ongoing to test the efficacy and safety of immune checkpoint blockers in several cancer types Table 2 [ 90 , , - ].
Checkpoint inhibition is also associated with a unique spectrum of side effects including gastrointestinal, dermatologic, endocrine, hepatic, and other less common inflammatory events [ , ]. Treatment of moderate or severe side effects requires interruption of the checkpoint inhibitor and the use of corticosteroid [ , ].
To monitor the immune response, abundant of assays have been tried. Since the immune system is a very complex network, it is crucial to monitor the cell milieu, phenotype of cell subsets, cell surface molecules responsible for cell-cell interactions and intracellular signaling events of the immune system [ - ]. Several methods such as mass cytometry, direct labeling, imaging techniques can be used [ , , ].
Though there are criteria of clinical response of in cancer treatment, there are no specific criteria of monitoring the immunotherapy up to date [ 7 ].
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Genetic markers, tumor size changes, new tumor lesions, adverse effect, patients' survival are important indications in the clinical trials by immunotherapy [ , ]. Numbers of challenges of cancer immunotherapy still exist for translating these promising approaches to clinically feasible therapies that treat a larger range of cancer types though recent years' success. Caner is genomically unstable [ ]. Altered ploidy, heterogeneity and normal contamination are the features characterizing the cancer sequencing data that prompt the need for new bioinformatics approaches [ ].
Next-generation sequencing NGS can provide novel and insights into the molecular machinery inside the cancer cells [ ]. Besides expression profiling of transcripts and genes as well as detecting alternative splicing, it has enabled the discovery of single nucleotide variants SNV , insertions, deletions, amplifications and inter-chromosomal rearrangements in the whole genome and transcriptome [ ].
The advent of NGS and improvements in bioinformatic algorithms that predict immunogenicity of the mutated genes wound certainly lead to the development of more safe, efficient and effective personalized cancer therapy [ 3 , 90 , ]. In the process of cancer progression, tumors will acquire somatic mutations, and those cells that acquire certain mutations have survival advantages and will dominate localized tumor areas by displacing those lacking these genomic alterations [ , ].
Driver mutations dominate in all metastatic sites of cancer and the heterogeneity will certainly affects subclonal mutations [ ]. Tumor heterogeneity both inter- and intra-tumor heterogeneity , together with the clonal mutations are the main challenges of personalized cancer treatment [ ]. Therefore, repeated biopsies at progression and biomarker-driven personalized therapies are needed to determine resistant mechanisms and their potential targeted inhibition [ ]. Next-generation clinical trials taking into account the premise of tumor heterogeneity using genomic analysis of circulating cancer cells and circulating-free DNA are being developed [ , ].
The combination of different immune checkpoint inhibitors such as anti-CTLA-4 and anti-PD-1 have demonstrated enhanced efficacy; however, how to treat with the most suitable dosing and how to identify the most efficacious combinations are the main challenges. In addition, combining immunotherapy with other types of treatment such as chemotherapy, radiation therapy and targeted therapies can also be explored [ - ].
Preliminary evidences indicated that there will be promising synergistic effects when combining other types of therapies with immunotherapy [ , ]. In summary, with the advent of cancer immunotherapy and recent advances of it, curing cancer seems to be a real possibility for cancer patients.
Advancing cancer immunotherapy: a vision for the field
The development of cancer vaccines, CAR-T cell and checkpoint inhibitors has revolutionized the cancer treatment. Combination therapy might be a promising therapeutic strategy to treat cancer in the future. Recognition and management of toxicities of cancer immunotherapy will also be a key factor for treatment success. Personalized combination therapies that specifically drive each patient' cancer biology via new techniques will be the most promising strategies for cancer treatment.
Rius M, Lyko F. Epigenetic cancer therapy: rationales, targets and drugs. Immunotherapy of cancer. European journal of pharmacology. Barton MK.
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