Immune therapy of melanoma: Overview of therapeutic vaccines

Melanoma is the most serious type of skin cancer which develops from the occurrence of genetic mutations in the melanocytes. Based on the features of melanoma tumors such as location, genetic profile and stage, there are several therapeutic strategies including surgery, chemotherapy, and radiotherapy. However, because of the appearance resistance mechanisms, the efficiency of these treatments strategies may be reduced. It has been demonstrated that therapeutic monoclonal antibodies can improve the efficiency of melanoma therapies. Recently, several mAbs, such as nivolumab, pembrolizumab, and ipilimumab, were approved for the immunotherapy of melanoma. The antibodies inhibit immune checkpoint receptors such as CTL4 and pd-1. Another therapeutic strategy for the treatment of melanoma is cancer vaccines, which improve clinical outcomes in patients. The combination therapy using antibodies and gene vaccine give us a new perspective in the treatment of melanoma patients. Herein, we present the recent progressions in the melanoma immunotherapy, especially dendritic cells mRNA vaccines by reviewing recent literature.     

Radiotherapy: Brightness and darkness in the era of immunotherapy

The introduction of immunotherapy into cancer treatment has radically changed clinical management of tumors. However, only a minority of patients (approximately 10 to 30%) exhibit long-term response to monotherapy with immunotherapy. Moreover, there are still many cancer types, including pancreatic cancer and glioma, which are resistant to immunotherapy. Due to the immunomodulatory effects of radiotherapy, the combination of radiotherapy and immunotherapy has achieved better therapeutic effects in a number of clinical trials. However, radiotherapy is a double-edged sword in the sense that it also attenuates the immune system under certain doses and fractionation schedules, not all clinical trials show improved survival in the combination of radiotherapy and immunotherapy. Therefore, elucidation of the interactions between radiotherapy and the immune system is warranted to optimize the synergistic effects of radiotherapy and immunotherapy. In this review, we highlight the dark side as well as bright side of radiotherapy on tumor immune microenvironment and immune system. We also elucidate current status of radioimmunotherapy, both in preclinical and clinical studies, and highlight that combination of radiotherapy and immunotherapy attenuates combinatorial effects in some circumstances. Moreover, we provide insights for better combination of radiotherapy and immunotherapy.     

The combination of DNA methyltransferase inhibitor therapy and immunotherapy for acute myeloid leukemia

Acute myeloid leukemia (AML), the most common form of acute leukemia in adults, is characterized by abnormal proliferation and blocked maturation and differentiation of myeloid precursor cells. AML is an aggressive cancer that progresses rapidly without treatment. Therefore, effective treatment modalities should be implemented immediately after diagnosis. The mainstay of classical AML therapy has been chemotherapy, which is not suitable for relapsing or refractory patients, especially elderly patients. Among emerging novel therapeutic approaches for AML, epigenetic therapy and immunotherapy represent two exciting therapeutic developments. This review focuses on discussion of the therapeutic considerations for AML from the perspective of combination treatment, which incorporates both DNA methyltransferase inhibitor therapy, as one of the most promising epigenetic therapies, and immune checkpoint inhibitor or dendritic cell-based vaccination treatments, as examples of immunotherapy. Both challenges and rationale in the optimization of therapeutic approaches, as well as recent clinical trial developments, along this line are summarized.     

NK cell-mediated targeting of human cancer and possibilities for new means of immunotherapy

Insights into the molecular basis for natural killer (NK) cell recognition of human cancer have been obtained in recent years. Here, we review current knowledge on the molecular specificity and function of human NK cells. Evidence for NK cell targeting of human tumors is provided and new strategies for NK cell-based immunotherapy against human cancer are discussed. Based on current knowledge, we foresee a development where more cancers may be subject to treatment with drugs or other immunomodulatory agents affecting NK cells, either directly or indirectly. We also envisage a possibility that certain forms of cancers may be subject to treatment with adoptively transferred NK cells, either alone or in combination with other therapeutic interventions.     

Chemotherapy of small cell lung cancer

The author summarizes the most recent information on small cell lung cancer. Reviews the epidemiology, prognostic markers and stages of small cell lung cancer Details the more frequently used combined therapeutic modalities, the criteria of the optimal therapeutic approaches and the achieved remission rates. Based on the most recent data, summarizes the new chemotherapeutic agents and their most effective combinations, the second line treatment and immunotherapy. Finally tries to answer the most frequently asked questions.     

Cancer immunotherapy

Cancer is the second leading cause of death in the industrialized world. Most cancer patients are treated by a combination of surgery, radiation and/or chemotherapy. Whereas the primary tumor can, in most cases, be efficiently treated by a combination of these standard therapies, preventing the metastatic spread of the disease through disseminated tumor cells is often not effective. The eradication of disseminated tumor cells present in the blood circulation and micro-metastases in distant organs therefore represents another promising approach in cancer immunotherapy. Main strategies of cancer immunotherapy aim at exploiting the therapeutic potential of tumor-specific antibodies and cellular immune effector mechanisms. Whereas passive antibody therapy relies on the repeated application of large quantities of tumor antigen-specific antibodies, active immunotherapy aims at the generation of a tumor-specific immune response combining both humoral and cytotoxic T cell effector mechanisms by the host's immune system following vaccination. In the first part of this review, concurrent developments in active and passive cancer immunotherapy are discussed. In the second part, the various approaches for the production of optimized monoclonal antibodies used for anti-cancer vaccination are summarized.     

Peptide‐based therapeutic cancer vaccine: Current trends in clinical application

The peptide‐based therapeutic cancer vaccines have attracted enormous attention in recent years as one of the effective treatments of tumour immunotherapy. Most of peptide‐based vaccines are based on epitope peptides stimulating CD8⁺ T cells or CD4⁺ T helper cells to target tumour‐associated antigens (TAAs) or tumour‐specific antigens (TSAs). Some adjuvants and nanomaterials have been exploited to optimize the efficiency of immune response of the epitope peptide to improve its clinical application. At present, numerous peptide‐based therapeutic cancer vaccines have been developed and achieved significant clinical benefits. Similarly, the combination of peptide‐based vaccines and other therapies has demonstrated a superior efficacy in improving anti‐cancer activity. We delve deeper into the choices of targets, design and screening of epitope peptides, clinical efficacy and adverse events of peptide‐based vaccines, and strategies combination of peptide‐based therapeutic cancer vaccines and other therapies. The review will provide a detailed overview and basis for future clinical application of peptide‐based therapeutic cancer vaccines.     

Emerging concepts in designing next-generation multifunctional nanomedicine for cancer treatment

Nanotherapy has emerged as an improved anticancer therapeutic strategy to circumvent the harmful side effects of chemotherapy. It has been proven to be beneficial to offer multiple advantages, including their capacity to carry different therapeutic agents, longer circulation time and increased therapeutic index with reduced toxicity. Over time, nanotherapy evolved in terms of their designing strategies like geometry, size, composition or chemistry to circumvent the biological barriers. Multifunctional nanoscale materials are widely used as molecular transporter for delivering therapeutics and imaging agents. Nanomedicine involving multi-component chemotherapeutic drug-based combination therapy has been found to be an improved promising approach to increase the efficacy of cancer treatment. Next-generation nanomedicine has also utilized and combined immunotherapy to increase its therapeutic efficacy. It helps in targeting tumor immune response sparing the healthy systemic immune function. In this review, we have summarized the progress of nanotechnology in terms of nanoparticle designing and targeting cancer. We have also discussed its further applications in combination therapy and cancer immunotherapy. Integrating patient-specific proteomics and biomarker based information and harnessing clinically safe nanotechnology, the development of precision nanomedicine could revolutionize the effective cancer therapy.     

Current landscape and perspective of oncolytic viruses and their combination therapies

Oncolytic virotherapy has become an important strategy in cancer immunotherapy. Oncolytic virus (OV) can reshape the tumor microenvironment (TME) through its replication-mediated oncolysis and transgene-produced anticancer effect, inducing an antitumor immune response and creating favorable conditions for the combination of other therapeutic measures. Extensive preclinical and clinical data have suggested that OV-based combination therapy has definite efficacy and promising prospects. Recently, several clinical trials of oncolytic virotherapy combined with immunotherapy have made breakthroughs. This review comprehensively elaborates the OV types and their targeting mechanisms, the selection of anticancer genes armed in OVs, and the therapeutic modes of action and strategies of OVs to provide a theoretical basis for the better design and construction of OVs and the optimization of OV-based therapeutic strategies.     

The ubiquitin-like protein,ISG15, is a novel tumor-associated antigen for cancer immunotherapy

The recent announcement of the first FDA-approved therapeutic vaccine for prostate cancer, Sipuleucel-T, is a watershed moment for the field of tumor immunotherapy. However, while Sipuleucel-T provides a powerful tool to clinicians for the most prevalent form of cancer in men, there remains an unmet need for a similar therapeutic strategy against breast cancer, the most prevalent cancer in women. While current breast cancer vaccines in development target several antigens, the most prevalent is the tumor-associated antigen, HER2. Initial results with HER2 vaccines appear promising in terms of efficacy; however, the lack of HER2 overexpression by a majority of breast tumors and the safety concerns associated with current HER2-targeted immunotherapy suggest that additional therapeutic strategies would be beneficial. Recently, several studies have identified ISG15 as a molecule highly expressed in numerous malignancies. ISG15 is a small ubiquitin-like protein regulated by type-I interferon and classically associated with viral defense. Elevated ISG15 expression in breast cancer is especially well documented and is independent of HER2, progesterone receptor, and estrogen receptor status. Additionally, high ISG15 expression in breast cancer correlates with an unfavorable prognosis and poor responses to traditional treatment strategies such as chemotherapy and radiation. To overcome these challenges, we employ a novel strategy to specifically target tumor-associated ISG15 expression with immunotherapy. We demonstrate that vaccination against ISG15 results in significant CD8-mediated reductions in both primary and metastatic mammary tumor burden. These results validate ISG15 as a tumor-associated antigen for cancer immunotherapy.     

Combined modality immunotherapy and chemotherapy: a new perspective

The results of recent clinical trials have demonstrated that cancer vaccines continue to struggle to achieve tangible clinical benefits as monotherapy. Tumor-induced abnormalities in the immune system hamper anti-tumor T cell responses limiting the effectiveness of cancer immunotherapy. Recently, evidence has been mounting to suggest that immunotherapy has the possibility of achieving better success when used in combination with conventional chemotherapy. In clinical trials, immune responses elicited by cancer vaccines appear to augment the effectiveness of subsequent conventional cancer therapies.     

Recent development in clinical applications of PD-1 and PD-L1 antibodies for cancer immunotherapy

Antibodies against programmed death (PD) pathway are revolutionizing cancer immunotherapy. Currently five antibodies against PD-1/PD-L1 have been approved. The clinical use of these antibodies is rapidly expanding. Incorporation of PD antibodies into chemotherapy regimens is in active clinical investigations. The combination of pembrolizumab with carboplatin and pemetrexed has been approved for the first line therapy of metastatic non-squamous non-small cell lung cancer. Combination of PD-1/PD-L1 antibodies with small molecule inhibitors such as tyrosine kinase inhibitors and IDO inhibitors are in active clinical trials. This review summarized recent development in clinical trials of PD-1 and PD-L1 antibodies for cancer immunotherapy.     

Is it true that gut microbiota is considered as panacea in cancer therapy?

Recent studies demonstrated that a combination of the gut microbiome has the vital effect on the efficacy of anticancer immune therapies. Regulatory effects of microbiota have been shown in different types of cancer therapies such as chemotherapy and immunotherapy. Immune-checkpoint-blocked therapies are the recent efficient cancer immunotherapy strategies. The target of immune-checkpoint blocking is cytotoxic T lymphocyte protein-4 (CTLA-4) or blockade of programmed death-1 (PD-1) protein and its ligand programmed death ligand 1 (PD-L1) that they have been considered as cancer immunotherapy in recent years. In the latest studies, it have been demonstrated that several gut bacteria such as Akkermansia muciniphila, Bifidobacterium spp., Faecalibacterium spp., and Bacteroides fragilis have the regulatory effects on PD-1, PD-L1, and CTLA-4 blocked anticancer therapy outcome.     

Immunotherapy for head and neck cancer

Head and neck cancer represents a challenging disease. Despite recent treatment advances, which have improved functional outcomes, the long-term survival of head and neck cancer patients has remained unchanged for the past 25 years. One of the goals of adjuvant cancer therapy is to eradicate local regional microscopic and micrometastatic disease with minimal toxicity to surrounding normal cells. In this respect, antigen-specific immunotherapy is an attractive therapeutic approach. With the advances in molecular genetics and fundamental immunology, antigen-specific immunotherapy is being actively explored using DNA, bacterial vector, viral vector, peptide, protein, dendritic cell, and tumor-cell based vaccines. Early phase clinical trials have demonstrated the safety and feasibility of these novel therapies and the emphasis is now shifting towards the development of strategies, which can increase the potency of these vaccines. As the field of immunotherapy matures and as our understanding of the complex interaction between tumor and host develops, we get closer to realizing the potential of immunotherapy as an adjunctive method to control head and neck cancer and improve long-term survival in this patient population.     

Combinatorial treatments including vaccines,chemotherapy and monoclonal antibodies for cancer therapy

Accumulating evidence suggests that despite the potency of cytotoxic anticancer agents, and the great specificity that can be achieved with immunotherapy, neither of these two types of treatment by itself has been sufficient to eradicate the disease. Still, the combination of these two different modalities holds enormous potential for eliciting therapeutic results. Indeed, certain chemotherapeutic agents have shown immunomodulatory activities, and several combined approaches have already been attempted. For instance, chemotherapy has been proven to enhance the efficacy of tumor cell vaccines, and to favor the activity of adoptively transferred tumor-specific T cells. A number of mechanisms have been proposed for the chemotherapy-triggered enhancement of immunotherapy response. Thus, chemotherapy may favor tumor cell death, and by that enhance tumor-antigen cross-presentation in vivo. Drug-induced myelosuppression may induce the production of cytokines favoring homeostatic proliferation, and/or ablate immunosuppression mechanisms. Furthermore, the recently reported synergy between monoclonal antibodies and chemotherapy or peptide vaccination is based upon the induction of endogenous humoral and cellular immune responses. This would suggest that monoclonal antibodies may not only provide passive immunotherapy but can also promote tumor-specific active immunity. This article will review several strategies in which immunotherapy can be exploited in preclinical and clinical studies in combination with other agents and therapeutic modalities that are quite unique when compared with “conventional” combination therapies (ie, treatments with chemotherapeutic drugs or chemotherapy and radiotherapy based protocols). The results from these studies may have significant implications for the development of new protocols based on combinatorial treatments including vaccines, chemotherapy and monoclonal antibodies, suggesting an exciting potential for therapeutic synergy with general applicability to various cancer types. Given the complicity of immune-based therapies and cancer pharmacology, it will be necessary to bring together cancer immunologists and clinicians, so as to provide a robust stimulus for realizing the successful management of cancer in the near future.     

The current status of immunotherapy for cervical cancer

BackgroundImmunotherapy has been proven effective in several tumours, hence diverse immune checkpoint inhibitors are currently licensed for the treatment of melanoma, kidney cancer, lung cancer and most recently, tumours with microsatellite instability. There is much enthusiasm for investigating this approach in gynaecological cancers and the possibility that immunotherapy might become part of the therapeutic landscape for gynaecological malignancies.Cervical cancer is the fourth most frequent cancer in women worldwide and represents 7.9% of all female cancers with a higher burden of the disease and mortality in low- and middle-income countries. Cervical cancer is largely a preventable disease, since the introduction of screening tests, the recognition of the human papillomavirus (HPV) as an etiological agent, and the subsequent development of primary prophylaxis against high risk HPV subtypes. Treatment for relapsed/advanced disease has improved over the last 5 years, since the introduction of antiangiogenic therapy. However, despite advances, the median overall survival for advanced cervical cancer is 16.8 months and the 5-year overall survival for all stages is 68%. There is a need to improve outcomes and immunotherapy could offer this possibility. Clinical trials aim to understand the best timing for immunotherapy, either in the adjuvant setting or recurrent disease and whether immunotherapy, alone or in combination with other agents, improves outcomes.     

Targeted immunotherapy of cancer with CAR T cells: achievements and challenges

The adoptive transfer of chimeric antigen receptor (CAR)-expressing T cells is a relatively new but promising approach in the field of cancer immunotherapy. This therapeutic strategy is based on the genetic reprogramming of T cells with an artificial immune receptor that redirects them against targets on malignant cells and enables their destruction by exerting T cell effector functions. There has been an explosion of interest in the use of CAR T cells as an immunotherapy for cancer. In the pre-clinical setting, there has been a considerable focus upon optimizing the structural and signaling potency of the CAR while advances in bio-processing technology now mean that the clinical testing of these gene-modified T cells has become a reality. This review will summarize the concept of CAR-based immunotherapy and recent clinical trial activity and will further discuss some of the likely future challenges facing CAR-modified T cell therapies.     

Recombinant immunotherapeutics: current state and perspectives regarding the feasibility and market

Recombinant immunotherapeutics are important biologics for the treatment and prevention of various diseases. Immunotherapy can be divided into two categories, passive and active. For passive immunotherapy, the successes of antibody and cytokine therapeutics represent a promising future and opportunities for improvements. Efforts, such as cell engineering, antibody engineering, human-like glycosylation in yeast, and Fab fragment development, have led the way to improve antibody efficacy while decreasing its high manufacturing costs. Both new cytokines and currently used cytokines have demonstrated therapeutic effects for different indications. As for active immunotherapy, recently approved HPV vaccines have encouraged the development of preventative vaccines for other infectious diseases. Immunogenic antigens of pathogenic bacteria can now be identified by genomic means (reverse vaccinology). Due to the recent outbreaks of pandemic H1N1 influenza virus, recombinant influenza vaccines using virus-like particles and other antigens have also been engineered in several different recombinant systems. However, limitations are found in existing immunotherapeutics for cancer treatment, and recent development of therapeutic cancer vaccines such as MAGE-A3 and NY-ESO-1 may provide alternative therapeutic strategy.