Nonhuman primates are relevant models for research in hematology, immunology and virology

Nonhuman primates have been used for biomedical research for several decades. They have proved to be models that are relevant to humans because of the high level of gene homology which underlies physiological and biochemical similarities. The similarity of monkeys to humans has been used to investigate pathophysiological mechanisms in hematology, immunology and virology. New therapeutic procedures can be assessed in primates by using materials, in particular pharmacological reagents, and methods designed for humans. The relevance of these models also relies on the use of species-specific pathogens and the availability of recombinant, homologous cytokines. The introduction of more and more sophisticated cell and gene therapy protocols in hematopoietic cell transplantation and immunotherapy requires the development of preclinical trials similar to clinical settings. For several decades now, baboons and cynomolgus/rhesus monkeys have been the most useful primate models in experimental hematology, and this has contributed to numerous therapeutic advances. Primate models of AIDS have been developed to study the pathogenesis, transmission and immune responses to infection, and to test vaccines and drugs. Primate research should be restricted in quantity, and mainly designed with the aim of removing uncertainty as to the safety and clinical benefit to the patient, of new biomedical protocols.     

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.     

Mechanism of synergistic effect of chemotherapy and immunotherapy of cancer

In recent years, the combination of cancer immunotherapy with standard therapeutic modality is gaining credibility due to a number of clinical trials demonstrating therapeutic success of such combination therapies. However, the mechanism of this phenomenon is poorly understood. Here, we will discuss recent findings that suggest novel mechanisms of synergistic effect of cancer immunotherapy and chemotherapy.     

Polybacterial immunostimulators in medical practice

During 20 years different oral immunostimulators have been developed and tested in the National Center of Infectious and Parasitic Diseases in Sofia, Bulgaria. Some of them are widely and quite successfully used in clinical practice for immunotherapy and immunoprophxis (Respivax, Urostim, Dentavax). Data on the immunostimulating activity of polybacterial immunostimulants are presented. Numerous clinical investigations, including double-blind studies, have convincingly demonstrated their high efficacy in the prevention and treatment of non-specific infections of the respiratory organs, the urogenital tract, the oral mucosa and periodontium, as well as in the complex therapy of AIDS. All these facts suggest that immunostimulators, in particular polybacterial ones, are a highly promising tool of modern immunotherapy and immunoprophylaxis aimed at the beneficial modulation of immune response in humans.     

Can repeated plasma donation by asymptomatic HIV-infected individuals delay the onset of AIDS?

Healthy HIV-positive regular donors of plasma in a programme of passive immunotherapy for AIDS patients were studied over a period of about two years. None developed symptoms of clinical progression; most seemed to make substantial gains of CD4 cells by comparison with asymptomatic individuals who were not donating. The effects of donation did not seem to diminish with repetition, and donor CD4 counts tended towards stabilizing within normal limits. Asymptomatic HIV-positive individuals were compared immunologically with ''normals'' and people with AIDS, using a battery of 25 measurements on peripheral blood. The immunological profiles of donor and non-donor asymptomatics, indistinguishable at the start, became dissimilar: donors'' profiles resembled AIDS less, non-donors became less like ''normal'' and a few non-donor results could not be distinguished from AIDS. Improvement in the CD4 counts and amelioration of the immunological profile in donors provide prima facie evidence that plasmapheresis may be therapeutic for asymptomatic HIV-positive people. Further studies are justified.     

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.     

Cancer immunotherapy: recent breakthroughs and perspectives

Immunotherapy of cancer has long been considered as an attractive therapeutic approach but with no impact on clinical practice. Two clinical protocols of immunotherapy, one based on a cancer vaccine in patients with prostate cancer or melanoma and the other using an immunomodulator targeting T cells (anti-CTLA4 mAb) in melanoma patients, have demonstrated clinical efficacy in two phase?III clinical trials. To improve these encouraging clinical results, biomarkers to better select patients which may benefit from this therapy are actively searched. In addition, immunosuppression associated with cancer has to be overcome to allow a better immunostimulation. In contrast to chemotherapy, clinical variables to monitor the efficacy of immunotherapy has to be revisited and overall survival appears to be a better endpoint than clinical response defined by the RECIST criteria. Combination of immunotherapy with conventional treatments (chemotherapy, anti-angiogenic, etc.) should further improve this approach both in its effectiveness and in its clinical indications.     

肿瘤基因疫苗的研究进展

最近,美国FDA批准上市了第一个肿瘤治疗性疫苗,成为肿瘤治疗史上的一个里程碑事件。肿瘤免疫治疗领域目前正朝着发展新型疫苗技术方向前进,理想的肿瘤疫苗应该可以产生强大、持久和有效的免疫反应,同时疫苗的制造成本低廉,可以形成标准化生产工艺。本文中所提及的基因疫苗是在肿瘤多种免疫治疗方式中新出现的一种治疗方法。多项研究已经证明,肿瘤免疫基因治疗方式可以产生有效的免疫反应,获得很好的临床效果。在本综述中,我们简要概述当前肿瘤基因疫苗的发展现状及最新研究进展,探讨肿瘤基因疫苗的未来发展趋势。     

Single peptides and combination modalities for triple negative breast cancer

Unlike other types of breast cancers (BCs), no specific therapeutic targets have been established for triple negative breast cancer (TNBC). Therefore, chemotherapy and radiotherapy are the only available adjuvant therapeutic choices for TNBC. New emerging reports show that TNBC is associated with higher numbers of intratumoral tumor infiltrating lymphocytes. This is indicative of host anti-TNBC immune surveillance and suggesting that immunotherapy can be considered as a therapeutic approach for TNBC management. Recent progress in molecular mechanisms of tumor-immune system interaction and cancer vaccine development studies, fast discoveries and FDA approvals of immune checkpoint inhibitors, chimeric antigen receptor T-cells, and oncolytic virotherapy have significantly attracted attention and research directions toward the immunotherapeutic approach to TNBC. Here in this review different aspects of TNBC immunotherapies including the host immune system-tumor interactions, the tumor microenvironment, the relevant molecular targets for immunotherapy, and clinical trials in the field are discussed.     

Advanced liposomal vectors as cancer vaccines in melanoma immunotherapy

Malignant tumors represent a major source of disability and account for more than one of five deaths in Western countries. Among the different cancers, melanoma harbors two distinctive features. First, its has long been recognized as an immunogenic tumor, and second, an unprecedented rise in incidence is currently observed, in face of few therapeutic options. Thus, melanoma represent an ideal target for a cancer immunotherapy program. To date, a number of immunodominant epitopes from tumor associated antigens (TAA) are used as cancer vaccines in clinical trials, in spite of an acknowledged rapid degradation in vivo and low immunogenicity. However, most of the immunotherapy trials reported so far do not achieve consistent clinical results. Hence, there is an urgent need for the development of a carrier system and strong adjuvants suitable for a TAA-based cancer immunotherapy. Liposomes and their further development as virosomes with added adjuvancy may address both these issues. We report here our experience in the tailoring of dedicated advanced liposomal vectors that were developed in the context of an upcoming immunotherapy clinical trial for melanoma.     

Advanced Liposomal Vectors as Cancer Vaccines in Melanoma Immunotherapy

Malignant tumors represent a major source of disability and account for more than one of five deaths in Western countries. Among the different cancers, melanoma harbors two distinctive features. First, its has long been recognized as an immunogenic tumor, and second, an unprecedented rise in incidence is currently observed, in face of few therapeutic options. Thus, melanoma represent an ideal target for a cancer immunotherapy program. To date, a number of immunodominant epitopes from tumor associated antigens (TAA) are used as cancer vaccines in clinical trials, in spite of an acknowledged rapid degradation in vivo and low immunogenicity. However, most of the immunotherapy trials reported so far do not achieve consistent clinical results. Hence, there is an urgent need for the development of a carrier system and strong adjuvants suitable for a TAA-based cancer immunotherapy. Liposomes and their further development as virosomes with added adjuvancy may address both these issues. We report here our experience in the tailoring of dedicated advanced liposomal vectors that were developed in the context of an upcoming immunotherapy clinical trial for melanoma.     

Immune Response Against Head and Neck Cancer: Biological Mechanisms and Implication on Therapy

Head and neck carcinoma (HNC) are diseases arising from several tracts of the aerodigestive ways. Most HNC are squamous cell carcinoma (SCCHN). Immunotherapy is a treatment strategy aimed to reinforce the immune system. Several types of immunotherapy are available in the clinical scenario. Checkpoint inhibitors were developed later in SCCHN; nivolumab and pembrolizumab have reached the clinical approval, having both drugs demonstrated to significantly improve the overall survival, if compared with the standard of treatment (according to the results of the CheckMate 141 and KEYNOTE-040 trials). Nevertheless, immunotherapy may fail because of the genetics of SCCHN. In fact, two genetically different types of SCCHN have been discovered, one virus-related (HPV) and the other mutagens-related. They seem to show in clinical trials very different responses to immunotherapy. Given the existence of a number of factors predictive of response to immunotherapy in SCCHN, a future clinical approach may be to characterize the genetic and immunologic feature of SCCHN and to perform a well-tailored immunotherapy. This review will summarize the main immunotherapy strategies available in SCCHN, discussing their real efficacy, highlighting also the ways to improve them.     

用于肿瘤治疗的免疫检查点抑制剂相关预测生物标志物的研究进展

恶性肿瘤是严重威胁人类健康和社会发展的疾病。传统的肿瘤治疗方法如手术、放疗、化疗和靶向治疗等不能完全满足临床治疗的需求,新兴的免疫治疗成为了肿瘤治疗领域的研究热点。免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)作为一种肿瘤免疫治疗方法,已获批用于治疗多种肿瘤,如肺癌、肝癌、胃癌和结直肠癌等。然而,ICIs在临床使用过程中,只有少数患者会出现持久反应,一些患者还会出现耐药和不良反应。因此,预测生物标志物的鉴定和开发对提高ICIs的治疗效果至关重要。肿瘤ICIs预测生物标志物主要包括肿瘤生物标志物、肿瘤微环境生物标志物、循环相关生物标志物、宿主环境生物标志物以及组合生物标志物等,对患者筛查、个体化治疗和预后评估具有重要意义。本文就肿瘤ICIs治疗预测生物标志物的前沿进展作一综述。     

Therapeutic immune response induced by electrofusion of dendritic and tumor cells

To elicit a therapeutic antitumor immune response, dendritic cells (DCs) have been employed as a cellular adjuvant. Among various DC-based approaches, fusion of DCs and tumor cells potentially confers not only DC functionality, but also a continuous source of unaltered tumor antigens. We have recently demonstrated successful generation of fusion hybrids by a large-scale electrofusion technique. The immunogenicity and therapeutic potential of fusion hybrids were further analyzed in a model system of a murine melanoma cell line expressing beta-galactosidase (beta-gal) as a surrogate tumor antigen. A single vaccination with fusion hybrids plus IL-12 induced a therapeutic immune response against 3-day established pulmonary metastases. This immunotherapy was beta-gal specific and involved both CD4 and CD8 T cells. In vitro, fusion hybrids stimulated specific IFN-gamma secretion from both CD4 and CD8 immune T cells. They also nonspecifically induced IL-10 secretion from CD4 but not CD8 T cells. Compared to other DC loadings, our results demonstrate the superior immunogenicity of fusion. The current technique of electrofusion is adequately developed for clinical use in cancer immunotherapy.     

RNA-based gene therapy for the treatment and prevention of HIV: from bench to bedside

Gene therapy is considered a feasible approach for the treatment and prevention of HIV/AIDS. Targeting both viral genes and host dependency factors can interfere with the viral lifecycle and prevent viral replication. A number of approaches have been taken to target these genes, including ribozymes, aptamers, and RNAi based therapies. A number of these therapies are now beginning to make their way into clinical trials and providing proof of principle that gene therapy is a safe and realistic option for treating HIV. Here, we focus on those therapies that have progressed along the pipeline to preclinical and clinical testing.     

Immunotherapy for Alzheimer disease

Immunotherapy approaches for Alzheimer's disease currently are among the leading therapeutic directions for the disease. Active and passive immunotherapy against the β-amyloid peptides that aggregate and accumulate in the brain of those afflicted by the disease have been shown by numerous groups to reduce plaque pathology and improve behavior in transgenic mouse models of the disease. Several ongoing immunotherapy clinical trials for Alzheimer’s disease are in progress. The background and ongoing challenges for these immunological approaches for the treatment of Alzheimer's disease are discussed.     

An assessment of the role of chimpanzees in AIDS vaccine research

Prior to Simian Immunodeficiency Virus (SIV)-infected macaques becoming the 'model of choice' in the 1990s, chimpanzees were widely used in AIDS vaccine research and testing. Faced with the continued failure to develop an effective human vaccine, some scientists are calling for a return to their widespread use. To assess the past and potential future contribution of chimpanzees to AIDS vaccine development, databases and published literature were systematically searched to compare the results of AIDS vaccine trials in chimpanzees with those of human clinical trials, and to determine whether the chimpanzee trials were predictive of the human response. Protective and/or therapeutic responses have been elicited in chimpanzees, via: passive antibody transfer; CD4 analogues; attenuated virus; many types and combinations of recombinant HIV proteins; DNA vaccines; recombinant adenovirus and canarypox vaccines; and many multi-component vaccines using more than one of these approaches. Immunogenicity has also been shown in chimpanzees for vaccinia-based and peptide vaccines. Protection and/or significant therapeutic effects have not been demonstrated by any vaccine to date in humans. Vaccine responses in chimpanzees and humans are highly discordant. Claims of the importance of chimpanzees in AIDS vaccine development are without foundation, and a return to the use of chimpanzees in AIDS research/vaccine development is scientifically unjustifiable.     

The Vancouver Lymphadenopathy-AIDS Study: 5. Antecedent behavioural,clinical and laboratory findings in patients with AIDS and HIV-seropositive controls.

In a group of homosexual men in Vancouver studied prospectively since November 1982, 26 cases of acquired immune deficiency syndrome (AIDS) have arisen. To identify behavioural, clinical and laboratory findings that might predict the development of AIDS in people with antibody to human immunodeficiency virus (HIV), we compared data for 25 patients with AIDS with corresponding data for 80 controls serologically positive for HIV selected from the cohort. The clinical and laboratory data for the patients with AIDS preceded the diagnosis of the syndrome by a mean of 17.5 months. The controls had been both seropositive and AIDS-free for a mean of 16.7 months after acquisition of their data. We detected significant differences between the patients with AIDS and the controls in IgG and IgA levels, absolute number of helper T cells and ratio of helper to suppressor T cells but not in lifetime number of male sexual partners, frequency of receptive anal intercourse or receptive fisting, illicit drug use or history of infectious disease. We also detected an increased risk of AIDS among those who had an elevated number of sexual contacts in AIDS-endemic areas in the 5 years before enrollment. A history of increased early sexual contact in AIDS-endemic areas is likely to be associated with early infection and with an increased risk of AIDS among men with HIV infection of unknown duration. Thus, although our analysis had limited statistical power, we conclude that most lifestyle variables appear to act as exposure factors in HIV infection but not as cofactors in the development of AIDS.     

乳腺癌免疫治疗：生物标志物、药物及疫苗

虽然近年来肿瘤的治疗取得较大进展,乳腺癌依旧是威胁女性健康的主要杀手。近年来,乳腺癌相关的免疫治疗取得较大进展,肿瘤浸润淋巴细胞(TILs)、程序性死亡受体 1(PD 1)及其配体PD L1、肿瘤突变负荷等肿瘤标志物对乳腺癌免疫治疗具有预测作用,并与乳腺癌的预后相关。免疫检查点抑制剂,例如PD-1/PD-L1及细胞毒性T淋巴细胞抗原4(CTLA 4)抑制剂在乳腺癌中取得极大进展,各期临床试验结果显示不同的效用。肿瘤疫苗的使用为乳腺癌免疫治疗的另一途径,虽然部分疫苗在临床试验中取得较好成效,但绝大多数仍需深入研究,乳腺癌免疫治疗之途仅为开端,依旧需要大量研究。本文简要介绍了乳腺癌免疫治疗相关的生物标志物、免疫检查点抑制剂以及肿瘤疫苗的研究进展。     

Combinational adenovirus-mediated gene therapy and dendritic cell vaccine in combating well-established tumors

Recent developments in tumor immunology and biotechnology have made cancer gene therapy and immunotherapy feasible. The current efforts for cancer gene therapy mainly focus on using immunogenes, chemogenes and tumor suppressor genes. Central to all these therapies is the development of efficient vectors for gene therapy. By far, adenovirus （AdV）-mediated gene therapy is one of the most promising approaches, as has confirmed by studies relating to animal tumor models and clinical trials. Dendritic cells （DCs） are highly efficient, specialized antigen-presenting cells, and DC- based tumor vaccines are regarded as having much potential in cancer immunotherapy. Vaccination with DCs pulsed with tumor peptides, lysates, or RNA, or loaded with apoptotic/necrotic tumor cells, or engineered to express certain cytokines or chemokines could induce significant antitumor cytotoxic T lymphocyte （CTL） responses and antitumor immunity. Although both AdV-mediated gene therapy and DC vaccine can both stimulate antitumor immune responses, their therapeutic efficiency has been limited to generation of prophylactic antitumor immunity against re-challenge with the parental tumor cells or to growth inhibition of small tumors. However, this approach has been unsuccessful in combating well-established tumors in animal models. Therefore, a major strategic goal of current cancer immunotherapy has become the development of novel therapeutic strategies that can combat well-established tumors, thus resembling real clinical practice since a good proportion of cancer patients generally present with significant disease. In this paper, we review the recent progress in AdV-mediated cancer gene therapy and DC-based cancer vaccines, and discuss combined immunotherapy including gene therapy and DC vaccines. We underscore the fact that combined therapy may have some advantages in combating well-established tumors vis-a-vis either modality administered as a monotherapy.