Cytokines in cancer therapy

Cytokines are crucial factors in the activation and development of immune response, including responses against tumor cells. Interleukin (IL)-2, a T-cell growth factor, has been largely used to activate T and NK cells in vivo and to maintain such an activation for therapeutic purposes. When given to patients, IL-2 was shown to cause clinical responses, especially in metastatic melanoma and renal cancer patients, though its mechanism of action could not be completely elucidated. Cytokines (IL-2, IL-12, GM-CSF) are also used as natural adjuvants of vaccines of various formulation to help in activating and maintaining an antitumor immune response. This review summarizes findings deriving from the use of cytokines in cancer therapy and provides insights into future approaches when a more appropriate use of cytokines, together with new vaccines, is likely to improve clinical outcome.     

Therapeutic cancer vaccines: are we there yet?

Enthusiasm for therapeutic cancer vaccines has been rejuvenated with the recent completion of several large, randomized phase III clinical trials that in some cases have reported an improvement in progression free or overall survival. However, an honest appraisal of their efficacy reveals modest clinical benefit and a frequent requirement for patients with relatively indolent cancers and minimal or no measurable disease. Experience with adoptive cell transfer-based immunotherapies unequivocally establishes that T cells can mediate durable complete responses, even in the setting of advanced metastatic disease. Further, these findings reveal that the successful vaccines of the future must confront: (i) a corrupted tumor microenvironment containing regulatory T cells and aberrantly matured myeloid cells, (ii) a tumor-specific T-cell repertoire that is prone to immunologic exhaustion and senescence, and (iii) highly mutable tumor targets capable of antigen loss and immune evasion. Future progress may come from innovations in the development of selective preparative regimens that eliminate or neutralize suppressive cellular populations, more effective immunologic adjuvants, and further refinement of agents capable of antagonizing immune check-point blockade pathways.     

Progress and controversies in developing cancer vaccines

Immunotherapy has become a standard approach for cancer management, through the use of cytokines (eg: interleukin-2) and monoclonal antibodies. Cancer vaccines hold promise as another form of immunotherapy, and there has been substantial progress in identifying shared antigens recognized by T cells, in developing vaccine approaches that induce antigen-specific T cell responses in cancer patients, and in developing new technology for monitoring immune responses in various human tissue compartments. Dramatic clinical regressions of human solid tumors have occurred with some cancer vaccines, but the rate of those responses remains low. This article is part of a 2-part point:counterpoint series on peptide vaccines and adoptive therapy approaches for cancer. The current status of cancer vaccination, and associated challenges, are discussed. Emphasis is placed on the need to increase our knowledge of cancer immunobiology, as well as to improve monitoring of cellular immune function after vaccination. Progress in both areas will facilitate development of effective cancer vaccines, as well as of adoptive therapy. Effective cancer vaccines promise to be useful for treatment and prevention of cancer at low cost and with low morbidity.     

The iSBTc/SITC primer on tumor immunology and biological therapy of cancer: a summary of the 2010 program

The Society for Immunotherapy of Cancer, SITC (formerly the International Society for Biological Therapy of Cancer, iSBTc), aims to improve cancer patient outcomes by advancing the science, development and application of biological therapy and immunotherapy. The society and its educational programs have become premier destinations for interaction and innovation in the cancer biologics community. For over a decade, the society has offered the Primer on Tumor Immunology and Biological Therapy of Cancer™ in conjunction with its Annual Scientific Meeting. This report summarizes the 2010 Primer that took place October 1, 2010 in Washington, D.C. as part of the educational offerings associated with the society's 25th anniversary. The target audience was basic and clinical investigators from academia, industry and regulatory agencies, and included clinicians, post-doctoral fellows, students, and allied health professionals. Attendees were provided a review of basic immunology and educated on the current status and most recent advances in tumor immunology and clinical/translational caner immunology. Ten prominent investigators presented on the following topics: innate immunity and inflammation; an overview of adaptive immunity; dendritic cells; tumor microenvironment; regulatory immune cells; immune monitoring; cytokines in cancer immunotherapy; immune modulating antibodies; cancer vaccines; and adoptive T cell therapy. Presentation slides, a Primer webinar and additional program information are available online on the society's website.     

Promising approaches in cancer immunotherapy

Immunotherapy is a promising field, which enhances and harnesses the powers of the host immune system against cancer and in recent years, has become a major application of the fundamental research of cancer immunology. Cancer immunotherapy is often more targeted than non-specific therapy approaches, including radiotherapy or chemotherapy, as the immune system can be trained to remember cancer cells, highlighting a durable approach that can be maintained after the treatment completion. Immunotherapy functions by directing the immune system to attack the tumour cells via targeting tumour antigens, also enhancing the existing anti-tumour immune responses. Current strategies include non-specific immunotherapy, cancer vaccines, oncolytic virus therapy, monoclonal antibodies, immune checkpoints and T cell therapy. The combination of effective approaches can increase the immunotherapy efficacy, leading to durable anti-tumour immune responses. This review will discuss the immunotherapy approaches, particularly immune checkpoints and T cell therapy, which are the most common clinical applications in cancer immunotherapy.     

Towards development of T-cell vaccines

Recent studies on the recognition of antigens by CD4' and CD8' T cells have revealed new ways of preparing efficient T-cell vaccines. Here, Constantin Bona and colleagues discuss several approaches for the development of T-cell vaccines, with applications ranging from the induction of protective immunity against intracellular parasites to the development of therapeutic agents against autoimmune disorders, allergic diseases and cancer.     

Tumor-Infiltrating Lymphocyte Therapy for Melanoma: Rationale and Issues for Further Clinical Development

Cancer immunotherapy has become an important area for the future development of cancer therapy; this includes T-cell-based therapies that involve adoptive transfer of autologous T cells derived from the tumors or peripheral blood of cancer patients, vaccines, oncolytic virus therapy, and immunomodulatory antibodies and ligands. Here, we summarize the current approaches and clinical data in the field of adoptive T-cell transfer therapy using tumor-infiltrating lymphocytes (TILs) for metastatic melanoma. We also discuss current knowledge on the mechanism of transferred TILs in mediating tumor regression and the growing need for and recent advances in the identification of predictive biomarkers to better select patients for TIL therapy. The current technical limitations of current TIL expansion methods for out-scaling are discussed as well as how these are being addressed in order to further “industrialize” this form of cell therapy. Lastly, how TIL adoptive transfer can be incorporated into the current melanoma treatment continuum, especially as combination therapy with other immunomodulators and targeted drugs, is discussed.     

Effects of the Tumor Microenvironment on the Efficacy of Tumor Immunotherapy

Cancer immunotherapy utilizes vaccines targeting tumor antigens or tumor endothelium to prevent or regress tumors. Many cancer vaccines are designed to induce antigen-specific effector T cells that migrate to the tumor site. In an optimal situation, the effector T cells penetrate the tumor, release their effector molecules, induce tumor cell death and tumor regression. However, the tumor microenvironment is frequently immunosuppressive and contributes to a state of immune ignorance, impacting on the vaccine's ability to break tolerance to tumor antigen/s. This review discusses the factors in the tumor microenvironment that can affect the efficacy of cancer vaccines. In particular, the review focuses on pathways leading to effector T cell penetration of tumors or the inhibition of this process.     

Immunoregulatory T cells in tumor immunity

One mechanism of cancer immune evasion is the suppression of anti-tumor immunity by immunoregulatory T cells. Recent studies of these cells, especially CD4(+)CD25(+) T cells and NKT cells, have revealed molecular and cellular mechanisms of immunosuppression. Mouse studies have shown that either removing immunoregulatory T cells or blocking an immunoregulatory pathway induced by such cells unmasks natural tumor immunosurveillance and improves responses to cancer vaccines. Studies of the corresponding T-cell populations in human cancer patients support a similar role for immunoregulatory T cells in immunosuppression, implying that blocking immunoregulatory T-cell activity might improve the efficacy of tumor vaccines or the immunotherapy of cancer.     

Effects of the tumor microenvironment on the efficacy of tumor immunotherapy

Cancer immunotherapy utilizes vaccines targeting tumor antigens or tumor endothelium to prevent or regress tumors. Many cancer vaccines are designed to induce antigen-specific effector T cells that migrate to the tumor site. In an optimal situation, the effector T cells penetrate the tumor, release their effector molecules, induce tumor cell death and tumor regression. However, the tumor microenvironment is frequently immunosuppressive and contributes to a state of immune ignorance, impacting on the vaccine's ability to break tolerance to tumor antigen/s. This review discusses the factors in the tumor microenvironment that can affect the efficacy of cancer vaccines. In particular, the review focuses on pathways leading to effector T cell penetration of tumors or the inhibition of this process.     

Effects of the Tumor Microenvironment on the Efficacy of Tumor Immunotherapy

Cancer immunotherapy utilizes vaccines targeting tumor antigens or tumor endothelium to prevent or regress tumors. Many cancer vaccines are designed to induce antigen-specific effector T cells that migrate to the tumor site. In an optimal situation, the effector T cells penetrate the tumor, release their effector molecules, induce tumor cell death and tumor regression. However, the tumor microenvironment is frequently immunosuppressive and contributes to a state of immune ignorance, impacting on the vaccine's ability to break tolerance to tumor antigen/s. This review discusses the factors in the tumor microenvironment that can affect the efficacy of cancer vaccines. In particular, the review focuses on pathways leading to effector T cell penetration of tumors or the inhibition of this process.     

Cancer vaccines for established cancer: how to make them better?

Summary: If one envisions dendritic cells (DCs) as nature's adjuvant, then it is easy to predict that they would be advantageous for cancer immunotherapy. Advances in culture processes that generate large numbers of purified and functionally mature DCs raised the possibility that DCs might be promising clinical agents to generate effective immune responses against cancer. The use of mature DCs as cellular vaccines was proposed to be superior to conventional strategies aimed at treating cancer, yet a phase III clinical trial in patients with melanoma demonstrated no increased benefit of DCs over standard therapy. Despite this and other apparent failures, we propose that DC-based therapy should not be discarded but rather reassessed. The heterogeneity of DCs and their interaction with other innate cells and regulatory and effector pathways must be clearly understood before the full therapeutic benefit of DCs are recognized. Several aspects of DC vaccination require optimization including the following: effective delivery of vaccines to DCs in lymphoid tissues; incorporation of components that induce appropriate DC activation; and facilitation of innate and adaptive interactions and reduction of regulatory T-cell networks or suppressive microenvironments that hinder the function of immune effectors. Application of this knowledge is resulting in encouraging new data in pre-clinical settings, where multiple arms of the immune system are targeted for cancer therapy.     

Determining the immune mechanisms of protection from AIDS: correlates of immunity and the development of syngeneic macaques

Summary: The AIDS pandemic is a global emergency and a preventive vaccine is urgently needed. CD4 and CD8 T-cell responses appear important in controlling human immunodeficiency virus (HIV)-1 in humans and simian immunodeficiency virus (SIV) in macaques. The utility of vaccines that induce high levels of SIV- or HIV-specific T cells has recently become clearer. Since T cells recognize virus-infected cells rather than free virus, T-cell-based vaccines only have the capacity to control infections (non-sterilizing immunity) and to prevent continuing or persisting infection. An HIV/SIV infection of macaques that is partially controlled by vaccine-induced T-cell responses permits a critical window of opportunity for the efficient generation and recruitment of additional T- and B-cell immune responses to the incoming viral inoculum. Although CD8-depletion experiments in macaques have defined the utility of CD8 T responses in control of SIV infections in macaques, direct evidence on the utility of either CD4 or CD8 T-cell responses in protective immunity to SIV following vaccination is lacking. The availability of genetically identical macaques would allow cell transfer studies and help define with more certainty the role of cellular immune responses in protection from AIDS. The review also focuses on the development of syngeneic macaques by twinning and cloning technologies.     

Roadmap to a better therapeutic tumor vaccine

Cell-based cancer vaccines are a highly attractive alternative to standard cancer therapies. They theoretically have the capability of inciting a multitargeted therapeutic response that functions by reshaping the host-tumor interaction, tipping the balance in favor of tumor rejection. Due to the polyclonal immune response induced, they are less likely to result in therapeutic escape than most cancer treatments in use today. Their immune-based mechanism of action offers a unique approach to management that should not be limited by traditional modes of drug resistance. Their favorable side-effect profile further identifies them as a potential treatment modality of choice. Despite these positive features, a number of hurdles must be overcome in order for cancer vaccines to take their place in the clinic as part of standard cancer therapy. Vaccine protocols must be optimized both to induce a high-quality antitumor T-cell response and to abrogate established mechanisms of immune tolerance that actively function to shut antitumor T cells down. By applying basic knowledge of the molecular features of T-cell biology and immune tolerance to the design of trials that combine tumor vaccines with targeted immunomodulatory drugs, potent strategies for inducing effective antitumor immunity can be developed. The first of these combinatorial trials have already been reported and offer a tantalizing glimpse of the future of cancer immunotherapy.     

Genetic engineering of T cells for the immunotherapy of haematological malignancies

Accumulating experimental and clinical evidence has been obtained over recent years in support of the notion that the immune system has the potential to cure cancer. The most convincing example is the graft versus leukaemia effect observed after allogeneic haematopoietic stem cell transplantation. In the autologous setting, however, the isolation and expansion of naturally occurring tumour-specific T cells is a challenging task. Cancer antigens are often self-antigens and cancer-specific T cells are thus subject to selective mechanisms of central and peripheral tolerance. The significant advances in gene-transfer technologies developed over the last decade have offered new tools to overcome these limitations. Natural T cells can be genetically modified to generate high numbers of 'supernatural' tumour-reactive T cells from virtually every cancer patient. Supernatural T cells may express clonal receptors providing new specificities, factors increasing T-cell performance or safety factors enabling their elimination in case of toxicity. Technological improvements applied to novel concepts of T-cell biology and oncogenesis will allow to simultaneously equip T cells with different transgenes and expand a real 'army' of lymphocytes trained to selectively eradicate cancer cells.     

Molecular oncology in pancreatic cancer

Cancer of the pancreas still has a very poor prognosis despite improved diagnostic methods and therapeutic regimens. The reasons for the aggressiveness of this cancer are not known, and the molecular mechanisms that govern the growth of pancreatic cancer cells are still not clearly defined. During the past two decades the development of new molecular biological techniques has offered new perspectives for a better understanding of pancreatic cancer. Tumor markers such as CA19-9 and CEA are used for diagnosis and for following the postoperative course of cancer patients. Characterization of pancreatic cancer cells using several molecular biological techniques has revealed overexpression or altered expression of growth factors and adhesion molecules, implying altered cell-cell and growth-regulatory interactions. In pancreatic cancer mutations in oncogenes and tumor suppressor genes are frequently detected in p53 and K-ras. This article reviews the possible molecular approaches for diagnosis, prognosis, or even therapy of pancreatic cancer.Abbreviations ECM Extracellular matrix - EGF Epidermal growth factor - aFGF Acidic fibroblast growth factor - bFGF Basic fibroblast growth factor - TGF Transforming growth factor     

Epitope- and antigen-specific cancer vaccines.

Anti-idiotypic antibodies (Ab2) that functionally mimic epitopes associated with human cancer cells are the most specific cancer vaccines currently available. Ab2 can induce specific humoral anti-tumor immunity in cancer patients. However, the potential of Ab2 for inducing cellular immunity in cancer patients still requires demonstration. Clonotypic antibodies directed against the combining site for tumor Ag on human T-cell clones may provide highly effective reagents for inducing protective T-cell immunity against human cancer. A new generation of cancer vaccines, molecularly cloned tumor-associated antigens (Ag), has recently been developed. Recombinant Ag have been successfully expressed in vectors allowing large scale production of Ag for immunization of cancer patients. Recombinant tumor Ag was shown to induce specific and protective immunity in experimental animals. In contrast to Ab2, which may mimic a single cancer-associated epitope, recombinant Ag express multiple epitopes that are potentially immunogenic. Ag vaccines, therefore, may be more effective in arresting tumor growth than single epitope (Ab2) vaccines because tumor destruction by antibodies is dependent on antibody density on tumor cell surfaces. In light of the important roles that both B and T cells play in the control of tumor growth, the demonstration of induction of specific B and T cell-immunity by recombinant tumor Ag and Ab2 in experimental animals is encouraging. Ultimately, the immunomodulatory role of both types of vaccines has to be compared in cancer patients who are immunologically tolerant to many Ag/epitopes expressed by their growing tumors. The development of both Ab2 and recombinant Ag for single antigenic systems provides the first step towards this goal.     

Antiviral immune responses modulate the nature of central nervous system (CNS) disease in a murine model of multiple sclerosis

Summary: In animals and in humans, T-cell therapy can cure advanced disseminated leukemia that would otherwise be fatal. The therapeutic effect of immune T cells is quantitative. As the dose of effector T cells is increased, survival is proportionately increased. Therefore, effective T-cell therapy is predicated on the ability to procure large numbers of immune effector T cells. By using cultured T cells, the number of immune T cells can be increased in vivo substantially above che level achievable by vaccination. The survival of cultured T ceils in vivo is dependent upon both the culture conditions used and the therapeutic regimens employed. Under appropriate conditions, cultured T ceils can proliferate in vivo in response to stimulation by antigen, distribute widely and survive long term to provide effector function and immunologic memory. Given that T cells recognize peptides. the need for immunization with tumor can be circumvented by immunization with peptide. Peptide-specific T cells and the progeny of single T-cell clones can provide the necessary cellular functions to eradicate disseminated murine leukemia. The ability of cloned T cells to similarly provide substantial measurable immunity in humans has been validated in clinical trials. By priming with peptides and by using established culture conditions, T-cell therapy can now be directed against virtually any antigen within the host T-cell repertoire. The major remaining question to be answered is which proteins and which peptides are the most suitable targets for T-cell therapy trials.     

The role of CpG in DNA vaccines

One of the most exciting developments in the field of vaccine research in recent years has been DNA vaccines, with which immune responses are induced subsequent to the in vivo expression of antigen from directly introduced plasmid DNA. Strong immune responses have been demonstrated in a number of animal models against many viral, bacterial and parasitic pathogens, and several human clinical trials have been undertaken. The strong and long-lasting antigen-specific humoral (antibodies) and cell-mediated (T help, other cytokine functions and cytotoxic T cells) immune responses induced by DNA vaccines appear to be due to the sustained in vivo expression of antigen, efficient antigen presentation and the presence of stimulatory CpG motifs. These features are desirable for the development of prophylactic vaccines against numerous infectious agents. Furthermore, the strong cellular responses are also very desirable for the development of therapeutic DNA vaccines to treat chronic viral infections or cancer. Efforts are now focusing on understanding the mechanisms for the induction of these immune responses, which in turn should aid in the optimization of DNA vaccines. This review will focus on the role of CpG motifs in DNA vaccines.