The tangible success of vaccines over the past two centuries against infectious agents has had a significant impact on the advancement of closely related fields including immunology and drug design. In turn, the last four decades have seen the emergence of innovative immunological and technological approaches that have advanced the fight against chronic debilitating diseases with high societal and economic burden. We have learnt that the main principles of immunology and vaccine development, traditionally used to protect us against foreign pathogens, can potentially also be used to design vaccines and immunotherapies that can treat or prevent diseases such as cancer and cardiovascular disease or conditions such as drug addiction. A further encouragement for the development of vaccines against these major debilitating diseases has been the confirmed link between infectious agents and some cancers, which led to the development of preventive vaccines against HBV and HPV.
However, devising successful strategies and products in these new therapeutic areas has been met with challenges. This has lead to often frustratingly slow progress, illustrated by the fact that more than 20 years have elapsed between the US FDA approval of the first monoclonal antibody with therapeutic use in 1986 (OKT3 [also called muromonab], an IgG2a CD3-specific used in transplant rejection) and the approval of the first therapeutic cancer vaccine (sipuleucel-T for advanced late stage, metastatic, asymptomatic, hormone-refractory prostate cancer). During this period more than 20 prophylactic vaccines have been licensed Citation[1]. This significant gap is due, in most cases, to a lack in understanding of the mechanisms of maintenance and breakdown of antigenic self-tolerance, immunological networks and the medical risks and distinctions imposed by the staged development of pathological conditions. Seminal discoveries made in the mid and late 1990s on the establishment and maintenance of regulatory networks and their cellular and molecular components are today establishing the foundations of the most advanced efforts in the immunotherapeutic field.
Challenges complicating the design of immunotherapies and therapeutic vaccines are related to their targets being linked to biological pathways specific to the host. This approach contrasts with that used for prophylactic vaccines that are specifically aimed at microbial antigens. Therefore, new approaches used to design and test therapeutic vaccines and immunotherapies will require both innovative thinking and greater vigilance for patient safety. In this Special Focus Issue readers will find comprehensive reviews with tangible examples of the current state of the field and a critical analysis of its evolution.
The partial successes and failures in immunotherapies have suggested that a ‘one-size-fits-all’ strategy (currently employed for most preventive vaccines) may imply the use of combined medical approaches and that efficacy may consist of an incomplete or partial success tailored to each individual medical condition. Effective strategies against cancer, for example, have been refined after the identification of the Achilles’ heel in the development of specific stages of malignant transformation; these stages, also called checkpoints, are characterized by the overexpression or unique synthesis of molecules essential for tumor survival that can be targeted using antibodies and/or selective molecular inhibitors. Success of immunotherapies is particularly inhibited by the strong suppressive microenvironment that shields against productive antitumor responses. Furthermore, new approaches in the prevention and treatment of atherosclerosis are using vaccines designed to inhibit vascular cell wall inflammation generated by autoimmune responses against modified self-antigens ideally through the increase of specific Treg cell responses. Antiallergy vaccines, not covered in this issue, may also depend on stimulating Treg cells. Another challenge is the design of vaccines against drug addiction, which mostly target small molecules (such as cocaine and nicotine), their intermediate metabolites and/or their tissue receptors. In these cases, it will be critical to elicit sustained levels of high-affinity antibodies. Most of these strategies have so far been capable of achieving minimal residual or minimally progressive disease states and many have required the use of combined therapy using different treatment modalities including chemotherapy, cell- and antibody-based treatments, surgery or even the use of more than one vaccine. Nevertheless, these incremental successes have provided proof-of-concept that immunotherapies involving active immunization as a component will have an important impact in the future.
In addition to the technical challenges described above, concerns related to safety associated with timing of therapeutic interventions and the stage of disease need to be considered. Means to minimize toxicities associated with some of these individual or combined treatment modalities is a strong focus of current efforts.
This Special Focus Issue on ‘Therapeutic Vaccines and Immunotherapies: Current Challenges and New Frontiers’ covers a broad range of topics, including: cancer immunotherapy, with particular reference to prostate cancer Citation[2,3], non-small-cell lung cancer Citation[4], HPV therapeutic vaccines Citation[5] and dendritic cells in cancer immunotherapy Citation[6]; immunotherapy for autoimmune diseases Citation[7] and vaccines against atherosclerosis Citation[8]; and vaccines against substance abuse Citation[9] and tobacco addiction Citation[10]. This issue will provide a critical overview of the state of the art of therapeutic vaccines and immunotherapies highlighting both their strengths and weaknesses, and should stimulate reflection on what has been achieved and on the key hurdles ahead.
Disclaimer
The views presented here are those of the authors and not necessarily those of the companies/institutes with which the authors are affiliated.
Financial & competing interests disclosure
E Oviedo-Orta, JB Ulmer and SS Ahmed are employees of Novartis Vaccines and Diagnostics. SS Ahmed holds stock in Novartis Pharma. SA Plotkin has consulted for major vaccine manufacturers. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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