Progress in Tumor Research最新文献

Awareness of the need for collaboration across pediatric and adult cancer to care for adolescents and young adults (AYAs) arose from the recognition of the unique characteristics of AYAs with cancer. Neither pediatric nor adult oncology hospital departments are able to provide age-appropriate care single handedly. The best way to bridge the gap in care of AYA cancer patients is to centralize aspects of their care within dedicated AYA care programs, including the following essential components: provision of developmentally appropriate and multidisciplinary (supportive) care, availability of AYA inpatient and outpatient facilities and healthcare professional AYA expertise as collaboration between adult and pediatric departments. Barriers are related to the slowly emerging evidence of benefit, cultural differences (collaboration between pediatric and adult oncology professionals), administrative and logistic challenges (small number of AYAs makes it difficult to create an AYA program in every hospital) and financial aspects (dependency on philanthropic funds). The sustainable development of an AYA program requires acceptance as a standard of care at the clinical and patient community and at government level. To improve the quality, equity and quantity of research and innovation in AYA cancer care across the world, it is necessary to join forces and collaborate in international networks to study issues such as the features of quality care, collaboration between pediatric and adult clinical teams, trial groups and professional societies, and AYA-specific groups such as Critical Mass, Canteen or European Network for Teenagers and Young Adults with Cancer.

Within this chapter, we begin with the invaluable context of the experience of living after cancer as a young person. Then we move to describe the growing body of data indicating the consequences of cancer in patients diagnosed aged as teenagers and young adults (YAs). We identify that, while the variation in definitions used in the literature hamper firm conclusions, specific patterns of substantial morbidity are observed which are distinct from those seen in younger children. When combined with the epidemiology, the overall burden of late effects of adolescents and YA cancer and its treatment are a substantial public health problem. The progress in parts of Europe and the US in bringing together outcomes into medium-sized data sets, combined with the gaps in the data and remaining uncertainties, mean that the time is right for international epidemiological ascertainment of these adverse effects. There are potential benefits for commencing prospective clinical as well retrospective epidemiological study designs.

The definition of soft tissue and bone sarcomas include a large group of several heterogeneous subtypes of mesenchymal origin that may occur at any age. Among the different sarcomas, rhabdomyosarcoma, synovial sarcoma, Ewing sarcoma and osteosarcoma are aggressive high-grade malignancies that often arise in adolescents and young adults. Managing these malignancies in patients in this age bracket poses various clinical problems, also because different therapeutic approaches are sometimes adopted by pediatric and adult oncologists, even though they are dealing with the same condition. Cooperation between pediatric oncologists and adult medical oncologists is a key step in order to assure the best treatment to these patients, preferably through their inclusion into international clinical trials.

Glioma is one of the most devastating cancers, affecting children and young adults, and associated with a very high morbidity and poor prognosis. The propensity of glioma cells to invade normal brain structures makes current treatments poorly efficient and new therapeutic strategies an urgent need. We now know that many of the rules governing immune responses in other tissues are also valid for the brain, providing solid scientific background for developing new strategies exploiting the immune system to fight brain tumors. Some vaccines use tumor-specific mutated peptides (EGFRvIII, IDH1 or personalized peptides), but most are tumor-associated or undefined tumor-derived peptides (tumor-eluted peptides, peptides predicted from tumor-associated proteins or bound to HSPPC-96 complexes), in some cases pulsed on dendritic cells. Cell therapy is less advanced but the first clinical trials exploring the safety of T cells with chimeric antigen receptors incorporating antibodies to EGFRvIII, IL-13Rα2 or Her2 are ongoing. Finally, various strategies designed at reshaping the glioma microenvironment are being tested, including TGFβ inhibition, Treg depletion and immune checkpoint blockade. Altogether, combining vaccines, cell therapy and reshaping of the tumor microenvironment will be the foundation for a new era of therapeutics for brain tumors.

Metastatic lung cancer is the most common cause of cancer mortality globally in both men and women, with 5-year survival of less than 5%. Standard treatment approaches for metastatic lung cancer are based on chemotherapy, with radiation and surgery used for local control, but these rarely result in relapse-free survivals longer than 2-3 years, although they may provide symptom relief. Thus, additional tools are needed to treat this disease. In this chapter, we discuss the various immune-based cancer treatments for lung cancer patients that are being developed, and the increasing awareness that therapies targeted at overcoming immune evasion mechanisms may be essential to clinical efficacy.

Undoubtedly the discovery of immune checkpoints such as CTLA-4 and PD-1 has been crucial to the development of cancer immunotherapy. Although these molecules were originally discovered as molecules playing a role in T cell activation or apoptosis, subsequent preclinical research showed their important role in the maintenance of peripheral immune tolerance. Mice deficient of the immune checkpoints CTLA-4 or PD-1 develop autoimmune-like diseases that occur early after birth and are lethal in the case of CTLA-4 deficiency, or become apparent much later in life in the case of PD-1 deficiency. Blockade of CTLA-4 and PD-1 resulted in the development of antitumor immune responses that were effective as single agents or required additional treatment depending on the preclinical model. Therefore, it was surprising that single-agent anti-CTLA-4 and anti-PD-1 are so effective anticancer treatments in humans. These therapies have revolutionized cancer immunotherapy as they showed for the first time in many years of research in metastatic melanoma, which is considered one of the most immunogenic human cancers, an improvement in overall survival, with an increasing group of patients benefitting long-term from these treatments. In this chapter we discuss the discovery of immune checkpoints, the clinical application of their inhibitors and the future directions of this highly interesting class of molecules.

The history of immunotherapy is rooted in the treatment of melanoma and therapy with immune checkpoint-blocking agents is now a cornerstone for the treatment of metastatic melanoma. The first effective immunotherapies approved by the US Food and Drug Administration in melanoma included interleukin-2 for metastatic disease and interferon alpha in the adjuvant setting. These were followed by a group of new therapies, including checkpoint-blocking antibodies targeting cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1. Therapies intended to 'reeducate' T cells, such as tumor-infiltrating lymphocyte therapy, oncolytic viruses and tumor vaccines, have yielded promising results and are under development. Finally, the integration of the above therapies as well as development of new coinhibitory and costimulatory agents, though in early stages, appear very promising and likely represent the next phase in drug development for the treatment of metastatic melanoma.

Immunotherapy of cancer encompasses different strategies that elicit or enhance the immune response against tumors. The first results from clinical studies have provided promising data for the treatment of lung cancer patients with immunomodulating monotherapies. To improve the potential benefit of cancer immunotherapy, synergistic combinations of the various immunotherapy approaches or of different elements within each of the immunotherapy approaches are being explored. The rationale typically involves different but complementary mechanisms of action, eventually impinging on more than one immune system mechanism. As a prominent example, the simultaneous blockade of PD-1 and CTLA-4 is giving rise to therapeutic synergy, while still offering room for efficacy improvement. Moreover, combinations of immunomodulating agents with chemotherapy or targeted molecules are being tested. Animal models suggest that immunotherapies in combination with these various options offer evidence for synergistic effects and are likely to radically change cancer treatment paradigms. However, data obtained so far indicate that toxic side effects are also potentiated, which may even restrict the selection of patients that are suitable for these combinational approaches. Advancing the field of combinatorial immunotherapy will require changes in the way investigational agents are clinically developed as well as novel experimental end-points for efficacy evaluation. However, this combined therapeutic manipulation of both tumor and stromal cells may lead to a dramatic change in the therapeutic options of lung cancer patients in any disease stage that can only grossly be appreciated by the current studies.

T cells are a new and promising antigen-specific therapeutic option for the treatment of malignant diseases. To achieve antigen specificity against tumor antigens, T cells can be manipulated by gene transfer to express chimeric antigen receptors (CARs). CAR-expressing T cells are called redirected T cells. CARs are composed of an extracellular antibody-derived antigen recognition domain, a transmembrane domain and a cytoplasmatic signal domain. Therefore, redirected T cells combine the exchangeable specificity of an antibody with the cytotoxic machinery of a T cell. Early clinical trials with redirected T cells targeting cluster of differentiation (CD) 19 have shown impressive results in CD19-positive hematological cancers. However, for solid cancers only limited clinical experience exists and new and innovative concepts have to be developed to overcome tumor-mediated immune suppression. Herein, we describe the general design of a CAR, the function of the different domains and the different strategies to produce redirected T cells. Furthermore, we summarize and discuss the preclinical and clinical data indicating the tremendous potential of redirected T cells to become a mainstay of cancer immunotherapy.

Radiotherapy is an important cornerstone in cancer treatment. Ionizing gamma-irradiation is capable of inducing DNA damage and consequential cell death in a precise and effective manner. In recent years it has become clear, however, that this is not the only relevant mechanism of action. Radiotherapy alters the immune composition of the tumor and influences upregulation of MHC I and cancer-testis antigens, inducing immunogenic cell death and supporting dendritic cell activation. Paradoxically, it also increases the relative ratio of regulatory T cells to CD4+ cells, which hampers an effective immune response. Nevertheless, the overall stimulating influence of irradiation on the immune system has been recognized and illustrated in preclinical studies as well as clinical case reports. There have been several attempts to use radiotherapy as an in situ vaccine. The basic rationale is a synergistic effect of different immune therapies like dendritic cell vaccination and CTLA-4 blockade with irradiation. Changes in the immune phenotype after radiotherapy can facilitate dendritic cell functioning. Immune therapy is also able to overcome the inhibitory pool of regulatory T cells through CTLA-4 inhibition, a weak point of radiotherapy. Although successful in preclinical models, there is still a lot of ground that needs to be covered. The optimal radiation dose is crucial, as well as timing and patient selection. Once these unknown parameters are explored, there is a lot of potential in the powerful combination of local immunization and systemic immune treatments for future novel cancer regimens.