RESUMO
Despite the significant progress in tumor prevention, early detection, diagnosis and treatment made over recent decades, cancer is still an enormous public health challenge all around the world, with the number of people affected increasing every year. A great deal of effort is therefore being devoted to the search for novel safe, effective and economically sustainable treatments for the growing population of neoplastic patients. One main obstacle to this process is the extremely low percentage of therapeutic approaches that, after successfully passing pre-clinical testing, actually demonstrate activity when finally tested in humans. This disappointing and expensive failure rate is partly due to the pre-clinical murine models used for in vivo testing, which cannot faithfully recapitulate the multifaceted nature and evolution of human malignancies. These features are better mirrored in natural disease models, i.e., companion animals affected by cancers. Herein, we discuss the relevance of spontaneous canine tumors for the evaluation of the safety and anti-tumor activity of novel therapeutic strategies before in-human trials, and present our experience in the development of a vaccine that targets chondroitin sulphate proteoglycan (CSPG)4 as an example of these comparative oncology studies.
Assuntos
Neoplasias/imunologia , Neoplasias/terapia , Animais , Modelos Animais de Doenças , Doenças do Cão/imunologia , Doenças do Cão/terapia , Cães , Humanos , Imunoterapia/métodosRESUMO
Renal cell carcinoma (RCC) is one of the most lethal urologic malignancies. Its incidence continues to rise worldwide with a rate of 2% per year. Approximately, one-third of the RCC patients are diagnosed at advanced stages due to the asymptomatic nature of its early stages. This represents a great hurdle, since RCC is largely chemoresistant/radioresistant, and targeted therapy of mRCC still has limited efficacy. The 5-year survival rate of metastatic RCC (mRCC) is only around 10%. Adoptive cell transfer (ACT), a particular form of cell-based anticancer immunotherapy, is a promising approach in the treatment of mRCC. The vaccination principle, however, faces unique challenges that preclude the efficacy of ACT. In this article, we review the main challenges of ACT in the treatment of mRCC and describe multiple methods that can be used to overcome these challenges. In this respect, the ultimate purpose of this review is to provide a descriptive tool by which to improve the development of novel protocols for ACT of mRCC.
Assuntos
Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Transferência Adotiva/métodos , Animais , Humanos , Imunoterapia/métodos , Taxa de SobrevidaRESUMO
At present, significant experimental and clinical data confirm the active involvement of the peripheral nervous system (PNS) in different phases of cancer development and progression. Most of the research effort focuses on the impact of distinct neuronal types, e.g., adrenergic, cholinergic, dopaminergic, etc. in carcinogenesis, generally ignoring neuroglia. The very fact that these cells far outnumber the other cellular types may also play an important role worthy of study in this context. The most prevalent neuroglia within the PNS consists of Schwann cells (SCs). These cells play a substantial role in maintaining homeostasis within the nervous system. They possess distinct immunomodulatory, inflammatory and regenerative capacities-also, one should consider their broad distribution throughout the body; this makes them a perfect target for malignant cells during the initial stages of cancer development and the very formation of the tumor microenvironment itself. We show that SCs in the tumor milieu attract different subsets of immune regulators and augment their ability to suppress effector T cells. SCs may also up-regulate invasiveness of tumor cells and support metastatic disease. We outline the interactive potential of SCs juxtaposed with cancerous cells, referring to data from various external sources alongside data of our own.
Assuntos
Sistema Nervoso Central/imunologia , Neoplasias/imunologia , Sistema Nervoso Periférico/imunologia , Células de Schwann/imunologia , Animais , Carcinogênese/imunologia , Sistema Nervoso Central/patologia , Progressão da Doença , Homeostase/imunologia , Humanos , Neoplasias/patologia , Neuroglia/imunologia , Neuroglia/patologia , Sistema Nervoso Periférico/patologia , Células de Schwann/patologia , Microambiente Tumoral/imunologiaRESUMO
In the past decade, remarkable progress has been made in immunotherapy against cancer. Specifically, the introduction of immune checkpoint inhibitors has revolutionized the field. However, many patients are unable to benefit significantly from this treatment option. One of the major reasons for this is most likely the absence of an adequate tumor-specific T cell response in these patients. A way to circumvent this problem might be to combine immune checkpoint inhibitor treatment with new strategies to activate tumor-specific T cells. One such strategy could be to activate and mature dendritic cells in situ. Dendritic cells carry an array of external and internal pattern recognition receptors that induce cell activation and maturation when interacting with their corresponding damage-associated or pathogen-associated molecular patterns (DAMPs or PAMPs). Targeting such molecular patterns directly to dendritic cells might be a way to evoke stronger immune responses. Here, we review our recent findings using antibody-targeted DNA. We summarize the results from our experiments showing that dendritic cells can be actively targeted in vivo through the αXß2 integrin subunit CD11c, and that DNA delivered through this receptor in vitro leads to maturation of dendritic cells via the cytosolic cGAS/STING DNA-sensing pathway.
Assuntos
DNA/imunologia , Células Dendríticas/imunologia , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Vacinas de DNA/imunologia , Animais , Humanos , Imunidade Inata , Vacinas de DNA/administração & dosagemRESUMO
Acute myeloid leukemia (AML) is the most common acute leukemia in adults and overall survival remains poor. Chemotherapy is the standard of care for intensive induction therapy. Patients who achieve a complete remission require post-remission therapies to prevent relapse. There is no standard of care for patients with minimal residual disease (MRD), and stem cell transplantation is a salvage therapy. Considering the AML genetic heterogeneity and the leukemia immune-suppressive properties, novel cellular immune therapies to effectively harness immunological responses to prevent relapse are needed. We developed a novel modality of immune therapy consisting of monocytes reprogrammed with lentiviral vectors expressing GM-CSF, IFN-α and antigens. Preclinical studies in humanized mice showed that the reprogrammed monocytes self-differentiated into highly viable induced dendritic cells (iDCs) in vivo which migrated effectively to lymph nodes, producing remarkable effects in the de novo regeneration of T and B cell responses. For the first-in-man clinical trial, the patient's monocytes will be transduced with an integrase-defective tricistronic lentiviral vector expressing GM-CSF, IFN-α and a truncated WT1 antigen. For transplanted patients, pre-clinical development of iDCs co-expressing cytomegalovirus antigens is ongoing. To simplify the product chain for a de-centralized supply model, we are currently exploring a closed automated system for a short two-day manufacturing of iDCs. A phase I clinical trial study is in preparation for immune therapy of AML patients with MRD. The proposed cell therapy can fill an important gap in the current and foreseeable future immunotherapies of AML.
Assuntos
Antígenos de Neoplasias/metabolismo , Vetores Genéticos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Imunoterapia , Interferon-alfa/metabolismo , Leucemia Mieloide Aguda/terapia , Monócitos/imunologia , Células Dendríticas/imunologia , Humanos , Lentivirus/genética , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/metabolismo , Medicina de Precisão , Transplante de Células-TroncoRESUMO
L-arginine depletion by regulatory cells and cancer cells expressing arginase-1 (Arg-1) is a vital contributor to the immunosuppressive tumor microenvironment in patients with cancer. We have recently described the existence of pro-inflammatory effector T cells that recognize Arg-1. Hence, Arg-1-specific self-reactive T cells are a naturally occurring part of the memory T-cell repertoire of the human immune system. Here, we further characterize a highly immunogenic epitope from Arg-1. We describe frequent T-cell-based immune responses against this epitope in patients with cancer, as well as in healthy donors. Furthermore, we show that Arg-1-specific T cells expand in response to the TH2 cytokine interleukin (IL)-4 without any specific stimulation. Arg-1-specific memory TH1 cells that respond to increased IL-4 concentration may, therefore, drive the immune response back into the TH1 pathway. Arg-1-specific T cells thus appear to have an important function in immune regulation. Because Arg-1 plays an important role in the immunosuppressive microenvironment in most cancers, an immune modulatory vaccination approach can readily be employed to tilt the balance away from immune suppression in these settings.
Assuntos
Arginase/imunologia , Vacinas Anticâncer/administração & dosagem , Epitopos de Linfócito T/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Animais , Vacinas Anticâncer/imunologia , Humanos , VacinaçãoRESUMO
Adoptive cell transfer (ACT) using T cell receptor (TCR) gene-modified T cells is an exciting and rapidly evolving field. Numerous preclinical and clinical studies have demonstrated various levels of feasibility, safety, and efficacy using TCR-engineered T cells to treat cancer and viral infections. Although evidence suggests their use can be effective, to what extent and how to improve these therapeutics are still matters of investigation. As TCR affinity has been generally accepted as the central role in defining T cell specificity and sensitivity, selection for and generation of high affinity TCRs has remained a fundamental approach to design more potent T cells. However, traditional methods for affinity-enhancement by random mutagenesis can induce undesirable cross-reactivity causing on- and off-target adverse events, generate exhausted effectors by overstimulation, and ignore other kinetic and cellular parameters that have been shown to impact antigen specificity. In this Focussed Research Review, we comment on the preclinical and clinical potential of TCR gene-modified T cells, summarize our contributions challenging the role TCR affinity plays in antigen recognition, and explore how structure-guided design can be used to manipulate antigen specificity and TCR cross-reactivity to improve the safety and efficacy of TCR gene-modified T cells used in ACT.