scholarly journals Towards Curative Cancer Immunotherapy: Overcoming Posttherapy Tumor Escape

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Gang Zhou ◽  
Hyam Levitsky
Keyword(s):  
Cancer Immunotherapy ◽  
Tumor Cells ◽  
Clinical Studies ◽  
Cytotoxic T Lymphocyte ◽  
Treatment Strategies ◽  
Therapeutic Modality ◽  
Tumor Escape ◽  
Immune Effector ◽  
Therapeutic Outcomes ◽  
Preclinical And Clinical Studies

The past decade has witnessed the evolvement of cancer immunotherapy as an increasingly effective therapeutic modality, evidenced by the approval of two immune-based products by the FDA, that is, the cancer vaccine Provenge (sipuleucel-T) for prostate cancer and the antagonist antibody against cytotoxic T-lymphocyte antigen-4 (CTLA-4) ipilimumab for advanced melanoma. In addition, the clinical evaluations of a variety of promising immunotherapy drugs are well under way. Benefiting from more efficacious immunotherapeutic agents and treatment strategies, a number of recent clinical studies have achieved unprecedented therapeutic outcomes in some patients with certain types of cancers. Despite these advances, however, the efficacy of most cancer immunotherapies currently under clinical development has been modest. A recurring scenario is that therapeutic maneuvers initially led to measurable antitumor immune responses in cancer patients but ultimately failed to improve patient outcomes. It is increasingly recognized that tumor cells can antagonize therapy-induced immune attacks through a variety of counterregulation mechanisms, which represent a fundamental barrier to the success of cancer immunotherapy. Herein we summarize the findings from some recent preclinical and clinical studies, focusing on how tumor cells advance their survival and expansion by hijacking therapy-induced immune effector mechanisms that would otherwise mediate their destruction.

scholarly journals Development of preclinical and clinical models for immune-related adverse events following checkpoint immunotherapy: a perspective from SITC and AACR

2021 ◽  
Vol 9 (9) ◽  
pp. e002627
Author(s):  
Nicholas L Bayless ◽  
Jeffrey A Bluestone ◽  
Samantha Bucktrout ◽  
Lisa H Butterfield ◽  
Elizabeth M Jaffee ◽  
...  
Keyword(s):  
Adverse Events ◽  
Cancer Immunotherapy ◽  
Immune Cell ◽  
Cytotoxic T Lymphocyte ◽  
Action Plan ◽  
Treatment Strategies ◽  
Model Systems ◽  
Preclinical Model ◽  
Programmed Death ◽  
Organ Systems

Recent advances in cancer immunotherapy have completely revolutionized cancer treatment strategies. Nonetheless, the increasing incidence of immune-related adverse events (irAEs) is now limiting the overall benefits of these treatments. irAEs are well-recognized side effects of some of the most effective cancer immunotherapy agents, including antibody blockade of the cytotoxic T-lymphocyte-associated protein 4 and programmed death protein 1/programmed-death ligand 1 pathways. To develop an action plan on the key elements needed to unravel and understand the key mechanisms driving irAEs, the Society for Immunotherapy for Cancer and the American Association for Cancer Research partnered to bring together research and clinical experts in cancer immunotherapy, autoimmunity, immune regulation, genetics and informatics who are investigating irAEs using animal models, clinical data and patient specimens to discuss current strategies and identify the critical next steps needed to create breakthroughs in our understanding of these toxicities. The genetic and environmental risk factors, immune cell subsets and other key immunological mediators and the unique clinical presentations of irAEs across the different organ systems were the foundation for identifying key opportunities and future directions described in this report. These include the pressing need for significantly improved preclinical model systems, broader collection of biospecimens with standardized collection and clinical annotation made available for research and integration of electronic health record and multiomic data with harmonized and standardized methods, definitions and terminologies to further our understanding of irAE pathogenesis. Based on these needs, this report makes a set of recommendations to advance our understanding of irAE mechanisms, which will be crucial to prevent their occurrence and improve their treatment.

Fusion Hybrid of Dendritic Cells and Engineered Tumor Cells Expressing Interleukin-12 Induces Type 1 Immune Responses against Tumor

2005 ◽  
Vol 91 (6) ◽  
pp. 531-538 ◽  
Author(s):  
Meiqing Shi ◽  
Liping Su ◽  
Sigou Hao ◽  
Xulin Guo ◽  
Jim Xiang
Keyword(s):  
Cancer Immunotherapy ◽  
Tumor Cells ◽  
Antitumor Immunity ◽  
Cytotoxic T Lymphocyte ◽  
Tumor Regression ◽  
Interleukin 12 ◽  
Myeloma Cells ◽  
Th1 Cytokine

Aims and Background Dendritic cell (DC)-tumor fusion hybrid vaccinees that facilitate antigen presentation represent a novel powerful strategy in cancer immunotherapy. Preclinical studies have demonstrated that IL-12 promotes specific antitumor immunity mediated by T cells in several types of tumors. In the present study, we investigated the antitumor immunity derived from vaccination of fusion hybrids between DCs and engineered J558/IL-12 myeloma cells secreting Th1 cytokine IL-12. Methods The expression vector pcDNA-IL-12 was generated and transfected into J558 myeloma cells and then bone marrow-derived DCs were fused with engineered J558/IL-12 cells. The antitumor immunity derived from vaccination of the fusion hybrid DC/J558/IL-12 was evaluated in vitro and in vivo. Results DC/J558/IL-12 cells secreted recombinant IL-12 (1.6 ng/mL), and inoculation of BALB/c mice with DC/J558/IL-12 hybrid induced a Th1 dominant immune response and resulted in tumor regression. Immunization of mice with engineered DC/J558/IL-12 hybrid elicited stronger J558 tumor-specific cytotoxic T lymphocyte (CTL) responses in vitro as well as more potent protective immunity against J558 tumor challenge in vivo than immunization with the mixture of DCs and J558/IL-12, J558/IL-12 and J558, respectively. Furthermore, the antitumor immunity mediated by DC/J558/1L-12 tumor cell vaccination in vivo appeared to be dependent on CD8+ CTL. Conclusions These results demonstrate that the engineered fusion hybrid vaccines that combine Th1 cytokine gene-modified tumor cells with DCs may be an attractive strategy for cancer immunotherapy.

scholarly journals Molecular Imaging and the PD-L1 Pathway: From Bench to Clinic

2021 ◽  
Vol 11 ◽  
Author(s):  
David Leung ◽  
Samuel Bonacorsi ◽  
Ralph Adam Smith ◽  
Wolfgang Weber ◽  
Wendy Hayes
Keyword(s):  
Clinical Studies ◽  
Diagnostic Tests ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Clinical Implementation ◽  
Pet Tracers ◽  
Multiple Tumor ◽  
Positron Emission ◽  
Programmed Death ◽  
Preclinical And Clinical Studies

Programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors target the important molecular interplay between PD-1 and PD-L1, a key pathway contributing to immune evasion in the tumor microenvironment (TME). Long-term clinical benefit has been observed in patients receiving PD-(L)1 inhibitors, alone and in combination with other treatments, across multiple tumor types. PD-L1 expression has been associated with response to immune checkpoint inhibitors, and treatment strategies are often guided by immunohistochemistry-based diagnostic tests assessing expression of PD-L1. However, challenges related to the implementation, interpretation, and clinical utility of PD-L1 diagnostic tests have led to an increasing number of preclinical and clinical studies exploring interrogation of the TME by real-time imaging of PD-(L)1 expression by positron emission tomography (PET). PET imaging utilizes radiolabeled molecules to non-invasively assess PD-(L)1 expression spatially and temporally. Several PD-(L)1 PET tracers have been tested in preclinical and clinical studies, with clinical trials in progress to assess their use in a number of cancer types. This review will showcase the development of PD-(L)1 PET tracers from preclinical studies through to clinical use, and will explore the opportunities in drug development and possible future clinical implementation.

scholarly journals Development and clinical applications of cancer immunotherapy against PD-1 signaling pathway

2019 ◽  
Vol 26 (1) ◽  
Author(s):  
Grace Wakabayashi ◽  
Yu-Ching Lee ◽  
Frank Luh ◽  
Chun-Nan Kuo ◽  
Wei-Chiao Chang ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cancer Immunotherapy ◽  
Cytotoxic T Lymphocyte ◽  
Immune Therapy ◽  
Death Receptor ◽  
Predictive Biomarkers ◽  
Cancer Therapeutics ◽  
Background Information ◽  
Therapeutic Outcomes ◽  
Clinical Benefits

AbstractDramatic advances in immune therapy have emerged as a promising strategy in cancer therapeutics. In addition to chemotherapy and radiotherapy, inhibitors targeting immune-checkpoint molecules such as cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed cell death receptor-1 (PD-1) and its ligand (PD-L1) demonstrate impressive clinical benefits in clinical trials. In this review, we present background information about therapies involving PD-1/PD-L1 blockade and provide an overview of current clinical trials. Furthermore, we present recent advances involving predictive biomarkers associated with positive therapeutic outcomes in cancer immunotherapy.

scholarly journals PLGA-particle vaccine carrying TLR3/RIG-I ligand Riboxxim synergizes with immune checkpoint blockade for effective anti-cancer immunotherapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Julia Koerner ◽  
Dennis Horvath ◽  
Valerie L. Herrmann ◽  
Anna MacKerracher ◽  
Bruno Gander ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Therapeutic Modality ◽  
Adjuvant Effect ◽  
Biodegradable Poly ◽  
Human Dendritic Cells

AbstractWith emerging supremacy, cancer immunotherapy has evolved as a promising therapeutic modality compared to conventional antitumor therapies. Cancer immunotherapy composed of biodegradable poly(lactic-co-glycolic acid) (PLGA) particles containing antigens and toll-like receptor ligands induces vigorous antitumor immune responses in vivo. Here, we demonstrate the supreme adjuvant effect of the recently developed and pharmaceutically defined double-stranded (ds)RNA adjuvant Riboxxim especially when incorporated into PLGA particles. Encapsulation of Riboxxim together with antigens potently activates murine and human dendritic cells, and elevated tumor-specific CD8+ T cell responses are superior to those obtained using classical dsRNA analogues. This PLGA particle vaccine affords primary tumor growth retardation, prevention of metastases, and prolonged survival in preclinical tumor models. Its advantageous therapeutic potency was further enhanced by immune checkpoint blockade that resulted in reinvigoration of cytotoxic T lymphocyte responses and tumor ablation. Thus, combining immune checkpoint blockade with immunotherapy based on Riboxxim-bearing PLGA particles strongly increases its efficacy.

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