Combining immunotherapy and radiotherapy in lung cancer: a promising future?
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ABSTRACT:
SUBMITTER: Zhou J
PROVIDER: S-EPMC7475524 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
Publications
Combining immunotherapy and radiotherapy in lung cancer: a promising future?
Zhou Jieling J Huang Qian Q Huang Zijian Z Li Jiqiang J
Journal of thoracic disease 20200801 8
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Project description:Since the approval of anti-CTLA4 therapy (ipilimumab) for late-stage melanoma in 2011, the development of anticancer immunotherapy agents has thrived. The success of many immune-checkpoint inhibitors has drastically changed the landscape of cancer treatment. For some types of cancer, monotherapy for targeting immune checkpoint pathways has proven more effective than traditional therapies, and combining immunotherapy with current treatment strategies may yield even better outcomes. Numerous preclinical studies have suggested that combining immunotherapy with radiotherapy could be a promising strategy for synergistic enhancement of treatment efficacy. Radiation delivered to the tumor site affects both tumor cells and surrounding stromal cells. Radiation-induced cancer cell damage exposes tumor-specific antigens that make them visible to immune surveillance and promotes the priming and activation of cytotoxic T cells. Radiation-induced modulation of the tumor microenvironment may also facilitate the recruitment and infiltration of immune cells. This unique relationship is the rationale for combining radiation with immune checkpoint blockade. Enhanced tumor recognition and immune cell targeting with checkpoint blockade may unleash the immune system to eliminate the cancer cells. However, challenges remain to be addressed to maximize the efficacy of this promising combination. Here we summarize the mechanisms of radiation and immune system interaction, and we discuss current challenges in radiation and immune checkpoint blockade therapy and possible future approaches to boost this combination.
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Project description:The advent of immunotherapy is currently revolutionizing the field of oncology, where different drugs are used to stimulate different steps in a failing cancer immune response chain. This review gives a basic overview of the immune response against cancer, as well as the historical and current evidence on the interaction of radiotherapy with the immune system and the different forms of immunotherapy. Furthermore the review elaborates on the many open questions on how to exploit this interaction to the full extent in clinical practice.
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Project description:Lung cancer is a leading cause of cancer-related deaths worldwide despite advances in treatment. In the past few decades, radiotherapy has achieved outstanding technical advances and is being widely used as a definitive, prophylactic, or palliative treatment of patients with lung cancer. The anti-tumor effects of radiotherapy are considered to result in DNA damage in cancer cells. Moreover, recent evidence has demonstrated another advantage of radiotherapy: the induction of anti-tumor immune responses, which play an essential role in cancer control. In contrast, radiotherapy induces an immunosuppressive response. These conflicting reactions after radiotherapy suggest that maximizing immune response to radiotherapy by combining immunotherapy has potential to achieve more effective anti-tumor response than using each alone. Immune checkpoint molecules, such as cytotoxic T-lymphocyte-associated protein 4, programmed cell death-1/programmed death-ligand 1, and their inhibitors, have attracted significant attention for overcoming the immunosuppressive conditions in patients with cancer. Therefore, the combination of immune checkpoint inhibitors and radiotherapy is promising. Emerging preclinical and clinical studies have demonstrated the rationale for these combination strategies. In this review, we outlined evidence suggesting that combination of radiotherapy, including particle therapy using protons and carbon ions, with immunotherapy in lung cancer treatment could be a promising treatment strategy.
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Project description:The emergence of immune checkpoint inhibitors (ICIs) as a pillar of cancer treatment has emphasized the immune system's integral role in tumor control and progression through cancer immune surveillance. ICIs are being investigated and incorporated into the treatment paradigm for lung cancers across stages and histology. To date, definitive concurrent chemoradiotherapy followed by consolidative durvalumab is the only National Comprehensive Cancer Network's recommended treatment paradigm including radiotherapy with ICI in lung cancers, although there are other recommendations for ICI with chemotherapy and/or surgery. This narrative review provides an overall view of the evolving integration and synergistic role of immunotherapy and radiotherapy and outlines the use of immunotherapy with radiotherapy for the management of small cell lung cancer and non-small cell lung cancer. It also reviews selected, practice-changing clinical trials that led to the current standard of care for lung cancers.
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Project description:BackgroundImmunotherapy has shown promise in the treatment of esophageal cancer, but using it alone only benefits a small number of patients. Most patients either do not have a significant response or develop secondary drug resistance. The combination of radiotherapy and immunotherapy appears to be a promising approach to treating esophageal cancer.PurposeWe reviewed milestone clinical trials of radiotherapy combined with immunotherapy for esophageal cancer. We then discussed potential biomarkers for radiotherapy combined with immunotherapy, including programmed cell death-ligand 1 (PD-L1) status, tumor mutation burden (TMB), tumor-infiltrating lymphocytes, ct-DNA, imaging biomarkers, and clinical factors. Furthermore, we emphasize the key mechanisms of radiation therapy-induced immune stimulation and immune suppression in order to propose strategies for overcoming immune resistance in radiation therapy (RT). Lastly, we discussed the emerging role of low-dose radiotherapy (LDRT) , which has become a promising approach to overcome the limitations of high-dose radiotherapy.ConclusionRadiotherapy can be considered a triggering factor for systemic anti-tumor immune response and, with the assistance of immunotherapy, can serve as a systemic treatment option and potentially become the standard treatment for cancer patients.
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Project description:This survey is performed to update knowledge about methods and trends in lung cancer radiotherapy. A significant development has been noticed in radiotherapeutic techniques, but also in the identification of clinical prognostic factors. The improvement in the therapeutic line includes: application of the four-dimensional computer tomography (4DCT), taking advantage of positron emission tomography (PET-CT), designing of new computational algorithms, allowing more precise irradiation planning, development of treatment precision verification systems and introducing IMRT techniques in chest radiotherapy. The treatment outcomes have improved with high dose radiotherapy, but other fractionation alternations have been investigated as well.
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Project description:The use of checkpoint blockade immunotherapy has revolutionized the field of cancer therapy. Although Immune checkpoint blockade (ICB) can achieve persistent response in several cancers, only 20-40% of patients can benefit from this therapeutic method. Preclinical and clinical evidence show that Radiotherapy (RT) can enhance tumor immunogenicity and improve the effects of immune checkpoint inhibitors. However, the actual outcomes are not satisfactory. Our previous studies revealed that the oncogene, Lysine-specific demethylase 4C (KDM4C) could regulate the radiosensitivity of lung cancer cells in vitro and in vivo. However, the role of KDM4C in antitumor immunity remains inconclusive. To that end, we analyzed the composition of infiltrating immune cells in our mouse tumor model using flow cytometry and found that KDM4C silencing could promote the intratumoral infiltration of CD8+ T cells. Further functional analysis showed that KDM4C silencing could promote proliferation, migration and activation of CD8+ T cells in vivo and in vitro and delay CD8+ T cells exhaustion. Mechanistically, using RNA-seq and Chip-PCR analysis, we determined that KDM4C silencing promotes the binding of H3K36me3 to the Cxcl10 promoter region to increase its transcriptional activity and thus induce CD8+ T cell-mediated antitumor response. Our results suggest that KDM4C-specific inhibitor, SD70 can reprogram the epigenetic state and improve the tumor microenvironment. More importantly, we found that the combined use of SD70, RT, and PD-L1 monoclonal antibodies exhibited the strongest antitumor effects and prolonged the survival time of tumor-bearing mice. Together, our findings suggest that a combination of KDM4C-targeted treatment, radiotherapy, and immune checkpoint blockade is safe and efficient for treating lung cancer.
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Project description:Radiotherapy has been used for the treatment of cancer for over a century. Throughout this period, the therapeutic benefit of radiotherapy has continuously progressed due to technical developments and increased insight in the biological mechanisms underlying the cellular responses to irradiation. In order to further improve radiotherapy efficacy, there is a mounting interest in combining radiotherapy with other forms of therapy such as anti-angiogenic therapy or immunotherapy. These strategies provide different opportunities and challenges, especially with regard to dose scheduling and timing. Addressing these issues requires insight in the interaction between the different treatment modalities. In the current review, we describe the basic principles of the effects of radiotherapy on tumor vascularization and tumor immunity and vice versa. We discuss the main strategies to combine these treatment modalities and the hurdles that have to be overcome in order to maximize therapeutic effectivity. Finally, we evaluate the outstanding questions and present future prospects of a therapeutic triad for cancer.
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