Project description:Immunotherapy has become standard of care in advanced non-small cell lung cancer (NSCLC) in a number of settings. Radiotherapy remains an important and potentially curative treatment for localized and locally advanced NSCLC not amenable to surgery. While the principal cytotoxic effect of ionizing radiation is via DNA damage, the effect on tumour microenvironment, promoting dendritic cell presentation of tumour-derived antigens to T cells stimulating the host adaptive immune system to mount an immune response against tumours cells, has become of particular interest when combining immunomodulating agents with radiation. The 'abscopal effect' of radiation where non-irradiated metastatic lesions may respond to radiation may be immune-mediated, via radiation primed anti-tumour T cells. Immune priming by radiation offers the potential for increasing the efficacy of immunotherapy and this is subject to on-going clinical trials underpinned by immunological bioassays. Increasing understanding of the interaction between tumour, radiation and immune cells at a molecular level provides a further opportunity for intervention to enhance the potential synergy between radiation and immunotherapy. Applying the potential efficacy of combination therapy to clinical practice requires caution particularly to ensure the safety of the two treatment modalities in early phase clinical trials, many of which are currently underway. We review the biological basis for combining radiation and immunotherapy and examine the existing pre-clinical and clinical evidence and the challenges posed by the new combination of treatments.
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.
Project description:The role of radiotherapy and immunotherapy with immune checkpoint inhibitors (ICI) is of emerging interest in many solid tumours, including breast cancer. There is increasing evidence that the host's immune system plays an important role in influencing the response to treatment and prognosis in breast cancer. Several pre-clinical studies and clinical trials have reported on the 'abscopal effect-regression of distant untreated tumour sites, mediated by an immunological response following ionizing radiation to a targeted tumour site. Stereotactic Ablative Body Radiotherapy (SABR) is a non-invasive technique used to augment various immune responses with an ablative tumoricidal dose when compared to conventional radiotherapy. SABR is characterized by typically 1-5 precision radiotherapy treatments that simultaneously deliver a high dose, whilst sparing normal tissues. Following SABR, there is evidence of systemic immune activation in patients with increased PD1 expression on CD8+ and CD4+ T cells. Studies continue to focus on metastatic triple-negative disease, a highly immunogenic subtype of breast cancer with poor prognosis. In this review, we discuss the immunological effect of SABR, alone and in combination with immunotherapy, and the importance of dose and fractionation. We also propose future strategies for treating oligometastatic disease, where this approach may be most useful for producing durable responses.
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.
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.
Project description:Immunotherapy has revolutionized the treatment of metastatic non-small cell lung cancer (NSCLC). Oligometastasis has been associated with better prognosis than widespread metastatic disease and may be curable by stereotactic body radiotherapy (SBRT). SBRT can stimulate immunogenic anti-tumor activity, which can be further augmented when combined with immunotherapy, such as immune checkpoint inhibitors (ICIs). Thus, its combination with immunotherapy was recognized as a promising treatment option, especially in the metastatic setting. However, the most optimal approach to combine SBRT with immunotherapy remains controversial with early clinical evidence emerging. Here, we review the current clinical evidence supporting the combination of SBRT with immunotherapy in the treatment of metastatic NSCLC. Also, we discuss the current controversies and areas for further exploration associated with this treatment strategy.
Project description:Head and neck squamous cell carcinoma (HNSCC) is a leading cause of morbidity and mortality globally. Despite significant advances in well-established treatment techniques, prognosis for advanced-stage HNSCC remains poor. Recent, accumulating evidence supports a role for immunotherapy in HNSCC treatment. Radiation therapy (RT), a standard treatment option for HNSCC, has immunomodulatory and immunostimulatory effects that may enhance the efficacy of immunotherapy. In several cancer types, combining RT and immunotherapy has been shown to improve tumor response rates, increase survival, and reduce toxicity compared to traditional chemotherapy and radiation therapy. This review provides a timely overview of the current knowledge on the use of RT and immunotherapy for treating HNSCC. It highlights the potential advantages of combining these therapies, such as improved tumor response rates, increased survival, and reduced toxicity. The review also discusses the challenges that need to be addressed when redefining the standard of care in HNSCC, and proposes further research to optimize treatment combinations, minimize radiation-induced toxicity, and identify suitable patient populations for treatment.
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.
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.
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.