Beyond checkpoint inhibition – Immunotherapeutical strategies in combination with radiation (original) (raw)
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Combination of Radiotherapy and Immune Checkpoint Inhibitors
Seminars in Radiation Oncology, 2015
The ability of ionizing radiation to cause cell death and inflammatory reactions has been known since the beginning of its therapeutic use in oncology. However, only recently this property of radiation has attracted the attention of immunologists seeking to induce or improve antitumor immunity. As immune checkpoint inhibitors are becoming mainstream cancer treatments, radiation oncologists have begun to observe unexpected out-of-the-field (abscopal) responses in patients receiving radiation therapy during immunotherapy. These unexpected responses were predicted by experimental work in preclinical tumor models and have clear biological bases. Accumulating experimental evidence that radiation induces an immunogenic cell death and promotes recruitment and function of T cells within the tumor microenvironment supports the hypothesis that radiation can convert the tumor into an in situ individualized vaccine. This property of radiation is key to its synergy with immune checkpoint inhibitors, antibodies targeting inhibitory receptors on T cells such as cytotoxic T lymphocyte antigen-4 and programmed death-1. By removing the obstacles hindering the activation and function of antitumor T cells, these agents benefit patients with pre-existing antitumor immunity but are ineffective in patients lacking these spontaneous responses. Radiation induces antitumor T cells complementing the activity of immune checkpoint inhibitors. Semin Radiat Oncol 25:28-33 C 2015 Elsevier Inc. All rights reserved.
Enhancing the efficacy of immunotherapy using radiotherapy
Clinical & Translational Immunology, 2020
Recent clinical breakthroughs in cancer immunotherapy, especially with immune checkpoint blockade, offer great hope for cancer sufferersand have greatly changed the landscape of cancer treatment. However, whilst many patients achieve clinical responses, others experience minimal benefit or do not respond to immune checkpoint blockade at all. Researchers are therefore exploring multimodal approaches by combining immune checkpoint blockade with conventional cancer therapies to enhance the efficacy of treatment. A growing body of evidence from both preclinical studies and clinical observations indicates that radiotherapy could be a powerful driver to augment the efficacy of immune checkpoint blockade, because of its ability to activate the antitumor immune response and potentially overcome resistance. In this review, we describe how radiotherapy induces DNA damage and apoptosis, generates immunogenic cell death and alters the characteristics of key immune cells in the tumor microenvironment. We also discuss recent preclinical work and clinical trials combining radiotherapy and immune checkpoint blockade in thoracic and other cancers. Finally, we discuss the scheduling of immune checkpoint blockade and radiotherapy, biomarkers predicting responses to combination therapy, and how these novel data may be translated into the clinic.
Immune checkpoint inhibitors and radiotherapy-concept and review of current literature
Annals of translational medicine, 2018
Traditional chemotherapeutic agents non-selectively eliminate cancer cells at the expense of normal tissue; in an attempt to minimize such effects, a new class of targeted agents, immunotherapy, was introduced in the late 1950s with the discovery of interferons and the development of the first cancer vaccine. Ever since, immunotherapy evolved, exploiting different cellular mechanisms including dendritic cell therapy, monoclonal antibodies, and cytokines. Immune checkpoint inhibitors (ICPI) are the most recent subclass of this family and we herein review the basis of exploiting this new subclass of immunotherapy with radiotherapy in the context of studies evaluating their effects on human subjects and focusing on the synergism between the molecular pathways operating in the background. PubMed was searched for studies evaluating the combined use of ICPI and radiotherapy among human subjects. The majority of studies noted an increased response rate in patients receiving combined therap...
Frontiers in pharmacology, 2018
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 ...
Radiation therapy and immunotherapy—a potential combination in cancer treatment
Current Oncology
BackgroundRadiation therapy (rt) is a longstanding treatment modality for cancer. In addition, immune checkpoint blockade has been a significant development in the field of immunotherapy, modifying key immunosuppressive pathways of cancer cells.MethodsThe aim of the present work was to review current concepts of rt and immunotherapy synergism, the abscopal effect, and the molecular effects of rt in the tumour microenvironment, its influence on immune stimulation, and potential clinical outcomes that might evolve from ongoing studies. We also discuss potential predictors of clinical response.ResultsUp-to-date literature concerning the mechanisms, interactions, and latest knowledge about rt and immunotherapy was reviewed and summarized, and is presented here.ConclusionsThe possibility of using hyperfractionated rt to combine an abscopal effect with the enhanced effect of immune treatment using checkpoint blockade is a very promising method for future tumour treatments.
Strategies for combining immunotherapy with radiation for anticancer therapy
Immunotherapy, 2015
Radiation therapy controls local disease but also prompts the release of tumor-associated antigens and stress-related danger signals that primes T cells to promote tumor regression at unirradiated sites known as the abscopal effect. This may be enhanced by blocking inhibitory immune signals that modulate immune activity through a variety of mechanisms. Indeed, abscopal responses have occurred in patients with lung cancer or melanoma when given anti-CTLA4 antibody and radiation. Other approaches involve expanding and reinfusing T or NK cells or engineered T cells to express receptors that target specific tumor peptides. These approaches may be useful for immunocompromised patients receiving radiation. Preclinical and clinical studies are testing both immune checkpoint-based strategies and adoptive immunotherapies with radiation.
Combinations of Immunotherapy and Radiation in Cancer Therapy
Frontiers in Oncology, 2014
The immune system has the ability to recognize and specifically reject tumors, and tumors only become clinically apparent once they have evaded immune destruction by creating an immunosuppressive tumor microenvironment. Radiotherapy (RT) can cause immunogenic tumor cell death resulting in cross-priming of tumor-specific T-cells, acting as an in situ tumor vaccine; however, RT alone rarely induces effective anti-tumor immunity resulting in systemic tumor rejection. Immunotherapy can complement RT to help overcome tumorinduced immune suppression, as demonstrated in pre-clinical tumor models. Here, we provide the rationale for combinations of different immunotherapies and RT, and review the pre-clinical and emerging clinical evidence for these combinations in the treatment of cancer.
The future of radiotherapy and immunotherapy concomitantly in cancer management
Medical Journal of Indonesia, 2019
Immunotherapy is a developing field in cancer treatment. Immunotherapy using immune checkpoint inhibitors has been successful in treating patients with metastatic disease, as well as patients who are refractory to standard treatments. Although immunotherapy has yielded considerably positive outcomes, its clinical benefits are limited to a small subset of patients. A combination of radiotherapy and immunotherapy has been shown to provide greater clinical benefits to more patients. Radiation, particularly hypofractionated radiation with stereotactic radiosurgery or stereotactic body radiotherapy, works by priming T cells, upregulating proinflammatory chemokines, and increasing the immunogenicity of tumor cells. Tumor cells develop immunosuppressive mechanisms that protect them from attack by the immune system. Immunotherapy works by disrupting the ability of tumor cells to setup these defenses. When combined with radiotherapy, it can synergistically enhance tumor cell death via cytoto...
Trial Watch: Immunotherapy plus radiation therapy for oncological indications
Malignant cells succumbing to some forms of radiation therapy are particularly immunogenic and hence can initiate a therapeutically relevant adaptive immune response. This reflects the intrinsic antigenicity of malignant cells (which often synthesize a high number of potentially reactive neo-antigens) coupled with the ability of radiation therapy to boost the adjuvanticity of cell death as it stimulates the release of endogenous adjuvants from dying cells. Thus, radiation therapy has been intensively investigated for its capacity to improve the therapeutic profile of several anticancer immunotherapies, including (but not limited to) checkpoint blockers, anticancer vaccines, oncolytic viruses, Toll-like receptor (TLR) agonists, cytokines, and several small molecules with immunostimulatory effects. Here, we summarize recent preclinical and clinical advances in this field of investigation.