Clinical Advances in Hematology & Oncology

September 2019 - Volume 17, Issue 9

Stereotactic Body Radiation Therapy and Immunotherapy

Mustapha Khalife, MD, Kamran Shahid, MD, Raetasha S. Dabney, MD, and Alexandria T. Phan, MD

The authors are affiliated with the division of hematology and oncology at the University of Texas Health Science Center at Tyler, UT Health North Campus Tyler, in Tyler, Texas. Dr Khalife is an assistant professor, and Drs Shahid, Dabney, and Phan are medical oncologists/hematologists. 

Corresponding author: 
Alexandria T. Phan, MD
UT Health North Campus Tyler
University of Texas Health Science Center at Tyler
11937 US Hwy 271
Tyler, TX 75708


Abstract: Immunotherapy has revolutionized the treatment of various types of cancers in recent years. Since the US Food and Drug Administration approval of the anti–cytotoxic T-lymphocyte–associated antigen 4 agent ipilimumab for late-stage melanoma in 2011, results from multiple clinical trials have proven the benefit of immunotherapy in the treatment of other cancers. However, therapeutic resistance to immunotherapy often develops. This has led investigators to combine immunotherapy with stereotactic body radiation therapy (SBRT) in an attempt to improve outcomes. The benefit of the combination is believed to stem from stimulating and suppressing various immune pathways and is further aided by the abscopal effect, in which tumors respond to radiation therapy even in nonradiated metastatic sites. When combined with immunotherapy, radiation causes the tumor to act much like a vaccine by exposing the tumor antigens to activate the immune response. This article reviews the association between the immune system and cancer, as well as the additional systemic benefit that SBRT can have in patients with advanced-stage malignancies being treated with immunotherapy. 


Immunotherapy has achieved good results in patients with various types and stages of malignancies. It has been widely embraced as a therapeutic option given the toxicities of conventional cytotoxic chemotherapy, along with the resistance that ultimately develops with conventional chemotherapy. Immunotherapy is a treatment modality in which the immune system is primed to recognize cancer cells as dangerous, and to eliminate them wherever they are in the organism. Stereotactic body radiation therapy (SBRT), by contrast, targets a specific area. The success of immunotherapy and SBRT has led to studies analyzing the combination of these treatment modalities. The power of the combination is believed to stem from a synergistic effect between immunotherapy and SBRT1-6 that is further aided by the abscopal effect, in which tumors outside of the radiation field respond to radiation therapy.

The Immune System and Its Association With Cancer

The immune system plays an important role in cancer.7 The downregulation and upregulation of different cellular receptors in the setting of cancer and the increased incidence of cancer in immunosuppressed patients support the association between cancer and immunity (Table 1). The result of the complex interaction between the immune system and cancer cells determines the course of the disease (Figure 1).8,9 The immune system constantly exerts immune surveillance to detect and try to eliminate cancerous or otherwise abnormal cells (Figure 2). Cancer cells can evade the immune system, however, through manipulation of their own immunogenicity, production of immunosuppressive mediators, and promotion of immunomodulatory cell types. The most widely studied mechanism of immunologic surveillance is the action of T lymphocytes (mainly CD8+ T lymphocytes) and their ability to distinguish between self-antigens and non–self-antigens. This mechanism is referred to as the “immune synapse” (Figure 1).  

Principles of Cancer Immunotherapy 

Immunotherapy achieves its therapeutic effect by restoring the ability of the immune system to detect and destroy cancer cells.10 In order to achieve that, it relies on a complex interaction between various types of immune cells (Table 2).11-13

Many immunotherapeutic approaches have been studied (Table 3). The major molecules to be successfully used in immunotherapy are the growing class of ligand-receptor pairs, commonly referred to as immune checkpoints. The 2 immune checkpoint receptors that have been most studied, cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed death 1 (PD-1), regulate immune responses at different levels and by different mechanisms. CTLA-4, the first immune checkpoint receptor targeted in melanoma patients, is expressed exclusively on T cells, where it primarily regulates the amplitude of the early stages of T-cell activation. Although CTLA-4 is expressed by activated CD8 killer T cells, the major physiologic impact of this receptor appears to arise through distinct effects on the 2 major subsets of CD4 T cells—downmodulation of helper T-cell activity and enhancement of regulatory T-cell suppressive activity. In contrast to CTLA-4, the major role of PD-1 is to limit the activity of T cells in the peripheral tissues at the time of an inflammatory response to infection and to limit autoimmunity. This translates to a major immune resistance mechanism within the tumor microenvironment. 

Rationale, Pros, and Cons of Combining Radiotherapy With Immunotherapy

Radiotherapy is an integral part of cancer treatment. The available radiation therapy modalities include SBRT, intensity-modulated radiation therapy, proton radiation, and 3-dimensional conformal radiation therapy. The benefits of combining radiotherapy and immunotherapy have been reported in different cancer types, including head and neck squamous cell carcinoma,14 metastatic pancreatic cancer,15 metastatic melanoma,16 lung cancer,17 and brain metastases.18 The benefit of the combination can be attributed to a synergistic effect between immunotherapy and radiotherapy. Immunotherapy works by potentiating the immune response. Instead of radiotherapy providing only local disease control and immunotherapy providing only systemic control, the 2 therapies may enhance each other’s effect.4-6 As a result, researchers have begun to combine immunotherapy with SBRT. 

Locally, SBRT can cause direct damage to cancer cells that causes antigen exposure, leading in turn to local and systemic immune system activation.4,19 It can also stimulate immunogenic cell death and sensitize cancer cells to immunotherapy by promoting the expression of major histocompatibility complex (MHC) class I molecules and other apoptosis-mediating proteins,20 triggering CD8+ T cells19 and releasing high mobility group box 1 (HMGB1) from tumor cells upon exposure to x-ray or carbon-ion radiotherapy.21 SBRT can also induce DNA damage, and the resulting DNA mutations in cells with DNA repair deficiency can increase the burden of neoantigens—which in turn can trigger an immune response.22

SBRT can trigger the systemic immune response via radiotherapy-induced microenvironmental changes to tumor cells as well as the surrounding stromal cells.4 In addition to sensitizing irradiated tumor cells to immunotherapy, radiotherapy can cause the cells to release tumor antigens that prime T cells to attack other tumor cells in the body, including those at distant, nonirradiated sites. In effect, radiotherapy can turn the tumor into a vaccine. 

In summary, the current scientific evidence indicates that conventional radiation affects the immunologic profile of tumors in a particular manner which, in turn, might induce beneficial effects at both the local and systemic levels (the abscopal effect). However, the extent of benefit and the amount of toxicity associated with such an approach are not well known. 

The Abscopal Effect in Immunotherapy and SBRT

The word abscopal is derived from the Latin ab (away from) and scopos (target). In oncology, localized radiation has been observed to initiate an antitumor response that kills cancer cells distant from the primary target. This phenomenon of radiotherapy shrinking the tumor locally and inducing an immune response systemically is known as the abscopal effect. By inducing a systemic increase in antigen recognition, radiotherapy may also induce the T cell–mediated inhibition of untreated distant tumors.23

A review by Hu and colleagues of 23 clinical cases describing the abscopal effect noted that most instances occurred in immunogenic tumors, such as renal cell carcinoma, melanoma, and hepatocellular carcinoma. However, with the continued development and use of immunotherapy strategies incorporating combinations of targeted immunomodulators and immune checkpoint blockade with radiation, the abscopal effect is becoming increasingly relevant in less-immunogenic tumors, such as breast cancer.24

Regarding radiation dose and fractionation effects, a body of literature addresses issues of single-fraction vs multifraction radiation, and whether a dose threshold exists for enhancing immune responses. Both preclinical and clinical reports have demonstrated improved outcomes using single-fraction vs multifraction radiation doses, as well as hypofractionated SBRT dosing vs conventional daily dosing.25 

The abscopal effect is believed to arise from the capability of local radiation to elicit systemic immune effects that control the nonirradiated tumor burden. In the tumor microenvironment, radiation acts as an immune modulator through several mechanisms. Localized radiation induces cell death and release of immunogenic factors via a process called “immunogenic cell death,” which subsequently triggers the release of a number of endogenous damage–associated molecules (calreticulin, high-mobility group box 1 protein, and adenosine triphosphate) that contribute to the priming of the immune system by triggering dendritic cells, resulting in improved antigen presentation to T cells.26

Concerns Over the Combination of Immunotherapy and SBRT

The main concern with using combined modality treatments in general is overlapping toxicities. Patients treated with immune checkpoint inhibitors may develop immune-related adverse events, such as fatigue, rash, skin disorders, colitis, and gastrointestinal events.27,28 When combined with SBRT, the side effects of immunotherapy might be significantly elevated given the potentiating effect that SBRT has on immunotherapy. One retrospective study has shown that adverse events were increased when immunotherapies were combined with radiotherapy for brain metastases.29 The increased toxicity from the combined modality treatment could stem from the fact that SBRT can expose tumor-specific and nontumor-specific antigens to the immune system. Some of the nontumor-specific antigens might prime autoreactive T cells, which attack and damage normal tissues if not properly negatively selected.30


When SBRT is given with immunotherapy, the immune cells can orchestrate an inflammatory environment that may function to inhibit cancer growth both locally and systemically.31

The benefit of combining radiotherapy and immunotherapy derives from a complex synergistic interaction between radiotherapy and the immune system.4 The ability to increase tumor antigen presentation also makes radiotherapy a promising modality in combination with chimeric antigen receptor T-cell therapies. 

These findings warrant preclinical studies to investigate the biological mechanisms underlying the increased toxicity, and to identify potential methods to lower such risks. Future prospective clinical studies are needed to improve our understanding of the benefits and risks associated with such combinations.


Drs Khalife, Shahid, Dabney, and Phan have no disclosures to report. 


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