Combining Radiotherapy and Cancer Immunotherapy: A Paradigm Shift

Abstract

The therapeutic application of ionizing radiation has been largely based on its cytocidal power combined with the ability to selectively target tumors. Radiotherapy effects on survival of cancer patients are generally interpreted as the consequence of improved local control of the tumor, directly decreasing systemic spread. Experimental data from multiple cancer models have provided sufficient evidence to propose a paradigm shift, whereby some of the effects of ionizing radiation are recognized as contributing to systemic antitumor immunity. Recent examples of objective responses achieved by adding radiotherapy to immunotherapy in metastatic cancer patients support this view. Therefore, the traditional palliative role of radiotherapy in metastatic disease is evolving into that of a powerful adjuvant for immunotherapy. This combination strategy adds to the current anticancer arsenal and offers opportunities to harness the immune system to extend survival, even among metastatic and heavily pretreated cancer patients. We briefly summarize key evidence supporting the role of radiotherapy as an immune adjuvant. A critical appraisal of the current status of knowledge must include potential immunosuppressive effects of radiation that can hamper its capacity to convert the irradiated tumor into an in situ, individualized vaccine. Moreover, we discuss some of the current challenges to translate this knowledge to the clinic as more trials testing radiation with different immunotherapies are proposed.

Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy

“…Antibodies that block negative immune regulatory pathways (checkpoint inhibitors) 5 , including CTLA-4 (cytotoxic T-lymphocyte–associated antigen 4) and PD-1 (programmed cell death 1) receptors, improve survival in patients with advanced disease such as melanoma, bladder, squamous cell head and neck and non-small-cell lung cancer 6–11 . A key clinical approach to improving cancer immunotherapy has been to combine radiotherapy with checkpoint inhibitors to induce the abscopal effect, a phenomenon where local tumor treatment produces systemic regression of metastatic lesions 12 . The abscopal effect is facilitated by the immune system and has been found anecdotally to mediate long-term, durable clinical responses.…”

Management of Italian Patients With Advanced Non–Small-Cell Lung Cancer After Second-Line Treatment: Results of the Longitudinal Phase of the LIFE Observational Study

“…Although SBRT has shown its superior effect on OS in the early stage of NSCLC patients compared with conventional-dose and fractionated radiotherapy, 83 tumor relapse and disease progression often occurred after ionizing irradiation. Apart from direct necrotic death of tumor cells caused by high-intense radiation, radiotherapy has crosstalk with the immune system, indeed, 84 presenting as: (1) induces immunogenic cell death to recruit antitumor T cells to the irradiated site 85,86 ; (2) upregulates expression of MHC I, which were previously downregulated for immune escape 87 ; and (3) expand the diversity of the T cell receptor (TCR) repertoire to detect varieties of tumor antigens. 88 Taken together, radiotherapy is an ingenious modality to convert tumor cells in situ vaccine and this provides a rationale for combing radiotherapy with immunotherapy.…”

Assessing the Effects of Concurrent versus Sequential Cisplatin/Radiotherapy on Immune Status in Lung Tumor–Bearing C57BL/6 Mice

“…Clinically, it has been shown that concurrent CRT regimens significantly improve 5-year survival compared with sequential CRT (8,9), and ICD may be responsible for these improved treatment outcomes (40). Ionizing radiation (15,16) and some types of chemotherapy, such as oxaliplatin and anthracyclines (13), are known to induce ICD. Using an in vitro model, Golden and colleagues (41) recently showed that ionizing radiation dose-dependently induced ICD, and when combined with carboplatin or paclitaxel, radiation treatment enhanced the ICD effect.…”

“…Administering chemotherapy and RTX concurrently may also result in immunogenic cell death (12)(13)(14), which has implications for the use of immunotherapy in combination with CRT. Ionizing radiation (15,16) and some types of chemotherapy, such as anthracyclines and oxaliplatin (13), are known to induce immunogenic cell death, whereas other therapies may result in tolerogenic cell death (17). Although cisplatin by itself is not known to produce immunogenic cell death (18), it is commonly combined with RTX, which is a powerful inducer of calreticulin exposure (16), leading to the induction of immunogenic cell death (18).…”