Application of individualized multimodal radiotherapy combined with immunotherapy in metastatic tumors.
Frontiers in immunology
Radiotherapy is one of the mainstays of cancer treatment. More than half of cancer patients receive radiation therapy. In addition to the well-known direct tumoricidal effect, radiotherapy has immunomodulatory properties. When combined with immunotherapy, radiotherapy, especially high-dose radiotherapy (HDRT), exert superior systemic effects on distal and unirradiated tumors, which is called abscopal effect. However, these effects are not always effective for cancer patients. Therefore, many studies have focused on exploring the optimized radiotherapy regimens to further enhance the antitumor immunity of HDRT and reduce its immunosuppressive effect. Several studies have shown that low-dose radiotherapy (LDRT) can effectively reprogram the tumor microenvironment, thereby potentially overcoming the immunosuppressive stroma induced by HDRT. However, bridging the gap between preclinical commitment and effective clinical delivery is challenging. In this review, we summarized the existing studies supporting the combined use of HDRT and LDRT to synergistically enhance antitumor immunity, and provided ideas for the individualized clinical application of multimodal radiotherapy (HDRT+LDRT) combined with immunotherapy.
10.3389/fimmu.2022.1106644
Phase II multicenter trial: first-line immunochemotherapy with or without radiotherapy in metastatic esophageal squamous cell cancer (SCR-ESCC-01).
Future oncology (London, England)
This randomized phase II trial (NCT05978193) combines low-dose radiotherapy (LDRT) and conventionally fractionated radiotherapy (CFRT) with immunochemotherapy for metastatic esophageal squamous cell carcinoma, aiming to assess the potential enhanced effect of radiotherapy on immunotherapy. Patients are administered a PD-1 inhibitor along with paclitaxel and platinum-based chemotherapy (arm B), or combined with LDRT and CFRT (arm A). Immunotherapy is given every 3 weeks with chemotherapy for 4 cycles, followed by immunotherapy maintenance therapy for up to 24 months. In arm A, LDRT (2 Gy, 2 fractions; delivered to the primary and all metastatic tumors) precedes each immunochemotherapy cycle for 4 cycles, followed by CFRT (40-50 Gy, 20-25 fractions; delivered to the primary tumor) starting from the fifth immunotherapy cycle. The primary end point is median progression-free survival. NCT05978193 (clinicaltrials.gov).
10.2217/fon-2023-0674
Low-dose radiotherapy effects the progression of anti-tumor response.
Translational oncology
The history of low-dose radiotherapy (LDRT or LDR) as a treatment modality for malignant tumors dates back to the 1920s. Even with the minimal total dose administered during treatment, LDRT can result in long-lasting remission. Autocrine and paracrine signaling are widely recognized for fostering the growth and development of tumor cells. LDRT exerts systemic anti-tumor effects through various mechanisms, such as enhancing the activity of immune cells and cytokines, shifting the immune response towards an anti-tumor phenotype, influencing gene expression, and blocking crucial immunosuppressive pathways. Additionally, LDRT has been demonstrated to enhance the infiltration of activated T cells and initiate a series of inflammatory processes while modulating the tumor microenvironment. In this context, the objective of receiving radiation is not to directly kill tumor cells but to reprogram the immune system. Enhancing anti-tumor immunity may be a critical mechanism by which LDRT plays a role in cancer suppression. Therefore, this review primarily focuses on the clinical and preclinical efficacy of LDRT in combination with other anti-cancer strategies, such as the interaction between LDRT and the tumor microenvironment, and the remodeling of the immune system.
10.1016/j.tranon.2023.101710
Preclinical study and phase II trial of adapting low-dose radiotherapy to immunotherapy in small cell lung cancer.
Med (New York, N.Y.)
BACKGROUND:Immune checkpoint inhibitors (ICIs) provide modest but unsatisfactory benefits for extensive-stage small cell lung cancer (ES-SCLC). Developing strategies for treating ES-SCLC is critical. METHODS:We preliminarily explored the outcomes of salvage low-dose radiotherapy (LDRT) plus ICI on refractory SCLC patients. Next, we evaluated the combinational efficacy in murine SCLC. The tumor immune microenvironment (TIME) was analyzed for mechanistic study. Subsequently, we conducted a multicenter, prospective phase II trial that administered concurrent thoracic LDRT plus chemoimmunotherapy to treatment-naive ES-SCLC patients (MATCH trial, NCT04622228). The primary endpoint was confirmed objective response rate (ORR), and the key secondary endpoints included progression-free survival (PFS) and safety. FINDINGS:Fifteen refractory SCLC patients treated with LDRT plus ICI were retrospectively reviewed. The ORR was 73.3% (95% confidence interval [CI], 44.9-92.2). We identified a specific dose of LDRT (15 Gy/5 fractions) that exhibited growth retardation and improved survival in murine SCLC when combined with ICIs. This combination recruited a special T cell population, TCF1 PD-1 CD8 stem-like T cells, from tumor-draining lymph nodes into the TIME. The MATCH trial showed a confirmed ORR of 87.5% (95% CI, 75.9-94.8). The median PFS was 6.9 months (95% CI, 5.4-9.3). CONCLUSIONS:These findings verified that LDRT plus chemoimmunotherapy was safe, feasible, and effective for ES-SCLC, warranting further investigation. FUNDING:This research was funded by West China Hospital (no. ZYJC21003), the National Natural Science Foundation of China (no. 82073336), and the MATCH trial was fully funded by Roche (China) Holding Ltd. (RCHL) and Shanghai Roche Pharmaceuticals Ltd. (SRPL).
10.1016/j.medj.2024.06.002
Low-dose radiation therapy mobilizes antitumor immunity: New findings and future perspectives.
International journal of cancer
Radiotherapy has unique immunostimulatory and immunosuppressive effects. Although high-dose radiotherapy has been found to have systemic antitumor effects, clinically significant abscopal effects were uncommon on the basis of irradiating single lesion. Low-dose radiation therapy (LDRT) emerges as a novel approach to enhance the antitumor immune response due to its role as a leverage to reshape the tumor immune microenvironment (TIME). In this article, from bench to bedside, we reviewed the possible immunomodulatory role of LDRT on TIME and systemic tumor immune environment, and outlined preclinical evidence and clinical application. We also discussed the current challenges when LDRT is used as a combination therapy, including the optimal dose, fraction, frequency, and combination of drugs. The advantage of low toxicity makes LDRT potential to be applied in multiple lesions to amplify antitumor immune response in polymetastatic disease, and its intersection with other disciplines might also make it a direction for radiotherapy-combined modalities.
10.1002/ijc.34801
Low-Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy.
Cancer discovery
Developing strategies to inflame tumors is critical for increasing response to immunotherapy. Here, we report that low-dose radiotherapy (LDRT) of murine tumors promotes T-cell infiltration and enables responsiveness to combinatorial immunotherapy in an IFN-dependent manner. Treatment efficacy relied upon mobilizing both adaptive and innate immunity and depended on both cytotoxic CD4 and CD8 T cells. LDRT elicited predominantly CD4 cells with features of exhausted effector cytotoxic cells, with a subset expressing NKG2D and exhibiting proliferative capacity, as well as a unique subset of activated dendritic cells expressing the NKG2D ligand RAE1. We translated these findings to a phase I clinical trial administering LDRT, low-dose cyclophosphamide, and immune checkpoint blockade to patients with immune-desert tumors. In responsive patients, the combinatorial treatment triggered T-cell infiltration, predominantly of CD4 cells with Th1 signatures. Our data support the rational combination of LDRT with immunotherapy for effectively treating low T cell-infiltrated tumors. SIGNIFICANCE: Low-dose radiation reprogrammed the tumor microenvironment of tumors with scarce immune infiltration and together with immunotherapy induced simultaneous mobilization of innate and adaptive immunity, predominantly CD4 effector T cells, to achieve tumor control dependent on NKG2D. The combination induced important responses in patients with metastatic immune-cold tumors..
10.1158/2159-8290.CD-21-0003