EFFECTS OF PROTON THERAPY COMBINED WITH IMMUNOTHERAPY

Mechanisms of combination therapy

Radiation therapy has a complicated effect on tumor immunity, which can sometimes suppress anti‐tumor responses, contributing to its limited effectiveness. 89 Thus, combining radiation therapy with immunotherapy has emerged as a potential solution through their synergistic and abscopal effects. 101 , 102 , 103 Because proton therapy has the following features, it is reasonable to combine it with immunotherapy: (i) Relatively low peripheral lymphocytotoxicity: As described in section 4 on the Impact of Proton Therapy on Peripheral Blood Immune Cells, proton therapy exerts a less adverse impact on lymphocyte subpopulations, such as CD4+ and CD8+ T cells, which are indispensable for an effective immune response. 104 Therefore, the antitumor effects of proton therapy can be enhanced by activating the immune system. (ii) Relatively strong abscopal effect: Proton therapy predominantly induces necrosis in both tumor cells and immune cells instead of apoptosis, releasing more tumor antigens, which can more effectively activate the immune system and thereby enhance the efficacy of immunotherapies. 56 , 57 , 105 (iii) Complicated TME immune landscape: Both immune‐suppressive (TAM2s, MDSCs, Tregs, and PD‐L1) and immune‐activated (TAM1s, CD8+T Cells) cells/molecules in the TME can simultaneously increase following proton therapy. Therefore, combining proton therapy with immunotherapy, such as using immune checkpoint blockades (ICBs), could modulate the TME to enhance immune infiltration and activity. 106 Chen et al. proved this theory in HCC. 85

Proton therapy combined with ICBs

ICBs such as PD‐1, PD‐L1, and CTLA‐4 inhibitors have been widely used in cancer treatment (PD‐1 inhibitors: nivolumab; PD‐L1 inhibitors: durvalumab; PD‐1 inhibitors: tremelimumab and ipilimumab). In 2020, Nguyen et al. proposed combining proton therapy with ICBs as a therapeutic strategy for locally advanced HNSCC in old patients. 107 Several clinical studies have supported this perspective. For example, a case study involving anaplastic pituitary adenoma (APA) showed that treatment with ipilimumab and nivolumab achieved complete remission of the recurred APA after proton irradiation and temozolomide chemotherapy, resulting in no residual tumor burden for 34 months and improved survival rates. 108 Similarly, in two cases of leptomeningeal disease associated with melanoma, combining proton craniospinal irradiation with nivolumab and ipilimumab extended the OS to 7 months and PFS to 5 months while maintaining acceptable toxicity levels. 109 However, contradictory results have been reported in one case. Maslov et al. found that a patient with adenoid cystic carcinoma who received IMPT followed by nivolumab treatment died 3 months later, suggesting that the effectiveness of this combined therapy may be overestimated. 110 In addition to case reports, Kim et al. conducted a phase II trial on recurrent or metastatic squamous cell carcinoma of the head and neck in 2024. Combining durvalumab and tremelimumab with proton therapy increased the overall response rate (ORR) to 30.4%, median OS to 11.1 months (95% CI, 6.5–15.8), and median PFS to 3.7 months (95% CI, 1.6–5.7). 111 Moreover, ongoing research is evaluating the safety and efficacy of a combination of stereotactic body proton therapy with durvalumab in NSCLC, where the precision of proton therapy can mitigate adverse effects while enhancing the therapeutic window of immunotherapies. 112 Notably, compared with photon therapy, proton therapy has the potential to reduce the risk of tumor progression during ICB therapy because patients receiving proton therapy have higher lymphocyte counts, which could improve the PFS and duration of response. 113 Considering that the clinical evidence is insufficient and primarily focuses on a few cancer types, further large‐scale prospective studies are necessary to explore the combination of proton therapy and ICBs across various tumors in clinical practice. Additionally, compared with the combination therapy of photon radiotherapy and ICBs, there is a lack of foundational research on the mechanisms underlying the effect of proton therapy. A mechanistic study was conducted by Chen et al., who discovered that an anti‐PD‐L1 antibody could reverse the suppressive immune landscape induced by proton therapy in HCC. Specifically, there was an increase in tumor‐infiltrating T cells and a decrease in MDSC recruitment within the TME. 85 The possible combinations of ICBs are summarized in Table 3.

Tumor Type | Combined Therapy | Evidence | Research group
HNSCC | Durvalumab, Tremelimumab | Phase II Clinical Trial | Kim et al.111
Central Nervous System Germ Cell Tumors | Cisplatin, Cyclophosphamide, Etoposide, and/or Bleomycin | Single Tertiary Center Clinical Trial | Hong et al.114
Leptomeningeal Disease associated with Melanoma | Ipilimumab, Nivolumab | Case Reports | Sener et al.109
Anaplastic Pituitary Adenoma | Ipilimumab, Nivolumab | Case Reports | Shah et al.108
Adenoid Cystic Carcinoma | Nivolumab | Case Reports | Maslov et al.110
NSCLC | Durvalumab | Review | Mcmillan et al.112
Cisplatin and Paclitaxel | Phase I Clinical Trial | Contreras et al.115
Platinum‐based Chemotherapy | Phase II Clinical Trial | Hoppe et al.116
Albumin‐Bound Paclitaxel and Cisplatin | Clinical Trial | Jin et al.117
ESCA | Fluorouracil, and/or Taxanes, and/or Platinum | Clinical Trial | Abana et al.118
HCC | anti‐PD‐L1 antibody | Experimental Study | Chen et al.85
Pancreatic Cancer | CAR‐T Therapy (targeting mesothelin) | Experimental Study | Amit et al.119
Capecitabine | Phase II Clinical Trial | Rapp et al.120
Medulloblastoma | CAR‐T Therapy (targeting GD2) | Experimental Study | Ni et al.86
Hodgkin Lymphoma | ABVD; ABVE‐PC; DECA; IE | Clinical Trial | Hoppe et al.121
Intrahepatic Cholangiocarcinoma | GCD | Case Reports | Nosaka et al.122

Proton therapy combined with chimeric antigen receptor T Cell (CAR‐T) therapy

In 1993, the Israeli scientist Zelig Eshhar introduced the concept of CAR‐T therapy, 123 which was first applied in a phase I clinical study on ovarian cancer. 124 The main mechanism of CAR‐T cell therapy involves the use of genetic modifications to enable T cells to specifically recognize and attack tumor antigens. This approach can partially overcome tumor cells' immune escape. 125 Since then, CAR‐T cell therapy has been extended to the treatment of leukemia, lymphoma, multiple myeloma, and other hematological malignancies. 126 In recent years, researchers have attempted to apply CAR‐T therapy to modulate the TME in solid tumors by targeting immune checkpoints (PD‐1, CTLA‐4, TIM‐3, LAG‐3, B7‐H3, VISTA, and B7S1), immune suppressive cells (MDSCs, Tregs), immune suppressive cytokines (TGF‐β, IL‐10), tumor vasculature, cancer‐associated stromal cells, reprogramed metabolism and hypoxia. 127 , 128 CAR‐T therapy has been successful in HCC 129 and GBM. 130 Numerous reviews have suggested that combining radiation therapy with CAR‐T cell therapy may be beneficial. 131 , 132 , 133 Recently, proton radiation combined with CAR‐T cell therapy has emerged as a novel tumor treatment strategy (Table 3). For pancreatic cancer, the combination of proton therapy with CAR‐T therapy targeting mesothelin enhanced treatment effectiveness, as proton therapy significantly increased the expression of mesothelin in tumor cells and subsequently contributed to greater infiltration of CAR‐T cells into the tumor. Furthermore, the reactive TME (promotion of TAM1 polarization and reduction in MDSCs), along with the abscopal effect (upregulation of IFN‐γ levels in the serum) can help inhibit tumor growth. 119 In the following year, Ni et al. discovered that pFLASH could sensitize medulloblastoma to GD2 CAR‐T cell therapy by improving CAR‐T cell infiltration and activation. 86 Thus, the combination of proton therapy and CAR‐T cells is a promising direction for future research.