Enhancing the abscopal effect of radiation and immune checkpoint inhibitor therapies with magnetic nanoparticle hyperthermia in a model of metastatic breast cancer

Abstract

Purpose: Enhancing immune responses in triple negative breast cancers (TNBCs) remains a challenge. Our study aimed to determine whether magnetic iron oxide nanoparticle (MION) hyperthermia (HT) can enhance abscopal effects with radiotherapy (RT) and immune checkpoint inhibitors (IT) in a metastatic TNBC model. Methods: One week after implanting 4T1-luc cells into the mammary glands of BALB/c mice, tumors were treated with RT (3 Â 8 Gy)±local HT, mild (HT M , 43 C/20 min) or partially ablative (HT Abl , 45 C/ 5 min plus 43 C/15 min),±IT with anti-PD-1 and anti-CTLA-4 antibodies (both 4 Â 10 mg/kg, i.p.). Tumor growth was measured daily. Two weeks after treatment, lungs and livers were harvested for histopathology evaluation of metastases. Results: Compared to untreated controls, all treatment groups demonstrated a decreased tumor volume; however, when compared against surgical resection, only RT þ HT M þIT, RT þ HT Abl þIT and RT þ HT Abl had similar or smaller tumors. These cohorts showed more infiltration of CD3 þ T-lymphocytes into the primary tumor. Tumor growth effects were partially reversed with T-cell depletion. Combinations that proved most effective for primary tumors generated modest reductions in numbers of lung metastases. Conversely, numbers of lung metastases showed potential to increase following HT þ IT treatment, particularly when compared to RT. Compared to untreated controls, there was no improvement in survival with any treatment. Conclusions: Single-fraction MION HT added to RT þ IT improved local tumor control and recruitment of CD3 þ T-lymphocytes, with only a modest effect to reduce lung metastases and no improvement in overall survival. HT þ IT showed potential to increase metastatic dissemination to lungs.

Hyperthermia Targeting the Tumor Microenvironment Facilitates Immune Checkpoint Inhibitors

“…A case report also found that hyperthermia and ipilimumab combined with IL-2 achieved complete clinical remission of stage IV triple-negative breast cancer with lung metastasis (127). Despite the favorable results, a preclinical study combining magnetic iron oxide nanoparticle hyperthermia and anti-PD-1 and anti-CTLA-4 with a 4T1-luc cell mouse model also showed decreased tumor volume but increased metastatic dissemination and no improvement in overall survival (128). In fact, a study has shown that tumors quickly overcame immune responses by inhibiting the function of CD8 and CD4 T cells, driving a shift to a higher Treg/Teff ratio and upregulating PD-L1/PD-1 expression, which result suggested that tumor microenvironment after hyperthermia is variable and is favorable for anti-PD-1/PD-L1mAb treatment for only a narrow time window (105).…”

Heating technology for malignant tumors: a review

“…A breakthrough in heat-triggered tumor targeted drug delivery is one trend that would further strengthen popularity of the combination with chemotherapy [70,268,[274][275][276][277]. Finally, the recent trend to combine thermal therapies with immunotherapies has demonstrated significant potential to address recurrence and metastasis in preclinical and clinical pilot studies [425][426][427][428]. When this is supported by further clinical evidence, a further growing interest in hyperthermic applications can be expected.…”

Using nanoparticles forin situvaccination against cancer: mechanisms and immunotherapy benefits

“…An enhanced populations of T-cells following the combinatorial therapies presumably due to greate tumor damage/necrosis relative to monotherapy in tumors were noted. Although promising, the abscopal effects using this approach was modest [144]. These studies (Table 2) suggest that optimizing the MNP hyperthermia duration, frequency, and precise control of thermal energy deposition is needed prior to its application as an ISV.…”