Human Oncology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Radiation Oncology, University of Pittsburgh Medical Center Health System, Pittsburgh, Pennsylvania, USA.
J Immunother Cancer. 2023 Jan;11(1). doi: 10.1136/jitc-2022-005463.
The antitumor effects of external beam radiation therapy (EBRT) are mediated, in part, by an immune response. We have reported that a single fraction of 12 Gy EBRT combined with intratumoral anti-GD2 hu14.18-IL2 immunocytokine (IC) generates an effective in situ vaccine (ISV) against GD2-positive murine tumors. This ISV is effective in eradicating single tumors with sustained immune memory; however, it does not generate an adequate abscopal response against macroscopic distant tumors. Given the immune-stimulatory capacity of radiation therapy (RT), we hypothesized that delivering RT to sites of disease would augment systemic antitumor responses to ISV.
We used a syngeneic B78 murine melanoma model consisting of a 'primary' flank tumor and a contralateral smaller 'secondary' flank tumor, treated with 12 Gy EBRT and intratumoral IC immunotherapy to the primary and additional EBRT to the secondary tumor. As a means of delivering RT to all sites of disease, both known and occult, we also used a novel alkylphosphocholine analog, NM600, conjugated to Y as a targeted radionuclide therapy (TRT). Tumor growth, overall survival, and cause of death were measured. Flow cytometry was used to evaluate immune population changes in both tumors.
Abscopal effects of local ISV were amplified by delivering as little as 2-6 Gy of EBRT to the secondary tumor. When the primary tumor ISV regimen was delivered in mice receiving 12 Gy EBRT to the secondary tumor, we observed improved overall survival and more disease-free mice with immune memory compared with either ISV or 12 Gy EBRT alone. Similarly, TRT combined with ISV resulted in improved overall survival and a trend towards reduced tumor growth rates when compared with either treatment alone. Using flow cytometry, we identified an influx of CD8 T cells with a less exhausted phenotype in both the ISV-targeted primary and the distant secondary tumor following the combination of secondary tumor EBRT or TRT with primary tumor ISV.
We report a novel use for low-dose RT, not as a direct antitumor modality but as an immunomodulator capable of driving and expanding antitumor immunity against metastatic tumor sites following ISV.
外照射放射疗法（EBRT）的抗肿瘤作用部分是通过免疫反应介导的。我们已经报告，单次 12GyEBRT 联合肿瘤内抗 GD2 hu14.18-IL2 免疫细胞因子（IC）可产生针对 GD2 阳性鼠肿瘤的有效原位疫苗（ISV）。这种 ISV 可有效根除具有持续免疫记忆的单个肿瘤；然而，它不能针对宏观远处肿瘤产生足够的远隔效应。鉴于放射疗法（RT）的免疫刺激能力，我们假设将 RT 递送至疾病部位将增强对 ISV 的全身抗肿瘤反应。
我们使用源自 B78 鼠黑色素瘤的同种异体模型，该模型由“原发性”侧腹肿瘤和对侧较小的“继发性”侧腹肿瘤组成，对原发性肿瘤给予 12GyEBRT 和肿瘤内 IC 免疫疗法，并对继发性肿瘤给予额外的 EBRT。为了将 RT 递送至所有已知和隐匿的疾病部位，我们还使用了一种新型烷基膦胆碱类似物，与 Y 缀合的 NM600 作为靶向放射性核素治疗（TRT）。测量肿瘤生长、总生存和死亡原因。流式细胞术用于评估两个肿瘤中免疫群体的变化。
对继发性肿瘤给予低至 2-6Gy 的 EBRT 即可放大局部 ISV 的远隔效应。当原发性肿瘤 ISV 方案在接受 12GyEBRT 治疗继发性肿瘤的小鼠中给予时，与单独给予 ISV 或 12GyEBRT 相比，我们观察到总生存改善和更多具有免疫记忆的无病小鼠。同样，与单独治疗相比，TRT 联合 ISV 可改善总生存并降低肿瘤生长率趋势。通过流式细胞术，我们在原发性肿瘤 ISV 联合继发性肿瘤 EBRT 或 TRT 后，在靶向 ISV 的原发性和远处继发性肿瘤中均观察到 CD8 T 细胞的涌入，且具有较少衰竭表型。
我们报告了低剂量 RT 的一种新用途，它不是直接的抗肿瘤方式，而是一种免疫调节剂，能够在给予 ISV 后驱动和扩大针对转移性肿瘤部位的抗肿瘤免疫。
