Triple therapy makes radiation shrink distant kidney tumors in mice
Combining liposomal everolimus plus YM155, radiation and IL-2 shrank both irradiated and untreated kidney tumors in mice. No two-part combination matched it.
Summary
Sometimes radiation aimed at one tumor makes tumors elsewhere in the body shrink. This 'abscopal effect' is rare, even in kidney cancer. Mayo Clinic researchers tested a three-part strategy in mice with kidney tumors on both flanks: tumor-targeted liposomes carrying two drugs (everolimus and YM155), radiation to one tumor only, and the immune-boosting signal interleukin-2. The full combination cut growth in both the irradiated tumor and the untreated tumor far more than any pair of treatments. The untreated tumors also contained more cancer-killing CD8+ T cells and fewer CD163+ macrophages, a type of immune cell that can protect tumors. Mice did not lose weight. The effect was weaker in a second tumor model. This is early mouse work, not a human treatment.
Detailed Summary
The abscopal effect is when radiation to one tumor triggers an immune response that shrinks tumors outside the radiation field. It is rare in patients, even in immunogenic cancers like renal cell carcinoma (RCC). Barriers include poor T cell priming, limited T cell entry into distant tumors, and an immunosuppressive tumor microenvironment. Checkpoint inhibitors combined with radiation have given inconsistent results, so better strategies are needed.
A Mayo Clinic team built a trimodal regimen. EY-L is a tumor-targeted liposome co-delivering the mTOR inhibitor everolimus and the survivin inhibitor YM155. The team had previously shown it radiosensitizes RCC and increases CD8+ T cell infiltration. They added localized radiation and systemic interleukin-2 (IL-2), based on earlier work suggesting YM155 and IL-2 together deplete regulatory T cells and myeloid-derived suppressor cells.
The main test used female Balb/c mice with Renca tumors implanted on both flanks (n = 5 per group). Only right-flank tumors received 10 Gy radiation, on days 5 and 12. EY-L was given twice weekly for three weeks. IL-2 (1.2 µg, intraperitoneal) was given on days 12, 16 and 20. A second model, LVRCC67 in male C57BL/6 mice, followed a similar design.
The triple therapy gave the strongest suppression at both sites. At day 35, irradiated tumors averaged 1009.6 mm³ with EY-L, 570.7 mm³ with EY-L plus radiation, and 140.2 mm³ with the triple regimen. Non-irradiated tumors averaged 1504.6, 724.1 and 124.7 mm³. That is roughly 92% smaller than EY-L alone and 83% smaller than EY-L plus radiation at the distant site. Radiation plus IL-2 without EY-L did not significantly suppress either tumor. EY-L plus IL-2 behaved like EY-L alone. Body weight rose about 10% from baseline, so there was no overt toxicity.
Tissue analysis supported an immune mechanism. Ki67-positive nuclei in non-irradiated tumors fell from 95.8% in controls to 88.5% (EY-L), 81.4% (EY-L plus radiation) and 53.2% (triple). The authors report more CD8+ T cell infiltration and fewer CD163+ macrophages in these untreated tumors. The study also included CD8+ T cell depletion experiments and spatial transcriptomics. Spatial transcriptomics used one non-irradiated tumor per group, with key observations checked by immunohistochemistry. In the LVRCC67 model, trends were similar but modest, which the authors attribute to differences in immune responsiveness.
This is a preclinical proof of concept that rational combinations can push radiation toward a systemic immune effect. Caveats are important: groups were small, tumor measurements and image analysis were non-blinded, the cell lines were not authenticated, and subcutaneous mouse tumors poorly model human RCC. The results held in only one model at full strength, and toxicity was assessed mainly by body weight. Human safety, dosing and benefit are unknown.
Key Findings
- Triple therapy (EY-L + radiation + IL-2) cut endpoint irradiated Renca tumors to 140.2 ± 41.1 mm³ vs 1009.6 ± 253.2 mm³ with EY-L alone and 570.7 ± 234.0 mm³ with EY-L + radiation (n=5)
- Non-irradiated (abscopal) tumors reached only 124.7 ± 39.6 mm³ with triple therapy vs 1504.6 ± 608.2 mm³ (EY-L) and 724.1 ± 342.0 mm³ (EY-L + radiation), about 92% and 83% smaller
- Radiation + IL-2 without EY-L did not significantly suppress tumor growth at either site, and EY-L + IL-2 performed like EY-L alone
- Ki67-positive nuclei in non-irradiated tumors fell from 95.8% (control) to 53.2% with triple therapy, vs 88.5% (EY-L) and 81.4% (EY-L + radiation)
- Non-irradiated tumors from triple-treated mice showed more CD8+ T cell infiltration and fewer CD163+ macrophages
- No significant weight loss in any group; body weight rose about 10% above baseline
- The LVRCC67 model showed similar but more modest effects, which the authors attribute to differing immune responsiveness
Methodology
Bilateral subcutaneous syngeneic RCC models were used: Renca in female Balb/c mice and LVRCC67 in male C57BL/6 mice, with n=5 mice per group randomized before treatment. Only right-flank tumors received 10 Gy radiation (days 5 and 12). EY-L was given twice weekly for three weeks and IL-2 on days 12, 16 and 20. Tumor volume was measured by calipers. Tumors were analyzed by immunohistochemistry (Ki67, CD8, CD163; 15 fields from 3 tumors per group) and by CD8+ T cell depletion with an anti-CD8 antibody. Visium spatial transcriptomics was run on one non-irradiated tumor each from control and triple groups. Statistics used Shapiro–Wilk normality testing, then t-tests or ANOVA with Tukey, or Mann–Whitney or Kruskal–Wallis with Dunn.
Study Limitations
Groups were small (n=5), tumor measurements and image analysis were non-blinded, the cell lines were not authenticated, and spatial transcriptomics used just one tumor per group. Subcutaneous mouse models may not predict human RCC, and the effect was weaker in the LVRCC67 model. Conflict-of-interest information was not available in the supplied text.
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