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Combination Immunotherapy with Partial Versus Whole Tumor Radiotherapy in a Preclinical Melanoma Tumor Model.

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Title: Combination Immunotherapy with Partial Versus Whole Tumor Radiotherapy in a Preclinical Melanoma Tumor Model.
Authors: Koerner, S.A.1 (AUTHOR), Rajkumar, H.2 (AUTHOR), Edinger, R.2 (AUTHOR), Lalonde, R.J.3 (AUTHOR), Patel, R.B.3 (AUTHOR)
Source: International Journal of Radiation Oncology, Biology, Physics. 2023 Supplement, Vol. 117 Issue 2, pe241-e241. 1p.
Subjects: Immune checkpoint inhibitors, Tumor-infiltrating immune cells, Immunotherapy, Medical dosimetry
Abstract: Partial tumor radiotherapy (PTRT) with immune checkpoint inhibition (ICI) is currently the subject of clinical trials and may be used clinically for large volume tumors when the full gross tumor volume (GTV) cannot be safely treated with full dose. PTRT delivers RT to a portion of the GTV, underdosing or not treating the remainder of the GTV, hypothesizing that ICI-mediated tumor infiltrating lymphocyte (TIL) infiltration will produce adequate disease control in un- or under-irradiated GTV. Standard treatment is whole tumor radiotherapy (WTRT), and potential differences in disease control between PTRT and WTRT with ICI have not been robustly assessed. We hypothesized that PTRT with ICI and WTRT with ICI will demonstrate similar tumor regression, and both RT regimens will demonstrate superior tumor regression as compared to ICI alone. B78 melanoma flank tumors were generated in C57B/L6 mice, with randomization at tumor size of 1 cm to experimental cohorts of PTRT + ICI and WTRT + ICI and control groups of no RT ± ICI. Custom lead shields were fabricated to deliver 16 Gy single fraction PTRT (50% tumor treatment) and WTRT, with dosimetry confirmation via radiochromic film. ICI was delivered through I.P. injection of murine anti-CTLA4 and anti-PD-L1 at days 0, 3, and 6 post-RT. Tumor regression was assessed via differences in tumor volume at ten days post completion of ICI, and mean cohort tumor volumes were compared with ANOVA (α <0.05). Variances between individual cohorts were assessed via t -test (α <0.05). Treatment cohorts demonstrated significant variance in tumor volume at ten days following treatment completion (p = 0.007, Table 1). WTRT + ICI demonstrated superior tumor regression when compared to PTRT + ICI (p = 0.006), ICI alone (p = 0.002), and control cohorts (p = 0.013). There was no difference in tumor regression between PTRT + ICI and ICI alone (p = 0.709), and PTRT + ICI did not achieve significant regression when compared to control (p = 0.083). Tumor regression did not differ between cohorts receiving no RT ± ICI (p = 0.103). Our results in this ICI resistant melanoma model demonstrated superior tumor regression with WTRT + ICI as compared to PTRT + ICI and ICI alone, suggesting that even with concurrent ICI, PTRT may not be sufficient treatment for melanoma. PTRT + ICI tumor regression was similar to ICI alone, suggesting that PTRT may not overcome immune resistance in the unirradiated tumor volume. Further investigation of optimal RT regimens to potentiate ICI response is warranted and correlative studies examining spatial immunomodulation in unirradiated and irradiated portions of the same tumor are underway. [ABSTRACT FROM AUTHOR]
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Abstract:Partial tumor radiotherapy (PTRT) with immune checkpoint inhibition (ICI) is currently the subject of clinical trials and may be used clinically for large volume tumors when the full gross tumor volume (GTV) cannot be safely treated with full dose. PTRT delivers RT to a portion of the GTV, underdosing or not treating the remainder of the GTV, hypothesizing that ICI-mediated tumor infiltrating lymphocyte (TIL) infiltration will produce adequate disease control in un- or under-irradiated GTV. Standard treatment is whole tumor radiotherapy (WTRT), and potential differences in disease control between PTRT and WTRT with ICI have not been robustly assessed. We hypothesized that PTRT with ICI and WTRT with ICI will demonstrate similar tumor regression, and both RT regimens will demonstrate superior tumor regression as compared to ICI alone. B78 melanoma flank tumors were generated in C57B/L6 mice, with randomization at tumor size of 1 cm to experimental cohorts of PTRT + ICI and WTRT + ICI and control groups of no RT ± ICI. Custom lead shields were fabricated to deliver 16 Gy single fraction PTRT (50% tumor treatment) and WTRT, with dosimetry confirmation via radiochromic film. ICI was delivered through I.P. injection of murine anti-CTLA4 and anti-PD-L1 at days 0, 3, and 6 post-RT. Tumor regression was assessed via differences in tumor volume at ten days post completion of ICI, and mean cohort tumor volumes were compared with ANOVA (α <0.05). Variances between individual cohorts were assessed via t -test (α <0.05). Treatment cohorts demonstrated significant variance in tumor volume at ten days following treatment completion (p = 0.007, Table 1). WTRT + ICI demonstrated superior tumor regression when compared to PTRT + ICI (p = 0.006), ICI alone (p = 0.002), and control cohorts (p = 0.013). There was no difference in tumor regression between PTRT + ICI and ICI alone (p = 0.709), and PTRT + ICI did not achieve significant regression when compared to control (p = 0.083). Tumor regression did not differ between cohorts receiving no RT ± ICI (p = 0.103). Our results in this ICI resistant melanoma model demonstrated superior tumor regression with WTRT + ICI as compared to PTRT + ICI and ICI alone, suggesting that even with concurrent ICI, PTRT may not be sufficient treatment for melanoma. PTRT + ICI tumor regression was similar to ICI alone, suggesting that PTRT may not overcome immune resistance in the unirradiated tumor volume. Further investigation of optimal RT regimens to potentiate ICI response is warranted and correlative studies examining spatial immunomodulation in unirradiated and irradiated portions of the same tumor are underway. [ABSTRACT FROM AUTHOR]
ISSN:03603016
DOI:10.1016/j.ijrobp.2023.06.1169