Translational Studies

Multisite Stereotactic Ablative Radiotherapy (SAbR) to Improve Immune Response of High-Dose Interleukin-2 for Metastatic Kidney Cancer Patients

Metastatic RCC (mRCC) continues to have poor prognosis despite recent developments. Given its high immunogenicity, immune-based treatments have been exploited in the treatment of mRCC. High-dose interleukin-2 (HD IL-2), a non-specific cytokine, has been shown to induce durable treatment response in patients with mRCC leading to its FDA approval in 1992. Immune check-point inhibitors and their combination with targeted therapy are now first-line therapy for mRCC. Although response rate has improved with the newer combination agents, complete responses remain poor and both short- and long-term serious toxicities remain a challenge.

One strategy to improve the response rate without potentially increasing side effect in patients with mRCC is to induce a tumor-specific immune response by combining current immune-based therapies with stereotactic ablative body radiation (SAbR). SAbR is thought to enhance anti-tumor immunity by facilitating tumor breakdown, antigen presentation, and T-cell function in addition to a wide range of immune modulating effects, which may synergize with immune therapies. In one of the largest retrospective studies, we have recently published our experience of the safety and efficacy of such combination in patients.

Given its well-known immune-enhancing effects, we hypothesized that adding SAbR will improve the historically reported 20-25% response rate and 7-9% complete response with HD IL-2 in patients with metastatic clear cell RCC. This trial has currently completed accrual and translational studies are being performed to investigate the role of SABR+IL-2 in eliciting an antitumor response mediated by the patients’ immune systems. These studies will enable us to gain deeper insight into the potential influence of tumor neo-antigen on adaptive immune system, leading to anti-tumor immunity in these patients.

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Figure legend: A schematic showing how HD IL-2 synergizes SAbR-induced cytotoxic T-cell mediated tumor cell killing.