Radiotherapy as an immunological booster in patients with metastatic melanoma or renal cell carcinoma treated with high-dose Interleukin-2: evaluation of biomarkers of immunologic and therapeutic response

Abstract

BackgroundTumor cells killed by radiation therapy (RT) are a potentially good source of antigens for dendritic cell (DC) uptake and presentation to T-cells. RT upregulates cell death receptors such as Fas/CD95 and MHC-I, induces the expression of co-stimulatory molecules on tumor cells, and promotes production of pro-inflammatory cytokines. High-dose interleukin-2 (HD-IL-2) bolus has been shown to obtain objective response rates ranging from 15% to 17% in patients with metastatic melanoma or renal cell carcinoma (RCC), with 6% to 8% of cases experiencing a durable complete response. However, HD-IL-2 is also associated with severe side-effects; if it is to remain a component of the curative treatment strategy in patients with metastatic melanoma or RCC, its therapeutic efficacy must be improved and patients who are most likely to benefit from treatment must be identified a priori. We designed a clinical study combining immunomodulating RT and HD-IL-2 to evaluate their clinical and immunological efficacy and to explore the predictive and prognostic value of 1) tumor-specific immune response and 2) serum levels of proangiogenic cytokines.Methods/designThe primary endpoint of this proof-of-principle phase II study is immune response. Secondary endpoints are the identification of biomarkers potentially predictive of response, toxicity, response rate and overall survival. Three daily doses of booster radiotherapy (XRT) at 6–12 Gy will be administered to at least one metastatic field on days −3 to −1 before the first and third cycle. Treatment with IL-2 (dose 18 MIU/m2/day by continuous IV infusion for 72 hours) will start on day +1 and will be repeated every 3 weeks for up to 4 cycles and then every 4 weeks for a further 2 cycles. Immune response against tumor antigens expressed by melanoma and/or RCC will be evaluated during treatment. Circulating immune effectors and regulators, e.g. cytotoxic T lymphocytes and regulatory T cells, as well as serum levels of proangiogenic/proinflammatory cytokines will also be quantified.DiscussionThis study aims to evaluate the potential immunological synergism between HD-IL-2 and XRT, and to identify biomarkers that are predictive of response to IL-2 in order to spare potentially non responding patients from toxicity.Trial registrationEudraCT no. 2012-001786-32ClinicalTrials.gov Identifier: NCT01884961

Combining Radiotherapy With Anti-angiogenic Therapy and Immunotherapy; A Therapeutic Triad for Cancer?

“…While currently most (pre)clinical research is mainly focused on the combination of radiotherapy with immune checkpoint inhibitors, several alternative immunomodulatory approaches are also being explored. For example, the combination of radiotherapy with immunostimulatory factors such as interleukin-2 (IL-2) (152, 153), granulocyte-macrophage colony-stimulation-factor (GM-CSF) (154), and agonists of the T cell co-stimulatory receptor OX40 (155, 156) has yielded promising responses in early phase clinical trials. Also strategies to trigger an anti-tumor immune response by intratumoral injection of TLR9 agonists in combination with concurrent low-dose radiotherapy on the injection site has shown promising results and excellent safety and tolerability in different tumor types, including low-grade B cell lymphomas (157), cutaneous T cell lymphoma (158) and follicular lymphoma (159).…”

Molecular Aspects and Future Perspectives of Cytokine-Based Anti-cancer Immunotherapy

“…Interleukin 2 is also effective to treat patients with melanoma when combined with dacarbazine monotherapy or anti-VEGF monoclonal antibody (mAb) monotherapy, but do not increase the effectiveness of neuroblastoma therapy in combination with dinutuximab (anti-GD2 mAb) (Ladenstein et al, 2018;Tarhini et al, 2018;Weide et al, 2019). Several clinical trials have also evaluated the effectiveness of the combination of radiotherapy and IL2, however, this approach has not been further developed (Oudard et al, 2011;Ridolfi et al, 2014;van den Heuvel et al, 2015).…”

The Safety of available immunotherapy for the treatment of glioblastoma

“…79 Given its role in enhancing T cell proliferation, high dose IL-2 has led to significant autoimmune reactions including thyroiditis and vitiligo. 81 Constitutional symptoms are commonly encountered with IFN-α treatment in melanoma. Other toxicities include neuropsychiatric issues, hepatotoxicity, neutropenia, thrombocytopenia, lymphopenia, and other autoimmune reactions.…”