SPARC-1: A Phase I Trial of Neoadjuvant IL-1beta and PD-1 Blockade in Localized Renal Cell Carcinoma

Background:Immune checkpoint blockade has significantly improved outcomes for patients with renal cell carcinoma (RCC) in the metastatic setting. However, there is currently no neoadjuvant systemic therapy that improves outcomes for patients with localized RCC. Emerging data suggests that immunosuppressive myeloid cell populations within the tumor microenvironment (TME) represent a key mechanism of adaptive immune resistance. In pre-clinical models, targeting interleukin 1 beta (IL-1beta) can successfully re-establish anti-tumor immunity by shifting the myeloid cells towards M1-like tumor associated macrophages (TAM) and decreasing infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs). The SPARC-1 study is testing the hypothesis that neoadjuvant therapy with combined IL-1beta blockade (canakinumab) plus PD-1 blockade (spartalizumab) is safe and can successfully remodel the myeloid compartment towards a pro-inflammatory state in patients with localized RCC.

Methods:This is a single-center, single-arm, phase I trial of patients with localized clear cell RCC (ccRCC) planned for nephrectomy (stage T1b-T4NanyM0). 14 patients will receive immunotherapy with combination canakinumab (300mg IV) plus spartalizumab (400mg IV) every 4 weeks x 2 doses given 6 weeks prior to nephrectomy. The primary endpoints are safety and feasibility. Secondary endpoints include tumor CD8 T cell infiltration, tumor MDSC infiltration and objective response rate. SPARC-1 offers a unique opportunity to utilize fresh tumor tissue to identify changes in the immune TME with single-cell discrimination following therapy. Therefore, correlative studies will include single-cell RNA-sequencing, multi-color flow cytometry and multiplexed immunofluorescence to quantify changes in the density and spatial proximity of distinct immune cell populations within the TME. The study is open with 4 patient currently enrolled at the time of submission. Clinical trial information: NCT04028245.