Immune Correlates of Abscopal Response in a Lead-in Phase II Trial of Neoadjuvant Stereotactic Ablative Radiotherapy (SABR) for Renal Cell Carcinoma Inferior Vena Cava Tumor Thrombus

Abstract

We report on outcome, abscopal responses and immunologic correlates of the lead-in phase of a phase II trial of neoadjuvant (NA) stereotactic ablative radiotherapy (SABR) to inferior vena cava tumor thrombus (IVC-TT) followed by radical nephrectomy and thrombectomy (RN-T) for 6 patients with renal cell carcinoma (RCC). Serum was collected before, during and after SABR and surgery along with radiated IVC-TT, primary tumor, normal kidney and lung metastasis. Serum was analyzed for cytokines/chemokines, and IgG autoantibodies by microarrays and ELISA. Peripheral blood mononuclear cells (PBMC) were analyzed using mass cytometry (CyTOF) and T-cell receptor repertoire sequencing (TCRrs). Tumor and normal tissue were analyzed using immunohistochemistry and TCRrs. We enrolled 6 RCC patients and treated with NA- SABR (40Gy/5fx) followed by RN-T within a week. The regimen was tolerated well and at a median follow-up of 24 months, all patients are alive. Of the 3 non-metastatic patients, 2 are disease-free (DF) and 1 developed lung metastasis. Of the 3 patients with metastasis at diagnosis, 2 demonstrated abscopal response (1 complete and 1 partial) and 1 had progressive disease (PD). Overall autoantibody titers enhanced post-treatment in the DF patients but did not change in the patients with PD. ELISA of CA IX IgG titers showed the same trend. Pro-inflammatory cytokines/chemokines were increased only in the DF group. We explored the immune mechanisms that possibly caused the complete abscopal response in the patient that had a growing 2.3 cm lingular lung metastasis and smaller lung nodules at baseline. Post-treatment, the lingular lesion showed surrounding ground-glass densities suggesting local inflammation and resolved over the next 6 months. CT-guided biopsy of the lesion showed inflammatory and fibrohistiocytic reparative changes, abundant CD68+ macrophages and CD4+ and CD8+ T cells. Patient remains metastasis-free at 30 months. FoxP3+ cells were identified in both IVC-TT and regressing lung metastasis suggesting that these cells may attenuate cytotoxic T cells and persist to surveil upon tumor elimination. CyTOF showed significant increment of central and effector memory CD4 and CD8 cells overexpressing PD-1 only in the abscopal response patient. TCRrs of PBMC, primary tumor, regressing metastatic site and non-tumor adjacent tissues showed proliferation of multiple new, systemic and persistent tumor associated T cells induced by SABR that reached lung metastasis and their titers correlated with radiographic regression of the metastasis. Neo-Adjuvant SABR for IVC -TT is feasible, safe and in conjunction with surgery led to abscopal responses. SABR and surgery induced immunogenic systemic effects that correlated with improved patient outcome. SABR induced tumor neo-antigen presentation leading to proliferation of new and existing tumor associated T cells that traveled to the metastatic site to induce abscopal response.