Although targeted therapies have enhanced the efficiency of renal cell carcinoma (RCC) treatment, individual responses are usually limited with few complete remissions reported. An expanding therapy field in RCC is immunotherapy – small molecule and autologous treatments that can modulate the immune system to kill cancer cells. Although to date immunotherapies have only induced a response in a subpopulation of patients, a greater proportion of these responses are long lasting highlighting their potential.
Argos Therapeutics recently announced a pilot trial of their autologous immunotherapy AGS-003 as a neoadjuvant treatment prior to nephrectomy in localised RCC (NCT02170389). AGS-003 uses the patient’s own dendritic cells, differentiated from monocytes collected by leukopheresis, and loads these cells with antigens derived from the patient’s tumour. This is intended to induce a cytotoxic T-cell response against tumour cells.
Normally exposure to a foreign antigen activates helper CD4+ T-cells inducing upregulation of CD40L. CD40L binds to CD40 on immature dendritic cells inducing dendritic cell maturation and antigen processing for presentation to CD8+ cytotoxic T lymphocytes (CTLs). Dysfunction of helper CD4+ T-cells and dendritic cells is often seen in RCC patients resulting in a reduced immune response.
AGS-003 aims to address this reduced response by simulating the presence of CD4+ T-cells ex-vivo. Synthetic CD40L RNA and patient tumour-specific RNA are co-electroporated into the patient’s dendritic cells; providing the proteins required for CD40 activation and antigen presentation. By loading dendritic cells with total tumour RNA multiple different tumour antigens are presented to the immune system reducing the risk of clonal escape.
These activated, tumour-antigen loaded dendritic cells are then returned to the patient’s auxiliary lymph node basin via intradermal injection. There tumour antigens are presented to T-cells inducing the production of tumour-specific CD8+ CTLs. The ligation of CD40 in dendritic cells also results in interleukin-12 (IL-12) production – an essential cytokine required to promote the production of a memory T-cell response thereby increasing the likelihood of a long-term response.
AGS-003, in combination with and comparison to the TKI sunitinib, is currently being trialled in metastatic RCC patients (NCT01582672). Sunitinib has been reported to reduce RCC patient tumour-induced immunosuppression, reducing the levels of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) (Finke et al., 2008, Ko et al., 2009). Therefore it is deemed a suitable choice for combination treatments.
The preceding combinatorial phase II trial (NCT00678119) reported a 62% response rate (n=21) and significant increases in median survival (30.2 months) with 24% of patients surviving longer than five years (Amin et al., 2015). In comparison in previous sunitinib trials only 13% of patients survived for longer than 30 months (Motzer et al., 2013). In addition the adverse effects reported were similar to those in patients receiving only sunitinib and could be resolved with standard management.
The efficiency of AGS-003 treatment to induce a memory T-cell response can be measured by increased production of functional CD8+ CTLs. Comparison between baseline levels and levels after five doses of AGS-003 showed increased production in 71% of patients. The increase in CTL production, compared to baseline, was correlated with overall survival (Amin et al., 2015), suggesting that the response seen was the result of AGS-003 treatment.
The new trial will be the first to assess the ability of AGS-003 to interrupt cancer progression before it spreads and is open to all patients with recurrent or stage I/II RCC. If these and future trials continue to show positive results then AGS-003 could provide an effective alternative treatment for sporadic and inherited forms of localised or metastasised RCC.
- Amin A, Dudek AZ, Logan TF, Lance RS, Holzbeierlein JM, Knox JJ, Master VA, Pal SK, Miller WH Jr, Karsh LI, Tcherepanova IY, DeBenedette MA, Williams WL, Plessinger DC, Nicolette CA, & Figlin RA (2015). Survival with AGS-003, an autologous dendritic cell-based immunotherapy, in combination with sunitinib in unfavorable risk patients with advanced renal cell carcinoma (RCC): Phase 2 study results. Journal for immunotherapy of cancer, 3 PMID: 25901286.
- Finke JH, Rini B, Ireland J, Rayman P, Richmond A, Golshayan A, Wood L, Elson P, Garcia J, Dreicer R, Bukowski R (2008). Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clin Cancer Res. Oct 15;14(20):6674-82. PMID: 18927310.
- Ko JS, Zea AH, Rini BI, Ireland JL, Elson P, Cohen P, Golshayan A, Rayman PA, Wood L, Garcia J, Dreicer R, Bukowski R, Finke JH (2009). Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res. Mar 15;15(6):2148-57. PMID: 19276286.
- Motzer RJ, Escudier B, Bukowski R, Rini BI, Hutson TE, Barrios CH, Lin X, Fly K, Matczak E, Gore ME (2013). Prognostic factors for survival in 1059 patients treated with sunitinib for metastatic renal cell carcinoma. Br J Cancer. Jun 25;108(12):2470-7. PMID: 23695024.