Promising Immune Activation Found in mRCC for AGS-003

The investigational autologous dendritic cell vaccine AGS-003 successfully activated a cytotoxic T cell response that correlates with a prolongation in survival for patients with metastatic renal cell carcinoma

The investigational autologous dendritic cell vaccine AGS-003 successfully activated a cytotoxic T cell response that correlates with a prolongation in survival for patients with metastatic renal cell carcinoma (mRCC), according to an analysis presented at the 2013 Annual Meeting of the Society for Immunotherapy of Cancer.

The open-label phase II study examined AGS-003 plus sunitinib as a treatment for 21 patients with unfavorable-risk mRCC. The final median overall survival from the trial was 30.2 months, with approximately one-third of patients alive after nearly 4 years of follow-up. Following the announcement of these promising results earlier this year, Argos Therapeutics Inc., the company developing the drug, announced the initiation of a phase III investigation.

In a secondary analysis of the study, the absolute number of a distinct AGS-003-specific cytotoxic T cell signature correlated with the improvement in survival. One patient who received long-term treatment with AGS-003 maintained multifunctional expression of the CD28 and CCR7 receptors with negative CD45RA expression for more than 3 years post-treatment. Survival for this patient exceeded the 30-month median in the trial.

"We believe that these additional findings from our phase II trial support the in vivo mechanism of action of AGS-003," said Charles Nicolette, Argos' chief scientific officer and vice president of research and development, in a statement. “We also believe this is the first demonstration in a clinical trial that the magnitude of an adaptive immune response following immunotherapy correlates with prolonged survival."

The production of AGS-003 requires initial legwork, including upfront leukapheresis to collect dendritic cells. AGS-003 is then manufactured by transfecting the autologous dendritic cells with patient-specific RCC amplified RNA and synthetic, truncated human CD40 ligand RNA that has the potential to stimulate the immune system’s antineoplastic properties. After this process, the vaccine is reintroduced into the patient as an intradermal injection, eliciting a highly specific cytotoxic T-cell response through the initiation of a signaling cascade that causes the secretion of the cytokine IL-12.

This mechanism was examined in the analysis using immune monitoring multi-color flow cytometry for patients receiving at least 5 doses of AGS-003 (n=14). These data were then analyzed using an adaptation of binary tree-structure vector quantization, which partitioned cytotoxic T cell subsets into related groups without consideration to clinical outcomes.

Through this approach, the study identified a cytotoxic T cell signature associated with AGS-003. The signature was characterized by the co-expression of the receptors CD28, CCR7, and CD27 in the absence of CD45RA, an isoform of CD45 commonly associated with naïve T lymphocyte expression. The lack of this isoform suggests activation of memory T cell lymphocytes; however, CD45RO expression was not noted.

As a result of these findings, Argos is utilizing the identified cytotoxic T cell signature as a biomarker of response to AGS-003. Moreover, the company will use the quantization platform to track immune responses for patients with mRCC enrolled in the phase III development program.

Four hundred fifty patients are expected to be enrolled in the phase III ADAPT trial, which opened in January 2013. The trial is seeking participants with newly diagnosed clear cell mRCC who are identified as having an unfavorable risk with 1-3 baseline risk factors. Additionally, patients must be candidates for nephrectomy and treatment with sunitinib.

In the trial, patients will be randomized in a 2:1 ratio to receive AGS-003 plus sunitinib or sunitinib alone following a unilateral or partial nephrectomy. In the investigational arm, patients will undergo leukapheresis before receiving treatment. Sunitinib will be administered for a 6-week cycle at 50 mg daily for 4 weeks, with a 2-week treatment holiday. Treatment with AGS-003 consists of three 0.2 mL intradermal injections administered for 5 doses over the course of 15 weeks followed by quarterly doses. Treatment in both arms will be continued until disease progression.

In September, Argos announced that it planned to move the ADAPT study beyond North America. At this point, more than 100 patients have been screened for the trial at more than 80 global sites.

“The continued expansion of the ADAPT study to key centers in Europe and Israel demonstrates the increasing excitement and support throughout the international community in advancing cancer immunotherapy research,” said Doug Plessinger, vice president of Clinical and Medical Affairs at Argos in a statement. “This progress ensures we will remain on track to complete enrollment of the trial in the second half of 2014. Furthermore, we expect to activate more European sites in the United Kingdom and Italy, as well as 15-20 more in North America later this year.”

Final data from the ADAPT clinical trial are expected in December 2015. If positive, the company is expected to submit a Biologic License Application to the FDA. In April 2012, the development of the agent received a Fast Track designation from the FDA.