Renal cell carcinoma (RCC) is largely resistant to chemotherapy; although the shift to targeted therapies has yielded improved prognoses, many patients’ tumors acquire secondary mutations that develop resistance to targeted agents.1-3 However, advances in cell-based immunotherapy might yield a “second dawn” in RCC therapy.2,4 Phase 2 data reported in November 2013 by Argos Therapeutics indicate that induced memory T-cell immunity following administration of the investigative dendritic cell immunotherapy agent AGS-003 in combination with sunitinib is associated with improved overall survival (OS) among patients with metastatic RCC (mRCC).5

AGS-003, part of Argos’ ArcelisTM platform, is an investigational, fully personalized tumor RNA dendritic cell immunotherapy, designed to induce CD8+CD28+ memory T-cell-driven immune responses. Researchers from Argos and the University of Toronto in Ontario, Canada, presented their phase 2 results for patients with mRCC on November 9th at the 2013 Annual Meeting of the Society for Immunotherapy of Cancer. 

Their analysis found improvements for OS, progression-free survival, and tumor regression, noted Charles Nicolette, PhD, chief scientific officer and vice president of R&D at Argos Therapeutics.

Patients with intermediate- and poor-risk mRCC received standard 6-week cycles of sunitinib plus five doses of AGS-003 every 3 weeks, followed by AGS-003 every 12 weeks until tumor progression was detected. Data for a total of 14 evaluable patients were included in the analysis.5

Median OS was 39.5 months—more than double the expected survival time based on previous studies, Dr. Nicolette said. Although the study sample size was small (14 patients), the researchers also found an increase in the number of patients (52%) who survived more than 30 months, he said.

Using a binary tree-structured vector quantization analytical tool originally designed for use with large genomic datasets, the researchers identified unique cytotoxic T-cell signatures that help predict survival.

“These observations confirm the in vivo mechanism of action of AGS-003 and provide early biomarkers that could predict long-term clinical outcome,” the authors reported. “To the best of our knowledge, this is the first report correlating changes in the magnitude of an adaptive immune response post [dendritic cell] immunotherapy with clinical outcome.”

“Dendritic cells are the most potent immune system cells at alerting the immune system of a potential threat,” Dr. Nicolette said in an interview with cancertherapyadvisor.com.

AGS-003 targets a patient’s tumor gene mutations rather than normal (if up-regulated) proteins, Dr. Nicolette emphasized.

“We’re capturing not only the normal tumor proteins, but the mutated ones that are unique to each patient,” he continued.

The “vast majority” of tumor proteins are normal, Dr. Nicolette pointed out. Even when they are overexpressed, vaccines against these normal proteins do not appear to show great promise in eliciting strong immune responses, he explained. By training T cells to target mutated proteins on tumor cells, however, Argos researchers reasoned that they could prolong the lives of patients with mRCC.

“Only a handful of tumor proteins are mutated, which are responsible for a tumor cell being a tumor cell,” he said. The goal, therefore, is to “capture the diversity of the tumor’s antigen repertoire and … put it back into the patient.”

To train a patient’s immune system to attack mRCC tumor cells, researchers extract RNA from a small sample of tumor tissue, and amplify it “to huge amounts,” Dr. Nicolette said.

The phase 2 trial indicates this approach might work.

“The majority of the patients had regressions of metastatic lesions but we’ve never seen autoimmune attacks on the normal contralateral kidney,” he noted. “That shows us [AGS-003] is ignoring normal proteins present in the healthy kidney, and preferentially attacks what’s unique to the tumor.”

A randomized, controlled, multicenter open-label phase 3 trial, Autologous Dendritic Cell Immunotherapy (AGS-003) Plus Standard Treatment of Advanced Renal Cell Carcinoma (ADAPT), is now recruiting patients at more than 100 clinical sites, Dr. Nicolette noted. If all goes well, Argos hopes to pursue a Biologics License Application for AGS-003 with the FDA by the end of 2015, he said.

References

  1. Buti S, Bersanelli M, Sikokis A, et al. Chemotherapy in metastatic renal cell carcinoma today? A systematic review. Anticancer Drugs. 2013;24(6):535-554.
  2. Abe H, Kamai T. Recent advances in the treatment of metastatic renal cell carcinoma. Int J Urol. 2013;20(10):944-955.
  3. McDermottt DF, Atkins MB. Immune therapy for kidney cancer: a second dawn? Semin Oncol. 2013;40(4):492-498.
  4. Yoshimura K, Uemura H. Role of vaccine therapy for renal cell carcinoma in the era of targeted therapy. Int J Urol. 2013;20(8):744-755.
  5. DeBenedette M, Jurisica I, Gamble A, et al. Multi-functional cytotoxic T cell expansion correlates with overall survival after administration of autologous dendritic cell immunotherapy in renal cell cancer patients. J ImmunoTher Cancer. 2013;1(suppl 1):P207.