Results from a trial of a new therapeutic vaccine for renal cell carcinoma demonstrate that those patients with a measurable immune response to the vaccine have a prolonged overall survival.
The first renal cell carcinoma (RCC) patients have been treated with an RCC-specific therapeutic vaccine in early-stage clinical trials. The results of the trials are published in Nature Medicine and demonstrate that RCC patients who have a measurable immune response to the vaccine, IMA901, have a prolonged overall survival.
“These studies show that patients achieve better clinical benefit if they are able to mount immune responses to multiple peptides in the IMA901 vaccine. This confirms the hypothesis that a broad attack of the immune system on multiple targets simultaneously is beneficial,” said Harpreet Singh-Jasuja, MD, in an email correspondence. Dr. Singh-Jasuja is one of the coauthors of the study and chief scientific officer at Immatics Biotechnologies in Germany.
“The results of the phase I study are certainly intriguing and support the general concept that vaccination against RCC may be feasible,” said Dr. Howard L. Kaufman, director of the Rush University Cancer Center and professor of surgery, immunology, and microbiology.
A phase III pivotal trial is underway to test whether IMA901 can prolong overall survival among advanced RCC patients when added to a first-line treatment with sunitinib (Sutent), a widely used treatment for metastatic RCC. The international, randomized trial is slated to be completed by 2014.
IMA901 was developed by Immatics Biotechnologies. The company, based in Tbingen, Germany, focuses on developing therapeutic vaccines against cancer. IMA901 is the most advanced vaccine in the company’s pipeline, which includes vaccines for colorectal cancer, glioma, gastric cancer, and non–small-cell lung cancer-all of which are in earlier stages of clinical development. Results of a phase I/II trial of a vaccine that consisted of 13 antigens found in colorectal tumors were presented at this year’s American Society of Clinical Oncology meeting in June and showed clinical benefit.
IMA901, according to Immatics, is made up of 10 tumor-associated peptides present on the tumor cells of RCC patients. Each peptide was isolated using tissue samples from patients and validated as inducing a T cell response in clinical studies. All patients also express the human leukocyte antigen on their cancer cells.
The phase I trial included 28 patients, both treatment-naive and previously treated patients. Patients received consecutive IMA901 vaccinations in addition to the immunomodulator, granulocyte-macrophage colony-stimulation factor. One patient had a partial response at 3-month follow-up, and 11 patients had stable disease. T cell responses were associated with better disease control and lower levels of regulatory T cells, according to Singh-Jasuja. Those patients who had an immunogenic response to multiple tumor-associated peptides were more likely to have either a partial response or stable disease compared to patients who only responded to a single antigen in the vaccine. Regulatory T cells are thought to counteract the antitumor response of cancer vaccines.
The phase II trial enrolled 68 patients, randomized one to one to either the vaccine plus cyclophosphamide (an immunostimulant) or to the vaccine alone. Patients in the cyclophosphamide arm received a single injection of cyclophosphamide prior to the first vaccine injection.
The vaccine was generally well tolerated with local skin reactions in both phase I and II trials. No serious safety issues were reported in the phase I trial. Two adverse events in the phase II trial included a systemic allergic reaction to the 12th consecutive vaccination-likely induced by CM-CSF, according to the authors-and another patient with a grade 3 localized allergic reaction after the 11th vaccination. The second patient went on to receive further vaccinations with no sign of an allergic reaction.
One complete response and two partial responses were seen in the phase II trial. The disease control rate was 31%. Similar to the phase I trial, the immune response for the phase II portion of the study was 64%. The researchers found survival time was prolonged among patients who responded to multiple tumor-associated peptides. Cyclophosphamide was found to prolong survival in those patients with a measurable immune response to the vaccine. The authors attribute this affect to the role of cyclophosphamide in reducing regulatory T cells.
However, Kaufman noted that cyclophosphamide has been previously shown to decrease T regulatory cells and because this is not a controlled study, the direct antitumor effect of cyclophosphamide cannot be ruled out.
“The authors did report a strong correlation between immune response to the vaccine and survival, and this finding supports further development of the concept,” added Kaufman who added that the data should be interpreted with caution as the trial was conducted in late-stage RCC patients.
From an analysis of over 300 potential biomarkers, the study also identified two potential outcomes serum biomarkers, apolipoprotein A-1 (APOA1) and chemokine ligand 17 (CCL17), that may predict which patients could achieve both immune and clinical responses, and thus an overall survival benefit, according to the authors. It should be noted that all of the biomarker analyses were conducted retrospectively. Lower levels of APOA1 are found in various cancers-and are associated with oxidative stress. The ongoing phase III trial “aims to validate that these two biomarkers are predictive of improved overall survival,” said Singh-Jasuja.
The authors also suggest that myeloid-derived suppressor cells as well as T regulatory cells may play a role in RCC outcomes. This effect will be explored in the ongoing phase III trial with sunitinib-a tyrosine kinase inhibitor that itself reduced T regulatory cells as well as myeloid-derived suppressor cells, as documented in patients.
“In our view, one major issue in the field of cancer vaccine development is that previously antigens of insufficient number and possibly also insufficient quality have been used,” Singh-Jasuja explained. “We believe that this is also the reason why so few studies have shown a conclusive association of the detected immune response to the vaccine and clinical benefit.”
IMA901 combines 10 antigens in a single vaccine compared to other vaccines currently in late-stage development that consist of a single antigen. According to Singh-Jasuja, this allows for a broad immune system attack. Development of vaccines for RCC has been difficult as well-defined antigens have not been identified.
Immunotherapy has recently been seen as one of the most promising approaches to cancer treatment as it has the potential to extend lifespan, without the chances of resistance development seen for targeted agents. Ipilimumab (Yervoy) was approved in 2011 for metastatic melanoma showing an overall survival benefit, sipuleucel-T (Provenge) for prostate cancer is now available to patients, and a next-generation immunotherapy, anti-PD1, is currently in phase II trials for a range of different cancers, including lung cancer-a cancer not typically thought of as immunogenic.
“Vaccines continue to be promising because they have a significant safety profile, better antigenic targets are being identified and improved adjuvants are now available that can help overcome local tumor escape and immunosuppressive mechanisms,” noted Kaufman, who believes the future of vaccine therapy will be combinations with other agents.
Singh-Jasuja believes that while complex, immunotherapy will be successful if accompanied by predictive biomarker and pharmacodynamic biomarker isolation to both identify those patients who are most likely to respond and to track their progress. “Most importantly for the patients, cancer immunotherapy has the prospect of significantly expanding the life span of patients and not just expanding progression-free survival,” said Singh-Jasuja.