Abnormal driver mutations contribute to tumor progression and have been prime targets for many therapeutic studies in oncology; however, researchers are focusing more and more on the less-studied passenger mutations and their role in tumor progression.
Beatriz Carreno, PhD
Abnormal driver mutations contribute to tumor progression and have been prime targets for many therapeutic studies in oncology; however, researchers are focusing more and more on the less-studied passenger mutations and their role in tumor progression. Taking this approach, Careeno et al analyzed somatic mutations in melanoma as a potential source for patient-specific neoantigens capable of eliciting an immune response.
Results from the study1published inSciencesuggest that personalized vaccines directed against melanoma-associated somatic mutations broaden the antigenic breadth and clonal diversity of the antitumor response.
Data from three patients with melanoma, who were ipilimumab naïve, enrolled in the phase I clinical trial, which was approved by the US Food and Drug Administration (FDA) as part of an investigational new drug application. All patients had stage III resected cutaneous melanoma and lymph node metastasis indicating possible relapse.
Samples from individual patients were first sequenced to identify patient-specific somatic mutations in the tumor. The mutations were further analyzed to assess the feasibility of translation to produce foreign peptides that had in-silico binding affinity for the HLA-A*02:01 peptide, predicting better antigen presentation on tumor cell surface.2Seven neoantigen candidates out of these binders were selected per patient for a tailor-made vaccine that also included autologous, peptide-pulsed, CD40L/IFN-γ-matured dendritic cells.3Patients received 3 vaccines with 6-week intervals to maximize immune stimulation. The first set of vaccination was initiated in 2013.
“These were very high-risk patients who had tumor recurrence after surgery for tumor removal and were put on ipilimumab treatment,” said Gerald Linette, MD, PhD, a Washington University medical oncologist who led the clinical trial at Siteman Cancer Center and Barnes-Jewish Hospital. “While one patient was in complete remission, two other patients had measurable disease progression after ipilimumab treatment. Post vaccination with the neoantigens, all three patients showed brisk immune response; one patient showing a transient 30% tumor shrinkage during clinical evaluation. The tumor however grew again at next examination and then plateaued,” said Linette. To date, none of the patients showed any adverse effects, according to Linette.“The idea to utilize neoantigens to re-activate the patient’s immune system is not absolutely new,” said Beatriz Carreno, PhD, associate professor of medicine, division of oncology, Washington University School of Medicine in an interview with Targeted Oncology. “However, we have not had the immunological tools until now to address these questions in a systematic manner. Advances in our understanding of the basic biology underlying antigen presentation by major histocompatibility complexes have expanded the immune epitope database, increasing the capabilities of in silico analysis,” she said. “While the driver mutations often develop capability to evade immune surveillance, we wanted to check if the nonessential passenger mutations possess the capability to be recognized as ‘foreign’ by the immune system,” she explained.
Somatic mutations were identified in individual patients with melanoma by tumor sample sequencing at the McDonnell Genome Institution at Washington University. Further in silico analysis and neoantigen prediction were also performed by co-author Elaine Mardis, PhD, the co-director of the facility.
Post in-silico prediction, which involved biochemical validation of neoantigen expression on the cancer cell surface, a prerequisite for eliciting immune response, was done in collaboration with co-author Hilderbrand and his group at the University of Oklahoma Health Sciences Center. Using a combination of these approaches, authors identified neoantigens that had greater chances of being expressed on the cell surface and thereby having a better chance of triggering the immune response.
“The neoantigens are like red flags for the immune system that are normally suppressed by cancer cells. A vaccine containing dendritic cells, the antigen-presenting sentinels of the immune system, along with these red flags should be capable of promoting a strong antitumor response,” said Carreno.
The kinetics of T-cell response to neoantigens was monitored via peripheral blood mononuclear cells including analysis of CD8+ T cells. Rapid immune response to three of the seven neoantigens was observed in the patients as early as 2 weeks and peaked at 8 to 9 weeks after the first vaccination. While the majority of neoantigens produced type I response (high amounts of IFN-γ relative to IL-4, IL-5, and IL-13), two neoantigens elicited a type 2 skewed phenotype (high IL-4, IL-5, and IL-13 relative to IFN- γ). Neoantigen processing and presentation was validated by proteomic analysis. Vaccination increased the frequency of pre-existing TCR-β clone types and also revealed new clone types responding to all neoantigens.
“Our study has merged cancer genomics with immunotherapy to address questions about the capacity of our immune system to be modulated to counter attack tumor progression,” said Careeno. It's a proof-of-concept study that depicts that neoantigens can be used as immune antigens to stimulate a patient’s immune system in a highly personalized format. This study principle can be adopted by other researchers to treat hard-to-cure cancers.”
“The next steps will involve inclusion of more patients to validate these observation, said Linette. “While we are still learning some fundamentals, we need to proceed with caution. The preliminary data is very promising and points to a direction where a combination of surgical manipulation and personalized vaccination along with administration of checkpoint inhibitors will be the future norm to follow.”