In 2014, at Washington University School of Medicine in St. Louis, six melanoma patients received infusions of an anticancer vaccine composed of their own dendritic cells. Our WashU colleagues had extracted immune cells from the patients’ blood two months earlier, cultured them in the lab, and mixed in peptides selected and synthesized based on specific mutations present in the genomes of each patient’s tumor. The cells had then taken up the peptides much as they take up foreign antigens in the body in the course of normal immune patrol. When the clinical team administered the vaccines—each patient received three infusions over several months—they hoped that the dendritic cells would induce activation and expansion of T cells capable of identifying and destroying the cancer cells, while sparing healthy tissue.
This first test of personalized cancer vaccines in people grew out of our collaborative efforts to develop a computational pipeline to identify tumor-unique mutations that could induce immune responses in cancer patients, helping them to fight their diseases. The pipeline’s origin can be traced to the ideas of Bob Schreiber, a cancer immunologist also at WashU. For many years, Schreiber had studied mice that developed sarcomas after exposure to a chemical carcinogen as a model system for characterizing the interactions between cancers and the immune system. In 2011, he approached us about the possibility of sequencing the DNA of these cancer cells to identify unique cancer peptides, or neoantigens, with the potential to stimulate the immune system against cancer. In contrast to cell-based immune therapies, which directly provide the patient with tumor-attacking T cells, the idea was that these neoantigens could be used to create vaccines that stimulate the differentiation of endogenous killer T cells.
At that time, most cancer genomics efforts had focused on finding mutations in cancer genes for which there was a targeted small molecule treatment option. Schreiber’s thought to search for neoantigens seemed to us like an interesting new twist that could lead to a novel type of therapeutic intervention, so we began to build the analytical pipeline he had in mind. Using his mouse model, we identified and validated a neoantigen peptide that was present in the sarcomas of animals that lacked a fully functioning immune system, and that became the target of T cell–mediated elimination when introduced into an immune-capable mouse.1 In a second study, we demonstrated that neoantigens were the targets of T cells activated by checkpoint blockade therapy, and that the introduction of synthesized neoantigens as a vaccine was sufficient to eliminate the sarcoma from mice.2 By demonstrating the efficacy of the neoantigen vaccine in the mouse model, we established the potential for using this approach in cancer patients with demonstrable neoantigens.
As we worked with Bob Schreiber’s lab, we were approached by WashU colleagues Gerald Linette and Beatriz Carreno, a husband-and-wife team now at the University of Pennsylvania’s Perelman School of Medicine who studied melanoma, a type of skin cancer. They had previously developed and tested a dendritic cell vaccine using antigenic peptides from a protein, gp100, that was commonly mutated in melanoma patients. Adding patient-specific neoantigen peptides identified by our pipeline, they wanted to conduct a clinical trial of an enhanced vaccine.
The resulting pipeline, called pVACSeq, evaluates mutated peptide sequences identified from an individual patient’s cancer for their potential to elicit an immune response.3 This analysis includes, for example, the peptides’ ability to be bound by the patient’s particular major histocompatibility complex (MHC) proteins, which are used by both cancer cells and dendritic cells to present the neoantigens on their surface where they can be “seen” by the immune system. We used the pVACSeq pipeline to generate a list of 7 to 10 neoantigens for each of the six patients recruited into the clinical trial. From the blood samples obtained from the patients, our colleagues isolated dendritic cells and created each personalized vaccine by inducing them to take up the synthetic peptides for each set of neoantigens.
After completing the infusions, we evaluated whether the patients experienced an increase in T cells with receptors that bound to the peptides included in the vaccine. We also looked at the diversity of those receptors. Higher receptor diversity is an indicator of the robustness of the T cell populations’ ability to recognize presented neoantigens and elicit cancer cell killing.
Overall, each of the three patients we reported on had seven unique neoantigen peptides added to their vaccine, and of these, three neoantigens had elicited a T cell response, with increased diversity of T cell receptors for these neoantigens compared with pre-vaccine levels, in each melanoma patient.4 These results indicated that it was possible to prime the immune system to recognize nonself, cancer-specific peptides and to elicit an antitumor T cell response that targets cancer cells. In these patients, as well as another three patients whose datasets we completed after publication, we saw no evidence of severe adverse events following vaccine administration, highlighting the cancer cell specificity of the approach. However, our trial results also exposed the need for refining our neoantigen prediction pipeline, as not all of the peptides included in the vaccines elicited a T cell response.
Since the publication of our personalized melanoma vaccine trial, three subsequent studies have demonstrated the potential of neoantigen-based vaccines in treating human cancers. Both academic and industry sponsors are now conducting many more such clinical trials. (See table above.) This activity in the cancer neoantigen vaccine space is indicative of the excitement around the general concept of personalized cancer vaccines, which have thus far demonstrated highly specific immune responses against cancer cells without severe adverse events in patients. This enthusiasm exists in spite of several remaining challenges that must be addressed in clinical trials before taking the concept forward into mainstream cancer care.
