Neoantigen DNA vaccines are safe, feasible, and capable of inducing neoantigen-specific immune responses in patients with triple negative breast cancer

Abstract

PURPOSECancer neoantigens are important targets of cancer immunotherapy. Neoantigen vaccines have the potential to induce or enhance highly specific antitumor immune responses with minimal risk of autoimmunity. We have developed a neoantigen DNA vaccine platform capable of efficiently presenting both HLA class I and II epitopes. To test the safety, feasibility and efficacy of this platform, we performed a phase 1 clinical trial in triple negative breast cancer patients with persistent disease following neoadjuvant chemotherapy, a patient population at high risk of disease recurrence.EXPERIMENTAL DESIGNExpressed somatic mutations were identified by tumor/normal exome sequencing and tumor RNA sequencing. The pVACtools software suite was used to identify and prioritize cancer neoantigens. Neoantigen DNA vaccines were designed and manufactured in an academic GMP facility at Washington University School of Medicine. Neoantigen DNA vaccines were administered via electroporation following completion of standard of care therapy. Safety was measured by clinical and laboratory evaluation. Immune responses were assessed by ELISPOT, flow cytometry and TCR sequencing.RESULTS18 subjects received three doses of a personalized neoantigen DNA vaccine encoding on average 11 neoantigens per patient (range 4-20). The vaccinations were well tolerated with limited adverse events, primarily related to injection site reactions. Neoantigen-specific immune responses were induced in 16/18 patients as measured by ELISPOT and flow cytometry. At a median follow-up of 36 months, progression-free survival was 87.5% (95% CI: 72.7-100%) in the cohort of vaccinated patients compared to 49% (95% CI: 36.4-65.9%) in a cohort of institutional historical control patients (p=0.011).CONCLUSIONSNeoantigen DNA vaccines are safe, feasible, and capable of inducing a neoantigen-specific immune response. There is preliminary evidence of improved disease-free survival compared to historical controls.

Identification of HLA class I-restricted immunogenic neoantigens in triple negative breast cancer

“…vaccinated with an average of 11 neoAgs per patient (42), confirming the feasibility of this approach.…”

“…Thus, our current results obtained in TNBC patients suggest that the TMB found may originate a sufficient number of neoAgs for vaccination. In fact, it has been recently reported the results of a phase I clinical trial of a neoAg-based DNA vaccine in 18 TNBC patients, where authors vaccinated with an average of 11 neoAgs per patient ( 42 ), confirming the feasibility of this approach.…”

Combination TIGIT/PD-1 blockade enhances the efficacy of neoantigen vaccines in a model of pancreatic cancer

“…We demonstrated that dual blockade of TIGIT and PD-1 can enhance the CD8 T cell response to neoantigen vaccines. Of note, neoantigen-specific CD4 T cells have been identified in several neoantigen vaccine studies ( 9 , 35 ) including our own neoantigen DNA vaccine trial in TNBC ( 38 ). Neoantigen-reactive CD4 T cells have also been shown to mediate clinical regression in a patient with cholangiocarcinoma when neoantigen-reactive CD4 T cells were adoptively transferred ( 39 ), further confirming the important contribution of neoantigen-specific CD4 T cells towards antitumor immunity.…”