TY - JOUR T1 - Neoantigen vaccination induces clinical and immunologic responses in non-small cell lung cancer patients harboring EGFR mutations JF - Journal for ImmunoTherapy of Cancer JO - J Immunother Cancer DO - 10.1136/jitc-2021-002531 VL - 9 IS - 7 SP - e002531 AU - Fenge Li AU - Ligang Deng AU - Kyle R Jackson AU - Amjad H Talukder AU - Arjun S Katailiha AU - Sherille D Bradley AU - Qingwei Zou AU - Caixia Chen AU - Chong Huo AU - Yulun Chiu AU - Matthew Stair AU - Weihong Feng AU - Aleksander Bagaev AU - Nikita Kotlov AU - Viktor Svekolkin AU - Ravshan Ataullakhanov AU - Natalia Miheecheva AU - Felix Frenkel AU - Yaling Wang AU - Minying Zhang AU - David Hawke AU - Ling Han AU - Shuo Zhou AU - Yan Zhang AU - Zhenglu Wang AU - William K Decker AU - Heather M Sonnemann AU - Jason Roszik AU - Marie-Andree Forget AU - Michael A Davies AU - Chantale Bernatchez AU - Cassian Yee AU - Roland Bassett AU - Patrick Hwu AU - Xueming Du AU - Gregory Lizee Y1 - 2021/07/01 UR - http://jitc.bmj.com/content/9/7/e002531.abstract N2 - Background Neoantigen (NeoAg) peptides displayed at the tumor cell surface by human leukocyte antigen molecules show exquisite tumor specificity and can elicit T cell mediated tumor rejection. However, few NeoAgs are predicted to be shared between patients, and none to date have demonstrated therapeutic value in the context of vaccination.Methods We report here a phase I trial of personalized NeoAg peptide vaccination (PPV) of 24 stage III/IV non-small cell lung cancer (NSCLC) patients who had previously progressed following multiple conventional therapies, including surgery, radiation, chemotherapy, and tyrosine kinase inhibitors (TKIs). Primary endpoints of the trial evaluated feasibility, tolerability, and safety of the personalized vaccination approach, and secondary trial endpoints assessed tumor-specific immune reactivity and clinical responses. Of the 16 patients with epidermal growth factor receptor (EGFR) mutations, nine continued TKI therapy concurrent with PPV and seven patients received PPV alone.Results Out of 29 patients enrolled in the trial, 24 were immunized with personalized NeoAg peptides. Aside from transient rash, fatigue and/or fever observed in three patients, no other treatment-related adverse events were observed. Median progression-free survival and overall survival of the 24 vaccinated patients were 6.0 and 8.9 months, respectively. Within 3–4 months following initiation of PPV, seven RECIST-based objective clinical responses including one complete response were observed. Notably, all seven clinical responders had EGFR-mutated tumors, including four patients that had continued TKI therapy concurrently with PPV. Immune monitoring showed that five of the seven responding patients demonstrated vaccine-induced T cell responses against EGFR NeoAg peptides. Furthermore, two highly shared EGFR mutations (L858R and T790M) were shown to be immunogenic in four of the responding patients, all of whom demonstrated increases in peripheral blood neoantigen-specific CD8+ T cell frequencies during the course of PPV.Conclusions These results show that personalized NeoAg vaccination is feasible and safe for advanced-stage NSCLC patients. The clinical and immune responses observed following PPV suggest that EGFR mutations constitute shared, immunogenic neoantigens with promising immunotherapeutic potential for large subsets of NSCLC patients. Furthermore, PPV with concurrent EGFR inhibitor therapy was well tolerated and may have contributed to the induction of PPV-induced T cell responses.Data are available in a public, open access repository. Data are available on reasonable request. Raw data of bulk RNA sequencing of cell lines, single cell TCR paired αβ chain sequencing, TCR VβCDR3 sequencing generated and analyzed during the current study are available through NCBI Sequence Read Archive (code SRP188005). DNA sequencing data (for finding mutations) with potential patient identification was not included in the informed consent of enrolled patients, but data without identifying information can be shared on reasonable request. All other data are also available from the corresponding author on request. ER -