Neoantigen vaccination induces clinical and immunologic responses in non-small cell lung cancer patients harboring EGFR mutations.

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.

Informations de copyright

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: CH and FL are shareholders of Tianjin HengJia Biotechnology Development (‘HengJia Biotech’). GL was a consultant for HengJia Neoantigen Biotechnology (Tianjin), a branch company of HengJia Biotech. LD, QZ, CC, and CH are employees of HengJia Biotech. MD is a consultant for Novartis, Roche/Genentech, GSK, Array, Sanofi-Aventis, and Astrazeneca, and part of his research grants were from Roche/Genentech, GSK, Sanofi-Aventis, and Astrazeneca. United States patent applications have been filed on aspects of the described work, entitled: 'Immunogenic EGFR peptide compositions and their use in the treatment of cancer' (FL, GL), and 'Engineered T cell receptors targeting EGFR antigens and methods of use' (FL, GL). Chinese patent applications have been filed on aspects of the described work, entitled: ‘The clinical application of specific T cell receptors based on EGFR-L858R mutation’ (XD, LD, CH, and QZ), and ‘Method for identifying tumor-specific T cell receptors’ (XD). The remaining authors declare no competing financial interests.