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

Abstract

BackgroundNeoantigen (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.MethodsWe 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.ResultsOut 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.ConclusionsThese 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.

Evolution of CD8+ T Cell Receptor (TCR) Engineered Therapies for the Treatment of Cancer

“…Using this method, we have identified and validated peptides associated with the melanoma differentiation antigen SLC45A2 as shared melanoma-associated tumor targets and have generated TCRs recognizing these peptides. Similarly, we identified VGLL1 as a shared pancreatic and basal breast cancer tumorassociated antigen, for which TCRs showing antitumor activity have been isolated [27][28][29]. TCR-T cell clinical trials targeting these two TAAs are currently in the design stages.…”

“…Our group has reported a neoantigen peptide derived from the EGFR-L858R mutation (KITDFGRAK) that is immunogenic and presented by HLA-A*1101. Since EGFR-L858R is found in~40% of EGFR-mutated lung cancers, it constitutes a promising, widely shared NeoAg target for TCR-T therapy of HLA-A*1101/EGFR-L858R lung cancer patients [28]. Our group has generated several promising TCRs specific for this and other EGFR-derived NeoAgs, and we plan to test their efficacy in future clinical trials [28,29]).…”

“…Since EGFR-L858R is found in~40% of EGFR-mutated lung cancers, it constitutes a promising, widely shared NeoAg target for TCR-T therapy of HLA-A*1101/EGFR-L858R lung cancer patients [28]. Our group has generated several promising TCRs specific for this and other EGFR-derived NeoAgs, and we plan to test their efficacy in future clinical trials [28,29]). A number of other studies have also demonstrated the immunogenicity of shared NeoAgs that can be used to generate potentially therapeutic tumor specific TCRs [79][80][81].…”

Neoantigens and NK Cells: “Trick or Treat” the Cancers?

“…The potential neoantigens can be employed in the development of immunotherapies. So far, several neoantigens have been discovered in preclinical and clinical investigations, some of which are derived from shared mutations in a range of malignancies (30,31,(40)(41)(42)(43)(44)(45)(46)(47) (Table 1).…”

Immune checkpoint inhibitors for PD-1/PD-L1 axis in combination with other immunotherapies and targeted therapies for non-small cell lung cancer

“…In mice models bearing the NSCLC tumors, they were able to show that targeted therapy against ACAD8-T105I, BCAR1-G23V, and PLCG1-M245L led to improved immune cell response, demonstrating the feasibility of treatment in vivo . In a stage III/IV NSCLC study with 24 patients, neoantigens-based personalized vaccination was developed based on predictions using a panel of 508 tumor-associated genes from tumor biopsies, with peptides also demonstrating high affinity to HLA class I and II, determined through HLA typing ( 26 ). Researchers were able to demonstrate OS and median PFS of 8.9 and 6 months, respectively.…”