TY - JOUR
T1 - Neoantigen vaccination induces clinical and immunologic responses in non-small cell lung cancer patients harboring EGFR mutations
AU - Li, Fenge
AU - Deng, Ligang
AU - Jackson, Kyle R.
AU - Talukder, Amjad H.
AU - Katailiha, Arjun S.
AU - Bradley, Sherille D.
AU - Zou, Qingwei
AU - Chen, Caixia
AU - Huo, Chong
AU - Chiu, Yulun
AU - Stair, Matthew
AU - Feng, Weihong
AU - Bagaev, Aleksander
AU - Kotlov, Nikita
AU - Svekolkin, Viktor
AU - Ataullakhanov, Ravshan
AU - Miheecheva, Natalia
AU - Frenkel, Felix
AU - Wang, Yaling
AU - Zhang, Minying
AU - Hawke, David
AU - Han, Ling
AU - Zhou, Shuo
AU - Zhang, Yan
AU - Wang, Zhenglu
AU - Decker, William K.
AU - Sonnemann, Heather M.
AU - Roszik, Jason
AU - Forget, Marie Andree
AU - Davies, Michael A.
AU - Bernatchez, Chantale
AU - Yee, Cassian
AU - Bassett, Roland
AU - Hwu, Patrick
AU - Du, Xueming
AU - Lizee, Gregory
N1 - Publisher Copyright:
©
PY - 2021/7/8
Y1 - 2021/7/8
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.
AB - 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.
KW - EGFR
KW - EGFR inhibitor
KW - neoantigen vaccine
KW - non-small cell lung cancer
KW - tumor regression
UR - http://www.scopus.com/inward/record.url?scp=85109640836&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85109640836&partnerID=8YFLogxK
U2 - 10.1136/jitc-2021-002531
DO - 10.1136/jitc-2021-002531
M3 - Article
C2 - 34244308
AN - SCOPUS:85109640836
SN - 2051-1426
VL - 9
JO - Journal for immunotherapy of cancer
JF - Journal for immunotherapy of cancer
IS - 7
M1 - e002531
ER -