In a phase I trial, 24 late-stage NSCLC patients were immunized with personal neoantigen peptides (based on mutations detected by a 508 gene oncogene panel) and topical Imiquimod. The treatment was safe, induced objective responses in 7/16 EGFR-mutant (but 0/8 EGFR-wild-type) patients, and further extended survival with EGFR inhibitor therapy. Neoantigen-specific T cells were detected in PBMCs (predominantly in patients with EGFR-mutant NSCLC), were mainly targeting EGFR-mutant peptides, and were associated with treatment response. In an EGFR-mutant tumor cell line, EGFR inhibition increased antigen presentation gene expression and chemokine production.
Contributed by Alex Najibi
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.
Author Info: (1) Department of Melanoma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (2) Tianjin HengJia Biotechnology Development Co Ltd, Tianjin, China. (3) Depart
Author Info: (1) Department of Melanoma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (2) Tianjin HengJia Biotechnology Development Co Ltd, Tianjin, China. (3) Department of Melanoma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (4) Department of Melanoma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (5) Department of Melanoma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (6) Department of Melanoma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (7) Tianjin HengJia Biotechnology Development Co Ltd, Tianjin, China. (8) Tianjin HengJia Biotechnology Development Co Ltd, Tianjin, China. (9) Tianjin HengJia Biotechnology Development Co Ltd, Tianjin, China. (10) Department of Melanoma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (11) Mary Bird Perkins Cancer Center, Baton Rouge, Louisiana, USA. (12) Department of Oncology, Tianjin Beichen Hospital, Tianjin, China. (13) BostonGene Corporation, Waltham, Massachusetts, USA. (14) BostonGene Corporation, Waltham, Massachusetts, USA. (15) BostonGene Corporation, Waltham, Massachusetts, USA. (16) BostonGene Corporation, Waltham, Massachusetts, USA. (17) BostonGene Corporation, Waltham, Massachusetts, USA. (18) BostonGene Corporation, Waltham, Massachusetts, USA. (19) Tianjin HengJia Biotechnology Development Co Ltd, Tianjin, China. (20) Department of Melanoma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (21) Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (22) Department of Oncology, Tianjin Beichen Hospital, Tianjin, China. (23) Provincial Clinical College, Fujian Medical University, Fujian, China. (24) State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China. (25) Biological Sample Resource Sharing Center, Tianjin First Central Hospital, Tianjin, China. (26) Department of Immunology, Baylor College of Medicine, Houston, Texas, USA. (27) Department of Melanoma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (28) Department of Melanoma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (29) Department of Melanoma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (30) Department of Melanoma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (31) Department of Melanoma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (32) Department of Melanoma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (33) Department of Immunology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. (34) Department of Melanoma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. (35) Department of Oncology, Tianjin Beichen Hospital, Tianjin, China glizee@mdanderson.org dudaming73@163.com. (36) Department of Melanoma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA glizee@mdanderson.org dudaming73@163.com. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
