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EP1.01 - Advanced NSCLC (ID 150)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
EP1.01-55 - Neoantigen Deletion Leads to Hyperprogressive Disease (HPD) in Non-Small Cell Lung Cancer (NSCLC) Treated with PD-1/PD-L1 Inhibitors (Now Available) (ID 1179)
08:00 - 18:00 | Author(s): Feifei Gu
Hyperprogressive disease (HPD) is a distinct pattern of progression described in patients with cancer treated with PD-1/PD-L1 inhibitors. The incidence of HPD is reported to be 13.8% in advanced NSCLC. Recently multiple characteristics have been recognized to predict the risk of HPD, however the mechanism underlying have not been systemically studied.Method
We report a Chinese patient who developed hyperprogressive disease after 4 cycles of PD-1 blockade treatment. Clinical and demographic data was collected from electronic records. Whole exome sequencing (WES) of the primary tumor was performed to identify tumor mutation burden (TMB) and tumor neoantigen burden (TNB) following the restricted pipeline. Liquid biopsy targeting ctDNA and T cell receptor (TCR) was constructed to monitor the efficacy of immunotherapy.
A 70-year-old male with smoking history underwent chest CT scan in February 2018 and was found to have a right upper lobe mass with intrapulmonary metastasis in different lobes and multiple lymph nodes. Resection of right lower lung by video-assisted thoracic surgery (VATS) revealed poorly differentiated, squamous cell carcinoma. In July 2018, he progressed after two cycle of chemotherapy and radiation therapy targeting newly bone metastasis of lumbar spine, then he was screened to start Nivolumab at dose of 240mg daily/2 weeks. After four cycle of Nivolumab, he obtained PD and was assigned to palliative thoracic radiation therapy. The PD-L1 expression level of our patient was 1%≤TC＜5%, next generation sequencing (NGS) didn’t show alteration in genes related to HPD, such as MDM2/MDM4 or EGFR. Blood sample retrieved before and after immunotherapy revealed the increase in bTMB (from 7.70 Muts/Mb to 18.00 Muts/Mb), however TNB truly expressed as neoantigens were rather lower compared to TMB, indicating the low immunogenicity of tumor. We also found a sharp fluctuate in the detection of driver genes mutations in ctDNA (TP53,CDKN2A,ERBB3,FBXW7), and the majority of high-frequency TCR dropped significantly during immunotharapy.
It is reported that NSCLC with a high tumor mutation burden (TMB) may benefit from PD-1/PD-L1 inhibitors treatment, and TMB is considered as the surrogate of tumor neoantigen burden (TNB). However the deletion of neoantigen may occur at different level, including copy number variation at the DNA level, down-regulation of transcription level and inherited variation at the epigenetic level, resulting in the low immunogenicity of primary tumor. Deletion of neoantigen may provide a mechanism of immune evasion which leads to the resistance to PD-1/PD-L1 inhibitors. In this case, treatment of checkpoint inhibitors may activate certain signaling pathway of driver genes to support the hyperprogression disease (HPD). This case report focusing on neoantigen provides a new approach to predict the presence of hyperprogressive disease (HPD) before immunotherapy, and explains the potential mechanism of HPD.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
P2.01-86 - Highly Immunogenic Neoantigens Enhance Tumor Response to Immune Checkpoint Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) (ID 771)
10:15 - 18:15 | Author(s): Feifei Gu
Immune checkpoint inhibitors have revolutionized the treatment of metastatic non-small cell lung cancer (NSCLC) as significantly extending survival in patients relative to chemotherapy. However evidence to support the role of immune checkpoint inhibitors in EGFR-mutant lung cancers remains conflicting. In recent years, neoantigens become promising targets for cancer immunotherapy. Immunogenic neoantigens generated by somatic mutations can be recognized by the host immune system and then tumor clones presenting such neoantigens will be eliminated.Method
We report two advanced NSCLC patients with EGFR mutations who have both exhibited durable response to PD-1 blockade. We comprehensively analyzed predictive biomarkers and experimentally validated immunogenicity of peptides generated by driver mutations.Result
Patient 1 is a 34-year-old male diagnosed with lung adenocarcinoma (IV, cT4N2M1b). EGFR exon 19 deletion and TP53 point mutation (A161T) were identified by next generation sequencing in February 2017 and first line treatment was initiated with Icotinib. He obtained PD within 5 months. After 5 cycles of chemotherapy, brain metastasis was confirmed and EGFR T790M mutation was identified by lung biopsy in June 2018. The patient was enrolled in a phase III clinical trial of Nivolumab in July 2018. Patient 2 is a 61-year-old female diagnosed with stage IV lung adenocarcinoma harboring EGFR exon 19 deletion identified by next generation sequencing in March 2018. After multilines treatment including TKI therapy, chemotherapy and anti-angiogenic therapy, Nivolumab was given alone to the patient from November 2018. Both patients achieved partial response (PR) to Nivolumab based on imRECIST criteria. The PD-L1 expression level was > 50% and ≥ 5%, respectively in Patient 1 and Patient 2. We performed a target region sequencing which covered 811 cancer genes to determine tumor mutation burden (TMB) and tumor neoantigen burden (TNB). Both patients had moderate level of TMB and TNB. TMB was 6.00 muts/Mb and 4.69 muts/Mb while TNB was 2.67 neos/Mb and 2.68 neos/Mb, respectively in Patient 1 and Patient 2. In order to evaluate the immunogenicity of neoantigens, peptides representing top 7 putative neoantigens were synthesized and tested against PBMC in an IFNγ ELISpot assay. The results revealed tumor-specific T cell immunity targeting neoantigens derived from EGFR exon 19 deletion and TP53 point mutation and the latter exhibited the highest immunogenicity. Strikingly, the patient harboring these mutations achieved partial response for more than 9 months. Additionally, the dynamic changes of TCR profiling during Nivolumab treatment were examined to assess T cell immunity responses. Data shown the maintenance of a majority of high-frequency clonotypes, suggesting the preexisting high-avidity T cells may contribute to antitumor immune response.Conclusion
Our study suggests that EGFR-mutant NSCLC may still respond to PD-1 blockade. This is the first report on experimentally verifying the highly immunogenic neoantigens derived from EGFR driver mutation in patients receiving immunotherapy, which supports potential value of such neoantigens as therapeutic agents. Our study also shows the dynamic monitoring of TCR profiling could help predict T cell immune response.