Abstract 1133
Background
Immune checkpoint inhibitors are an important therapy. However, their essence is nonspecific and efficiency of single usage is not satisfactory. The mutant neoantigen specific T (Nas-T) cell, as an adoptive cell treatment, is a specific immunotherapy for each individual. Our previous research has proved that the combined immunotherapy of mutant Nas-T cell and PD1 antibody is more effective than PD1 alone in prolonging PFS (World Conference on Lung Cancer 2018). We aim to evaluate the characteristics of the immune repertoire (IR) as a predictive biomarker for immunotherapy and to construct personalized and specific TCR-T.
Methods
14 patients with advanced solid tumors who failed after multiline treatments were recruited. They were divided into durable clinical benefit (complete response, partial response or stable disease for more than 3 months) and non-durable clinical benefit (DCB and NCB) based on PFS. Peripheral blood was collected at baseline and each cycle. IR-seq of the CDR3 regions of human TCRβ chains was used to interrogate the TCRs frequency. We used single neoantigen to stimulate the infused T cells and performed RNAseq for the sorted CD137(+) cells to obtain the full-length TCR α and β chain. Lastly, we constructed TCR-T cells via transfecting the TCR α/β pair into the T cells of patients and co-cultured with neoantigen to analyze the functionality of TCRs.
Results
After neoantigen pulsing, the clonality of infused T cells pool significantly increased (P = 0.0001), suggesting some tumor-specific T-cells were expanded and enriched after neoantigen pulsing. Compared to baseline, T-cell repertoire of NCB and DCB after 1st cycle displayed significant changes: Shannon 1.19 vs 0.97 (P = 0.002); clonality 0.68 vs 1.19 (P = 0.001). Elevated clonality may indicate expanded tumor-specific T-cells which could recognize mutant neoantigen specifically. Besides, based on the in vitro TCR-T experiments, the constructed TCR-T cells can specifically recognize the mutant neoantigen and lyse the target cells expressing the corresponding neoantigen.Table:
1228P
Neoantigen Sequence | HLA-I typing | TCR Vα | TCR Vβ | |||
---|---|---|---|---|---|---|
Gene name | Sequence* | All V Hits With Score# | Clonal Sequence# | All V Hits With Score# | Clonal Sequence# | |
MTAP/SPINK1 Fused Gene | VLLPRHMKV | A0201 | TRAV35 (574.6) | TGTGCTGGGTATGGCTCTAGCAA CACAGGCAAACTAATCTTT | TRBV19 (646.8) | TGTGCCAGTCGGACAGGGGGA TCACCCCTCCACTTT |
FER | NYVSNVSKF | A2301 | TRAV29DV5 (667.6) | TGTGCAGCTTCAACTGGGGCAAA CAACCTCTTCTTT | TRBV7-2 (626.7) | TGTGCCAGCACCTCTGCCCCC TCCTACGAGCAGTACTTC |
SPINK1 | FLLSALALL | B4403 | TRAV20 (589.1) | TGTGCTGTTCCCCTGGGAACAGG CTTTCAGAAACTTGTATTT (response to neoantigen) | TRBV21-1 (557.8) | TGTGCCAGCAGCAAAGACCCT AGCGGGAATCAAGAGACCCAGTACTTC |
CLCN6 | ALIGAAASL | B6701 | TRAV19 (612.4) | TGTGCTCTTCTGAATTATGGTGGTGC TACAAACAAGCTCATCTTT | TRBV6-5 (675.4) | TGTGCCAGCAGTGGGACAGCCAATGA GCAGTTCTTC (response to neoantigen) |
MTAP | AESFMFRTW | C0401 | TRAV38-2DV8 (658.4) | TGTGCTTATTGGGAGCTTGTCTCTGGGG CTGGGAGTTACCAACTCACTTTC | TRBV5-1 (637.6) | TGCGCCAGCAGCTTGACTAGCGGGGGG TTCTACGAGCAGTACTTC |
TAP1 | RLSLFLALV | C0702 | TRAV16 (622.2) | TGTGCTCCCTGGGCCCTAGGAGGAGG TGCTGACGGACTCACCTTT | TRBV30 (403.4) | TGTGCCTGGAGTGTAACAGGGGGC AAAGCAGATACGCAGTATTTT |
MAN2C1 | FLQGRNFFL |
Conclusions
The mutant Nas-T cell is a personalized immunotherapy. IR is a potential predictive biomarker.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Shunchang Jiao.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
1707 - Clinical utility of precision immunoprofiling and monitoring of the tumor microenvironment using flow cytometry and CyTOF in patients with advanced NSCLC treated with atezolizumab: results from a phase II study for biomarker analysis (EPOC1702)
Presenter: Keisuke Kirita
Session: Poster Display session 3
Resources:
Abstract
3594 - Tumor mutation burden (TMB), PD-L1, IFN-γ signaling identify subgroups of patients (pts) who benefit from durvalumab (D, anti-PDL1) or D and tremelimumab (T, anti-CTLA4) treatment in urothelial bladder cancer (UC)
Presenter: Christophe Massard
Session: Poster Display session 3
Resources:
Abstract
744 - The decrease of TMB, TNB and HLA expression are the Mechanism of Drug Resistance of NSCLC to immunosuppressive PD-1/PD-l1.
Presenter: Sheng Yu
Session: Poster Display session 3
Resources:
Abstract
2350 - Eosinophilia during treatment of immune checkpoint inhibitors (ICIs) predicts succeeding onset of immune-related adverse events (irAEs)
Presenter: Rika Kizawa
Session: Poster Display session 3
Resources:
Abstract
5930 - A transcriptomic immunologic signature predicts favorable outcome in neoadjuvant chemotherapy treated triple negative breast tumors.
Presenter: Javier Pérez-peña
Session: Poster Display session 3
Resources:
Abstract
6127 - Alterations of TMB and TCR repertoires during Chemotherapy in East Asian lung cancer patients without TKI-related driver gene mutations
Presenter: Lele Song
Session: Poster Display session 3
Resources:
Abstract
1310 - Association of SCFA in gut microbiome and clinical response in solid cancer patients treated with andi-PD-1 antibody.
Presenter: Motoo Nomura
Session: Poster Display session 3
Resources:
Abstract
2286 - Extracellular matrix and tissue derived metabolites in a liquid biopsy identifies endotypes of metastatic melanoma patients with differential response to immune checkpoint inhibitor treatment
Presenter: Nicholas Willumsen
Session: Poster Display session 3
Resources:
Abstract
4107 - Pathologic scoring of pre-treatment H&E biopsies predicts overall survival in patients with metastatic clear cell renal cell carcinoma receiving nivolumab monotherapy
Presenter: Julie Stein
Session: Poster Display session 3
Resources:
Abstract
1291 - PD-L1 expression in uncommon EGFR-mutant non-small cell lung cancer and its response to immunotherapy
Presenter: Yun Fan
Session: Poster Display session 3
Resources:
Abstract