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
4600 - Patterns and outcomes related to rapid progressive disease in a cohort of advanced solid tumors treated with immune checkpoint inhibitors (ICIs).
Presenter: Lucio Ghiglione
Session: Poster Display session 3
Resources:
Abstract
3547 - Real World Outcomes of Immune-Related Adverse Events (irAEs) among Patients Receiving Immune Checkpoint Inhibitors (ICIs) in Hospital Settings
Presenter: Saby George
Session: Poster Display session 3
Resources:
Abstract
1124 - Sex-based heterogeneity of efficacy of anticancer immunotherapy
Presenter: Fabio Conforti
Session: Poster Display session 3
Resources:
Abstract
4133 - Comparative efficacy and safety of PD-1/PD-L1 inhibitors for patients with solid tumors: a systematic review and Bayesian network meta-analysis
Presenter: Qingyuan Huang
Session: Poster Display session 3
Resources:
Abstract
2548 - Excess weight and efficacy of anti-PD-1 antibodies in advanced cancer patients
Presenter: Jacobo Rogado
Session: Poster Display session 3
Resources:
Abstract
2228 - Safety and efficacy of anti-PD-1 inhibitor ABBV-181 in lung and head and neck carcinoma
Presenter: Antoine Italiano
Session: Poster Display session 3
Resources:
Abstract
2333 - Efficacy and safety of immune checkpoint inhibitors (ICIs) for treatment of advanced solid tumours in octogenarian patients
Presenter: Soraya Mebarki
Session: Poster Display session 3
Resources:
Abstract
4847 - Association of programmed cell death 1 (PD-1) inhibitor therapy with overall survival (OS) in stage IV melanoma treated with targeted therapies
Presenter: Aracelis Torres
Session: Poster Display session 3
Resources:
Abstract
2215 - Clinical outcomes of immune checkpoint inhibitors in older and younger patients with advanced solid tumours in a real-life setting
Presenter: Pauline Corbaux
Session: Poster Display session 3
Resources:
Abstract
2881 - Impact of corticosteroids and antibiotics on efficacy of immune-checkpoint inhibitors in advanced non-small cell lung cancer
Presenter: Joaquin Mosquera Martinez
Session: Poster Display session 3
Resources:
Abstract