Abstract 5065
Background
T cells bearing a chimeric antigen receptor (CAR) T-cell consisting of the fusion of the NKG2D NK receptor with the intracellular domain of CD3zeta (CYAD-01) can recognize eight stress ligands expressed in a large variety of cancers. However, activated T cells undergo stress and transiently express NKG2D ligands (NKG2DL). Consequently, CYAD-01 T cells kill sister cells preventing the large-scale manufacturing of CYAD-01 for clinical application.
Methods
Inclusion of the PI-3K inhibitor LY294002 into the manufacturing process was the first strategy used as an initial effort focused upon blunting the activity of the CAR T cells. We subsequently developed a process that included a NKG2D blocking antibody during the expansion phase of cell culture.
Results
LY294002 was shown to reversibly reduce NKG2D expression at the cell surface. Consequently, this inhibitor partially controlled fratricide during manufacturing and enhanced viability post-thawing which enabled the initiation of the THINK (NCT03018405) clinical trial. As the trial moved through the dose-escalation phase towards the upper dose level (production of more than 1010 cells), there was an increase in the level of manufacturing failures. This was largely linked to the effect of LY294002 upon T cell proliferation and the challenge faced manufacturing CAR T cells from patients with advanced cancer. Therefore, we subsequently developed a process that included a NKG2D blocking antibody during the expansion phase of cell culture. This strategy enabled the expansion of CYAD-01 T cells to the levels required for the THINK clinical trial. After fine tuning the process, the CYAD-01 CAR T cells generated showed high comparability to the CYAD-01 CAR T cells produced in the first part of the trial. This process has been in place for the THINK trial since January 2018.
Conclusions
Together, these results indicate that when fratricide is an issue preventing clinical development, CAR T cells can be efficiently manufactured through PI-3K inhibition and antibody mediated receptor blockade.
Clinical trial identification
Legal entity responsible for the study
Celyad SA.
Funding
Has not received any funding.
Editorial Acknowledgement
Disclosure
B. Demoulin B. Eytan, D. Gilham: Employee of Celyad SA.
Resources from the same session
5877 - TCR beta chain convergence defines the tumor infiltrating T cell repertoire of melanoma and non-small cell lung carcinoma.
Presenter: Timothy Looney
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
3212 - PI3K inhibition and modulation of immune and tumor microenvironment markers by copanlisib in patients with non-Hodgkin's lymphoma or advanced solid tumors
Presenter: Ahmad Awada
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
3574 - Pan-squamous genomic profiling stratified by anatomic tumor site and viral association
Presenter: Meagan Montesion
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
4113 - Toward the Standardization of Bioinformatics Methods for the Accurate Assessment of Tumor Mutational Burden (TMB)
Presenter: Han Chang
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
4468 - Prediction of primary resistance to anti-PD1 therapy (APD1) in 2nd line NSCLC
Presenter: Egbert Smit
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
4570 - Immunomodulatory germline variation impacts the development of multiple primary melanoma (MPM).
Presenter: Robert Ferguson
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
1169 - Leukocyte telomere length and recurrence risk after EGFR-TKIs therapy in patients with advanced lung adenocarcinoma
Presenter: Ming Yang
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
1707 - Gene embedding: a novel machine learning approach to identify gene candidates related to immunotherapy responsiveness
Presenter: Chi Tung Choy
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
2123 - Common and rare DPYD variants are predictive for 5FU/capecitabine (5FU) toxicity: The MRC COIN and COIN-B trials
Presenter: Ayman Madi
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
5671 - The landscape of NTRK fusions in Chinese solid tumor patients
Presenter: Qi Ling
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract