Abstract 5777
Background
THOR-707 is a reprogrammed, site-directed, single pegylated, recombinant human IL-2 (rIL-2) variant that lacks binding affinity for the α chain of the IL-2 receptor. Because THOR-707 has near-native binding affinity for the βγ chain of the IL-2 receptor, it produces an immune-active, CD8+ T effector-driven anti-tumor effect. At the same time because it lacks α chain affinity, it limits the proliferation of immune suppressive CD4+ Tregs and other innate lymphoid cells known to mediate the life-threatening complications of VLS. These pharmacologic properties make THOR-707 an ideal immunooncology drug development candidate.
Methods
We employed in vivo and ex vivo models to study pharmacodynamic responses to THOR-707.
Results
We demonstrate all critical actions of IL-2 for anti-tumoral responses without inducing VLS, including: (1) maximal extravasation and expansion of key CD8+ T and NK cell populations in mice and NHPs (2) CD8+ T cell infiltration of tumor and lymph nodes in mouse tumor models, critical for antigen presentation by tumor cells and trans-presentation by antigen presenting cells and (3) induction of IFNγ release ex vivo by T cell receptor (TCR)-activated human T cells that is further potentiated by a PD-1 inhibitory antibody, important for upregulation of MHC I and II and enhancement tumor antigen presentation. In mouse syngeneic tumor models, THOR-707 promoted an increase in the number of infiltrating tumor-killing NK and CD8+ T cells without expansion of suppressive CD4+ Treg cells. Expression profiling of tumors revealed promotion of remodeling of cellular populations towards a composition favoring cytolytic phenotypes. Evaluation of TCR clonality revealed that treatment with THOR-707 increased intra-tumoral T cell diversity.
Conclusions
THOR-707 induction of CD8+ T cell tumor infiltration resulted in single agent dose-dependent anti-tumor efficacy, additive efficacy in combination with a PD-1 checkpoint inhibitor, promoted long-term survival in mice and NHPs and rejection of tumor cells on re-challenge. Based on these results, first in human studies are expected to begin this year in solid tumors both as a single agent and in combination with an immune-checkpoint inhibitor.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Synthorx, Inc.
Funding
Synthorx, Inc.
Disclosure
M.E. Milla: Leadership role, Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Synthorx, Inc.; Licensing / Royalties: Adaptive Biotechnologies, Inc. J.L. Ptacin: Full / Part-time employment: Synthorx, Inc. L. Ma: Full / Part-time employment: Synthorx, Inc. C.E. Caffaro: Full / Part-time employment: Synthorx, Inc. H.R. Aerni: Full / Part-time employment: Synthorx, Inc. K.M. San Jose: Full / Part-time employment: Synthorx, Inc. M.J. Pena: Full / Part-time employment: Synthorx, Inc. R.W. Herman: Full / Part-time employment: Synthorx, Inc. Y. Pavlova: Full / Part-time employment: Synthorx, Inc. D.B. Chen: Full / Part-time employment: Synthorx, Inc. T.K. Ismaili: Full / Part-time employment: Synthorx, Inc. S. Li: Full / Part-time employment: Synthorx, Inc. J. Nguyen: Full / Part-time employment: Synthorx, Inc. N. Singh: Full / Part-time employment: Synthorx, Inc. L.K. Shawver: Leadership role, Shareholder / Stockholder / Stock options, Licensing / Royalties, Officer / Board of Directors: Synthorx, Inc.; Shareholder / Stockholder / Stock options: Cleave Biosciences; Shareholder / Stockholder / Stock options: Relay Therapeutics. L.K. Koriazova: Full / Part-time employment: Synthorx, Inc. I.B. Joseph: Full / Part-time employment: Synthorx, Inc.
Resources from the same session
2036 - Salivary metabolomics for colorectal cancer detection
Presenter: Hiroshi Kuwabara
Session: Poster Display session 3
Resources:
Abstract
1868 - Evaluation and diagnostic potential of plasma biomarkers in bladder cancer
Presenter: Veronika Voronova
Session: Poster Display session 3
Resources:
Abstract
3655 - Liquid biopsy assays using combined circulating tumor cells and circulating tumor DNA in the same patients for the diagnosis of primary lung cancer
Presenter: Yongjoon Suh
Session: Poster Display session 3
Resources:
Abstract
3685 - Peripheral Cytotoxic T Cell Correlates with Tumor Mutational Burden and is Predictive for Progression Free Survival in Advanced Breast Cancer
Presenter: Xiao-ran Liu
Session: Poster Display session 3
Resources:
Abstract
1050 - Splenic Metabolic Activity as Biomarker in Cervical Cancer
Presenter: Emiel De Jaeghere
Session: Poster Display session 3
Resources:
Abstract
1413 - Identification of distinct subtypes revealing prognostic and therapeutic relevance in diffuse type gastric cancer
Presenter: Seon-Kyu Kim
Session: Poster Display session 3
Resources:
Abstract
2140 - Recurrence risk evaluation in stage IB/IIA gastric cancer with TP53 codon 72 polymorphisms
Presenter: Satoshi Nishizuka
Session: Poster Display session 3
Resources:
Abstract
1573 - Identification and validation of a prognostic 4 genes signature for hepatocellular carcinoma: integrated ceRNA network analysis
Presenter: Yongcong Yan
Session: Poster Display session 3
Resources:
Abstract
1196 - Plasma KIM-1 is associated with clinical outcomes after resection for localized renal cell carcinoma: A trial of the ECOG-ACRIN Research Group (E2805)
Presenter: Wenxin Xu
Session: Poster Display session 3
Resources:
Abstract
2657 - Prognostic immunoprofiling of muscle invasive bladder cancer (MIBC) patients in a multicentre setting
Presenter: Katharina Nekolla
Session: Poster Display session 3
Resources:
Abstract