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
3611 - Phase II trial of SM 88 in Non-Metastatic Biochemical Recurrent Prostate Cancer.
Presenter: Benjamin Gartrell
Session: Poster Display session 3
Resources:
Abstract
2492 - A phase 1 study of Ad5 PSA/MUC-1/Brachyury Vaccine in Patients with Metastatic Castration Resistant Prostate Cancer (mCRPC)
Presenter: Marijo Bilusic
Session: Poster Display session 3
Resources:
Abstract
3142 - Multicenter Phase I Trial of a DNA Vaccine Encoding the Androgen Receptor Ligand Binding Domain (pTVG-AR, MVI-118) in Patients with Metastatic Prostate Cancer
Presenter: Douglas McNeel
Session: Poster Display session 3
Resources:
Abstract
4327 - Impact of germline mutations in Homologous Recombination (HR) genes on the response to Radium-223 for metastatic castration resistant prostate cancer (mCRPC)
Presenter: Elena Castro
Session: Poster Display session 3
Resources:
Abstract
3600 - Serum biomarkers of bone metabolism in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with Radium-223 (Ra223): Results from a prospective multicentre study
Presenter: Nuria Romero Laorden
Session: Poster Display session 3
Resources:
Abstract
3742 - Prognostic value of tumor suppression genes (TP53, PTEN, Rb) in metastatic hormone sensitive prostate cancer
Presenter: Miguel Gonzalez Velez
Session: Poster Display session 3
Resources:
Abstract
2643 - Germline sequencing of advanced prostate cancer patients in the BARCODE2 trial
Presenter: Sarah Benafif
Session: Poster Display session 3
Resources:
Abstract
4349 - Impact of treatment sequence in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): data from the prospective PROREPAIR-B study.
Presenter: Carlo Cattrini
Session: Poster Display session 3
Resources:
Abstract
3301 - Implications of Single Nucleotide Polymorphisms (SNPs) in Androgen Related-Genes in Outcome of metastatic castration-resistant prostate cancer (mCRPC) patients treated with Abiraterone (Abi) and Enzalutamide (Enza)
Presenter: Isabel Aragon
Session: Poster Display session 3
Resources:
Abstract
2275 - Activating mutations in AKT1/PIK3CA are associated with poor clinical outcomes in metastatic prostate cancer (mPC)
Presenter: Simon Fu
Session: Poster Display session 3
Resources:
Abstract