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
4489 - A Window of Opportunity Trial of Atorvastatin Targeting p53 Mutant Malignancies
Presenter: Joaquina Baranda
Session: Poster Display session 3
Resources:
Abstract
1945 - Randomized Phase II Study of Trabectedin/Olaparib Compared to Physician’s Choice in Subjects with Previously Treated Advanced or Recurrent Solid Tumors Harboring DNA Repair Deficiencies.
Presenter: Christoph Heilig
Session: Poster Display session 3
Resources:
Abstract
3021 - Homogenisation of Leftover Surgical Tissue across multiple cancer types: a Feasibility Study (HoLST-F)
Presenter: Lavinia Spain
Session: Poster Display session 3
Resources:
Abstract
2882 - Safety, efficacy, and immune effects of intratumoral tilsotolimod in patients with refractory solid tumors: updated results from ILLUMINATE-101
Presenter: Hani Babiker
Session: Poster Display session 3
Resources:
Abstract
1950 - Phase 1 Dose Escalation of MSC-1, a humanized anti-LIF monoclonal antibody, in patients (pts) with advanced solid tumors: Updated results
Presenter: Erkut Borazanci
Session: Poster Display session 3
Resources:
Abstract
2391 - A phase 1 study of Sym021, an anti-PD-1 antibody (Ab), alone and in combination with Sym022 (anti-LAG-3) or Sym023 (anti-TIM-3)
Presenter: Anna Spreafico
Session: Poster Display session 3
Resources:
Abstract
5692 - FPA150 (B7-H4 antibody) Phase 1 Update in Advanced Solid Tumors: Monotherapy and in Combination with Pembrolizumab
Presenter: Zev Wainberg
Session: Poster Display session 3
Resources:
Abstract
2416 - MG1124, a novel CEACAM1-targeted monoclonal antibody, has therapeutic potential as a combination partner of PD-1 inhibitors in NSCLC patients
Presenter: Eun Hee Lee
Session: Poster Display session 3
Resources:
Abstract
2661 - Tumor stroma targeting and modulation by OMTX705 ADC, a novel and potent immunotherapeutic treatment of solid tumors.
Presenter: Myriam Fabre
Session: Poster Display session 3
Resources:
Abstract
3681 - Durvalumab + monalizumab, mFOLFOX6, and bevacizumab in patients (pts) with metastatic microsatellite-stable colorectal cancer (MSS-CRC)
Presenter: May Cho
Session: Poster Display session 3
Resources:
Abstract