Abstract 4499: The peptide-drug conjugate sudocetaxel zendusortide (TH1902) potentiates anti-tumoral activity of the anti-PD-L1 checkpoint inhibitor and induces immune cell infiltration in a B16-F10 syngeneic melanoma model
Bibliographic record
Abstract
Abstract Tumor-infiltrating immune cells are involved in the control of cancer and are closely related to clinical outcomes. Sudocetaxel Zendusortide (TH1902), a peptide-drug conjugate (PDC) of the sortilin (SORT1)-binding peptide TH19P01 ester-linked to two docetaxel moieties, has been shown to exert superior anti-cancer activities in multiple cancer models including melanoma syngeneic and xenograft murine models. Melanomas express elevated levels of SORT1 and are considered as one of the most immunogenic tumors where immune checkpoint inhibitors are among the standard of care treatment used. Here, we first questioned whether TH1902 anti-cancer effects involved infiltration of immune cells in a murine SORT1-positive syngeneic, non-immunogenic and highly aggressive B16-F10 melanoma model in C57BL/6 mice. Weekly administration of docetaxel reduced by half the growth of B16-F10 tumor allografts, while administration of TH1902 as a single agent and at equivalent docetaxel doses, was well tolerated and resulted in tumor regression after only 2 treatments. Surprisingly, in this immunologically cold tumor, immunohistochemistry analysis of tumors for immune cell infiltration showed a net increase in total leukocytes (CD45+) infiltration within TH1902-treated tumors compared with docetaxel-treated tumors, especially with for tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs). Furthermore, the increased staining intensities for Perforin and Granzyme B were indicative of the elevated cytotoxic T and natural killer (NK) cells activity in TH1902-treated tumors. This corroborated with increased caspase-3 apoptotic activity. TH1902 and docetaxel doses were next halved and combined with the checkpoint inhibitor anti-PD-L1. In a first study, the TH1902/anti-PD-L1 combination resulted in increased tumor growth inhibition when compared with both agents alone. Interestingly, TH1902 as a single agent showed better tumor growth inhibition than docetaxel or docetaxel/anti-PD-L1 combination. In a second study, the TH1902/anti-PD-L1 combination significantly increased animal survival over either anti-PD-L1 or TH1902 as single agents (21 days increased median survival compared to 2.5 and 12.5 days respectively). We conclude that the superiority of TH1902 anticancer activity over docetaxel involves, in part, the modulation of infiltrating immune cells within the tumor microenvironment. This is the first demonstration that immune cell infiltration patterns play a pivotal role in the TH1902-associated anti-tumoral response. Combination of TH1902 with checkpoint inhibitors (anti-PD-L1) further reveals that this may lead to improved clinical outcomes in future immunotherapy translational approaches. Citation Format: Michel Demeule, Jean-Christophe Currie, Cyndia Charfi, Alain Zgheib, Isabelle Cousineau, Richard Béliveau, Christian Marsolais, Borhane Annabi. The peptide-drug conjugate sudocetaxel zendusortide (TH1902) potentiates anti-tumoral activity of the anti-PD-L1 checkpoint inhibitor and induces immune cell infiltration in a B16-F10 syngeneic melanoma model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4499.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".