Abstract A029: SQ3370: CAPAC platform enables tumor-localized therapy and minimizes systemic toxicities
Bibliographic record
Abstract
Abstract Conventional chemotherapies lack specificity for tumor tissue, have a low therapeutic index, and induce systemic toxicities including cardiomyopathy. SQ3370 utilizes the Click Activated Protodrugs Against Cancer (CAPAC) platform to localize doxorubicin (Dox) to tumor tissue while minimizing systemic exposure. SQ3370 consists of an intratumoral injection of a biopolymer followed by 5 daily intravenous doses of an attenuated protodrug of Dox. The tumor-localized activation of Dox is enabled by mutually reactive click chemistry groups on the biopolymer and protodrug, and is therefore agnostic to tumor characteristics that can vary from patient to patient. This allows the CAPAC platform to be readily applicable to diverse tumor types, including heterogeneous sarcoma subtypes. The lead candidate, SQ3370 is currently being evaluated in a Phase I study in patients with advanced solid tumors (NCT04106492). In preclinical studies, SQ3370 treatment showed reduced toxicity, enabling doses of 19.1-fold and 8.9-fold the maximum tolerated dose of conventional Dox in mice and dogs, respectively. Further, there was no evidence of cardiotoxicity in dogs at this dose. In syngeneic dual-tumor mouse models of MCA205 fibrosarcoma, MC38 colon carcinoma, and B16-F10 melanoma, only one tumor was injected with the biopolymer. Following 5 daily intravenous doses of the protodrug, dose-dependent antitumor responses were seen in the injected and non-injected lesions across all syngeneic models. Furthermore, T-cell infiltration was observed in both lesions of the MC38 dual-tumor model, suggesting activation of an antitumor immune response by SQ3370. The combination of SQ3370 with an immune adjuvant (TLR9 agonist) further prolonged overall survival, improved the antitumor response, and increased the number of complete responses compared to the monotherapy, likely by enhancing the immune activation effects of SQ3370. Conventional Dox can induce cardiomyopathy at incidences of 1-20% for cumulative doses from 300-500 mg/m2 in humans. In the Phase I trial, SQ3370 was well tolerated in patients receiving more than 1000 mg/m2 Dox in cumulative doses. Treated tumors included sarcoma (73%), breast cancer (7.7%), gyne (7.7%), and others (11.5%). Dose escalation is ongoing. Most frequent adverse events (AEs), included nausea, fatigue, and anemia. Ejection fraction (LVEF), indicative of cardiac function, remained normal during the study period. No AEs that led to discontinuation or death were related to SQ3370 by investigator assessment.In summary, SQ3370 facilitates localization of Dox at the tumor with minimal systemic toxicity and demonstrates the first proof of concept of the click chemistry-based CAPAC platform. The CAPAC Platform represents a new therapeutic modality to treat solid tumors by using a drug with known efficacy, such as Dox, and expanding its pharmacological capabilities. Citation Format: Jose M. Mejia Oneto, Sangeetha Srinivasan, Jesse M. McFarland, Matthew Tso, Masa Aleckovic. SQ3370: CAPAC platform enables tumor-localized therapy and minimizes systemic toxicities [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A029.
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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) | 0.006 | 0.002 |
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".