| Autor: |
M. Wayne Saville, Mia C. Weiss, Vivek Bhadri, Jose M. Mejia Oneto, Vivek Subbiah, Nam Bui, Alexander Guminski, Vineet Kwatra, Kathleen Batty, Sangeetha Srinivasan, Michael Zakharian, Nathan Yee, Rosalind Wilson, Sant P. Chawla, James Strauss |
| Rok vydání: |
2021 |
| Předmět: |
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| Zdroj: |
Journal for ImmunoTherapy of Cancer, Vol 9, Iss Suppl 2 (2021) |
| ISSN: |
2051-1426 |
| DOI: |
10.1136/jitc-2021-sitc2021.367 |
| Popis: |
BackgroundConventional chemotherapeutics lack specificity for tumor tissue and usually have anarrow therapeutic index. SQ3370, a novel therapy that activates doxorubicin (Dox) at the tumor sitewhile minimizing systemic exposure, is based on intratumoral injection of a protodrug-activatinghyaluronic acid-based biopolymer (SQL70) followed by five daily intravenous (IV) doses of an attenuatedprotodrug of Dox (SQP33). SQ3370 utilizes Shasqi’s proprietary Click Activated Protodrugs AgainstCancer (CAPAC) platform where mutually-reactive click chemistry groups in the two components allowrelease of active Dox specifically at the tumor site. In animals, SQ3370 allowed for an 8.95-fold increase in dosing with minimal systemic adverse eventsand no cardiotoxicity. SQ3370 treatment of mouse tumor models showed improved overall survival,enhanced T-cell infiltration, and a robust anti-tumor response against both biopolymer-injected andnon-injected lesions,1 suggesting that SQ3370 promotes activation of the native immune systemagainst the tumor.MethodsSQ3370-001 (NCT04106492) is a phase 1 trial open to patients with relapsed/refractory soft-tissue sarcoma or other advanced, potentially anthracycline-responsive solid tumors with an injectablelocal or metastatic lesion and =300 mg/m 2 prior exposure to Dox (or equivalent). Primary objectivesinclude safety, tolerability, and recommended Phase 2 dose. Additional objectives include preliminaryefficacy, plasma and tumor biopsy pharmacokinetics (PK), and immune response by peripheral bloodmass cytometry/tumor IHC.ResultsTo date, ten patients have been enrolled. SQ3370 treatment has been well-tolerated with nodose-limiting toxicities observed. Plasma PK appeared consistent with preclinical data; rapid conversionof SQP33 protodrug to active Dox occurred but slowed as the residence time of the injected biopolymerlengthened. Systemic exposure to active Dox peaked on days 1–2 post biopolymer injection, followed bya decline on days 3–5. Preliminary tumor analysis shows that substantial local exposure to Dox continues2 weeks after the last SQP33 dose. Immune response analysis of early patient samples suggestsincreased tumor immune cell infiltration that dynamically changes with each cycle of treatment.ConclusionsSQ3370 appears to be well-tolerated and demonstrates proof-of-concept for the first click-chemistry-based therapy in the clinic. Preclinical and clinical PK are consistent; high tumor exposure canbe achieved, so far without the typical clinical adverse events seen with IV Dox and potentiallyimproving the therapeutic index of a frequently-used chemotherapeutic agent.Trial RegistrationNCT04106492ReferenceSrinivasan S, Yee NA, Wu K, et al. SQ3370 activates cytotoxic drug via click chemistry at tumor andelicits sustained responses in injected and non-injected lesions. Advanced Therapeutics 2021;4(3):2000243. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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