MCT First Disclosures Archive
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SENTI-101 Induces Localized and Durable Anti-Tumor Immunity
This First Disclosure describes the lead selection and preclinical research supporting the development of SENTI-101, a novel allogeneic cell therapy preclinical product candidate for the treatment of peritoneal carcinomatosis, including advanced ovarian cancer. SENTI-101 uses mesenchymal stromal cells innate capacity to traffic and localize to solid tumors to deliver two potent immune stimulatory cytokines (IL-12 and IL-21) to the tumor microenvironment. Studies conducted by Senti Bio demonstrate that, with this approach, scientists safely turned “cold” tumors “hot” resulting in long term anti-tumor immunity and rendered them susceptible to checkpoint inhibition. SENTI-101 demonstrates anti-tumor activity and proposes a cell modality that may address an unmet need for patients with ovarian cancer.
Vimseltinib is a Selective CSF1R Inhibitor for TGCT
Colony stimulating factor 1 receptor (CSF1R)-dependent cells in the microenvironment (such as macrophages and osteoclasts) contribute to angiogenesis, tumor growth, metastasis, and bone degradation. In this First Disclosure, Smith and colleagues present the characterization of vimseltinib, a selective oral inhibitor of CSF1R in tenosynovial giant cell tumor (TGCT). Vimseltinib depleted macrophages and CSF1R-dependent cells and inhibited tumor growth in preclinical studies. Clinically, the authors present three patients whose CSF1R biomarkers and tumor burden were reduced. Their data supports the continued clinical development of vimseltinib for TGCT.
QBS10072S Treats Breast Cancer Metastasis
The triple-negative subtyp. of breast cancer (TNBC) carries the highest rate of parenchymal brain metastasis (BrM) and leptomeningeal metastasis (LM). In this manuscript, Deng and colleagues disclose the nitrogen mustard-based compound QBS10072S. QBS10072S delayed tumor growth and reduced leptomeningeal dissemination in a preclinical brain metastasis model. Interestingly, the compound was able to target micro-metastases, which remains a difficult aspect of detecting and treating LM. As the compound was well-tolerated, the continued development of QBS10072S for TNBC LM patients is warranted.
PRMT5 Inhibitor with Potent Anti-tumor Activity
Dysregulation of the protein arginine methyltransferase 5 (PRMT5) is associated with lymphomas, lung cancers, and breast cancers. In this First Disclosure, Brehmer and colleagues outline JNJ-64619178, an inhibitor of PRMT5 with potent anti-proliferative activity. JNJ-64619178 occupies the SAM and substrate pockets of PRMT5, trapping it in a catalytically inactive state. PMRT5 inhibition by JNJ-64619178 increased alternatively spliced events and resulted in the killing of primary AML samples ex vivo. Taken together, the results support the continued clinical study of JNJ-64619178 (NCT03573310).
Preclinical Evaluation of Dato-DXd, a TROP2-directed ADC
The approval of Trastuzumab deruxtecan demonstrates the potency of the DNA topoisomerase I inhibitor DXd in antibody-drug conjugates (ADCs). DXd-ADCs exhibit a short systemic half-life and ability to optimize the drug-antibody ratio. In this First Disclosure, Okajima and colleagues outline the design of another DXd-containing ADC targeting Trophoblast cell surface antigen 2 (TROP2). Datopotamab deruxtecan is designed to have a shorter half-life than sacituzumab govitecan, a TROP2-directed ADC approved by the FDA for TNBC. Dato-DXd showed potent anti-tumor activity and was absent of severe gastrointestinal toxicity. The results support the first-in-human phase 1 study for patients with advanced solid tumors (NCT03401385).
ASTX029 is a Dual-Mechanism Inhibitor of ERK
Relapse to MAPK pathway inhibitors (such as BRAF, MEK, and KRAS inhibitors) is common due to the reactivation of ERK and MAPK signaling. In this First Disclosure, Wallis, Munck, and colleagues outline the ERK inhibitor ASTX029. ASTX029 inhibits both the phosphorylation of ERK by MEK as well as its catalytic activity and, therefore, is categorized as a dual-mechanism inhibitor by the authors. The dual-mechanism ERK inhibitor demonstrated anti-tumor activity to MAPK inhibitor-resistant cancers in vitro and in vivo. Their work supports the continued clinical development of ASTX029 in advanced solid tumors.
TPX-0131, a Next-Generation ALK Inhibitor
ALK mutants limit the utility of current generations of ALK inhibitors. In this First Disclosure, Murray and colleagues from Turning Point Therapeutics describe TPX-0131, a macrocyclic inhibitor that fits completely into the ATP-binding pocket of ALK. TPX-0131 was potent against wild-type ALK as well as against the solvent front, gatekeeper, hinge region, and compound mutations that have limited previous inhibitors and is currently undergoing clinical study.
ASN004 – 5T4-Targeting ADC With High Drug-to-Antibody Ratio
ASN004 is an antibody-drug conjugate that targets the 5T4 oncofetal antigen (trophoblast glycoprotein) expressed on a wide range of malignant tumors. More specifically, ASN004 incorporates a novel single-chain scFv-Fc antibody, a Dolaflexin drug linker, and an Auristatin F payload with a 10-12 drug-to-antibody ratio. Single-dose studies with ASN004 (1 mg/kg) achieved complete tumor regressions in the A431 cervical cancer model. ASN004 was also shown to be more potent than trastuzumab-DM1 in a low-5T4/high-HER2 expressing gastric cancer model. The results demonstrate ASN004 as a promising therapeutic for 5T4-bearing tumors.
Diabodies Targeting the hERG1/β1 Molecular Complex
Bispecific antibodies target two antigens simultaneously in the same molecule. The single-chain diabody scDb-hERG1-β1 targets the hERG potassium channel and the β1 subunit of integrin receptors which form a complex in cancer cells. The diabody downregulated hERG1/β1 complex formation, inhibited Akt phosphorylation and HIF-1α expression and decreased cell survival. scDb-hERG1-β1 reduced colon and pancreatic xenografts and showed no general, renal, or cardiac toxicity. These results justify continued development of scDB-hERG1-β1 for patients with tumors expressing the hERG/β1 complex.
F-aza-T-dCyd, a novel cytidine analog
Cytidine analogs remain an area of active drug discovery and development with five FDA-approved drugs. Herein F-aza-T-dCyd (NSC801845), a novel fluorine-containing cytidine analog, is first disclosed and compared in cell culture and human tumor xenograft studies with gemcitabine and several investigational cytidine agents currently undergoing clinical development. In the 3 of 5 xenograft studies (HCT-116 colon, HL-60 leukemia, PDX BL-0382 bladder), F-aza-T-dCyd produced complete regression of the tumors in all mice with a response that proved durable beyond post-implant day. These findings indicate that further development of F-aza-T-dCyd as a potential chemotherapeutic is warranted.
MGC018, a duocarmycin-based ADC targeting B7-H3 for cancer
The immune regulatory receptor B7-H3 is overexpressed on many solid cancers. In this disclosure, Scribner and colleagues outline MGC018, a duocyarmycin-bearing antibody-drug conjugate targeted at B7-H3. MGC018 exhibited cytotoxicity toward B7-H3-positive human tumor cells and anti-tumor activity in preclinical tumor models of breast, prostate, and lung cancer, as well as melanoma. Additionally, antitumor activity was observed in patient-derived xenografts of breast, prostate, and head and neck cancer. MGC018 showed favorable pharmacokinetics in cynomolgus monkeys. Their data supports the continued development of MGC018 for the treatment of solid cancers.
MMAE delivery using the Bicycle toxin conjugate BT5528
EphA2 is a highly sought-after target in cancer therapy. In this First Disclosure, Bennett and colleagues describe a Bicycle peptide toxin-conjugate that targets EphA2. Unlike previous antibody-drug conjugates that target EphA2, the Bicycle peptide conjugate (BT5528) doesn’t cause bleeding and exhibits an idea “fast in, fast out” kinetic profile that properly balances efficacy and toxicity in patients. BT5528 has begun Phase I clinical trials (NCT04180371).
Tucatinib activity in preclinical HER2+ Solid Tumor Models.
Current small molecule inhibitors for HER2 (augmented in breast, bladder, colorectal, non-small cell lung, esophageal, and gastric cancers) have nearly equipotent inhibition of EGFR and HER2 which contribute to the severity of adverse events. In this article, Kulukian and colleagues disclose tucatinib, a selective HER2 inhibitor 1,000 times more potent for HER2 than EGFR in cellular signaling assays.
Differential properties of human CD137 agonist antibody 7A5
CD137 agonism is hypothesized to reinvigorate potent anti-tumor immunity due to its role in T-cell expansion and effector function. Previous CD137 agonists were limited by liver toxicity and modest activity. In this article, Kotanides and colleagues disclose 7A5, a novel antibody agonist for CD137. Treatment with 7A5 demonstrated a T-cell activated intratumoral immune gene expression signature and generated anti-tumor activity that was further enhanced by anti-PD-L1 therapy.