scholarly journals Correction to ‘Tumor-selective, antigen-independent delivery of a pH sensitive peptide-topoisomerase inhibitor conjugate suppresses tumor growth without systemic toxicity’

NAR Cancer ◽  
2021 ◽  
Vol 3 (4) ◽  
Author(s):  
Sophia Gayle ◽  
Robert Aiello ◽  
Nalin Leelatian ◽  
Jason M Beckta ◽  
Jane Bechtold ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Ph Sensitive ◽  
Systemic Toxicity ◽  
Topoisomerase Inhibitor ◽  
Tumor Selective

scholarly journals Tumor-selective, antigen-independent delivery of a pH sensitive peptide-topoisomerase inhibitor conjugate suppresses tumor growth without systemic toxicity

NAR Cancer ◽  
2021 ◽  
Vol 3 (2) ◽  
Author(s):  
Sophia Gayle ◽  
Robert Aiello ◽  
Nalin Leelatian ◽  
Jason M Beckta ◽  
Jane Bechtold ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Parp Inhibitor ◽  
Unmet Need ◽  
Human Tumor ◽  
Therapeutic Index ◽  
Ph Sensitive ◽  
Complete Suppression ◽  
Independent Manner ◽  
Topoisomerase Inhibitor

Abstract Topoisomerase inhibitors are potent DNA damaging agents which are widely used in oncology, and they demonstrate robust synergistic tumor cell killing in combination with DNA repair inhibitors, including poly(ADP)-ribose polymerase (PARP) inhibitors. However, their use has been severely limited by the inability to achieve a favorable therapeutic index due to severe systemic toxicities. Antibody-drug conjugates address this issue via antigen-dependent targeting and delivery of their payloads, but this approach requires specific antigens and yet still suffers from off-target toxicities. There is a high unmet need for a more universal tumor targeting technology to broaden the application of cytotoxic payloads. Acidification of the extracellular milieu arises from metabolic adaptions associated with the Warburg effect in cancer. Here we report the development of a pH-sensitive peptide-drug conjugate to deliver the topoisomerase inhibitor, exatecan, selectively to tumors in an antigen-independent manner. Using this approach, we demonstrate potent in vivo cytotoxicity, complete suppression of tumor growth across multiple human tumor models, and synergistic interactions with a PARP inhibitor. These data highlight the identification of a peptide-topoisomerase inhibitor conjugate for cancer therapy that provides a high therapeutic index, and is applicable to all types of human solid tumors in an antigen-independent manner.

scholarly journals Highly efficient and tumor-selective nanoparticles for dual-targeted immunogene therapy against cancer

2020 ◽  
Vol 6 (3) ◽  
pp. eaax5032 ◽  
Author(s):  
Kuan-Wei Huang ◽  
Fu-Fei Hsu ◽  
Jiantai Timothy Qiu ◽  
Guann-Jen Chern ◽  
Yi-An Lee ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Immunotherapy ◽  
Plasmid Dna ◽  
Systemic Toxicity ◽  
Great Promise ◽  
Anticancer Efficacy ◽  
Highly Efficient ◽  
Immunogene Therapy ◽  
Immunosuppressive Tumor Microenvironment ◽  
Tumor Selective

While immunotherapy holds great promise for combating cancer, the limited efficacy due to an immunosuppressive tumor microenvironment and systemic toxicity hinder the broader application of cancer immunotherapy. Here, we report a combinatorial immunotherapy approach that uses a highly efficient and tumor-selective gene carrier to improve anticancer efficacy and circumvent the systemic toxicity. In this study, we engineered tumor-targeted lipid-dendrimer-calcium-phosphate (TT-LDCP) nanoparticles (NPs) with thymine-functionalized dendrimers that exhibit not only enhanced gene delivery capacity but also immune adjuvant properties by activating the stimulator of interferon genes (STING)–cGAS pathway. TT-LDCP NPs delivered siRNA against immune checkpoint ligand PD-L1 and immunostimulatory IL-2–encoding plasmid DNA to hepatocellular carcinoma (HCC), increased tumoral infiltration and activation of CD8+ T cells, augmented the efficacy of cancer vaccine immunotherapy, and suppressed HCC progression. Our work presents nanotechnology-enabled dual delivery of siRNA and plasmid DNA that selectively targets and reprograms the immunosuppressive tumor microenvironment to improve cancer immunotherapy.

Plasmin‐activated doxorubicin prodrugs containing a spacer reduce tumor growth and angiogenesis without systemic toxicity

2004 ◽  
Vol 18 (3) ◽  
pp. 565-567 ◽  
Author(s):  
Laetitia Devy ◽  
Franciscus M. H. Groot ◽  
Silvia Blacher ◽  
Amin Hajitou ◽  
Patrick H. Beusker ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Systemic Toxicity ◽  
Reduce Tumor Growth

Comparison of an FAP-targeted, CD137 activating DARPin drug candidate with a non-targeted, CD137 activating antibody in a human PBMC transplanted HT-29 mouse tumor model.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14626-e14626 ◽  
Author(s):  
Julia Hepp ◽  
Alexander Link ◽  
Ulrike Fiedler ◽  
Christian Reichen ◽  
Clara Metz ◽  
...  
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Body Weight Loss ◽  
Systemic Toxicity ◽  
Drug Candidate ◽  
Tumor Growth Inhibition ◽  
Human Pbmcs ◽  
Ht 29

e14626 Background: Urelumab (BMS-663513) is a humanized monoclonal antibody binding to CD137 which, upon Fc-clustering, leads to activation of T-cells. Urelumab is currently in Phase 2 clinical development and has been reported to cause significant hepatotoxicities (around 15% Grade ≥2 ALT and AST elevation) when given as infusion every 3 weeks at doses ≥0.3 mg/kg. Currently ongoing clinical trials report decreased systemic toxicity but limited efficacy at lower doses of urelumab. We hypothesized that more effective triggering of CD137 without associated systemic toxicity may be achieved by targeting a CD137 agonistic engager without Fc to fibroblast activation protein (FAP) which is abundantly expressed in the stroma of many solid tumors. To achieve this, a targeted molecule belonging to the DARPin family of binding proteins was composed of one FAP- and two CD137-binding domains in a “beads on a string” format and tested in a mouse model with human PBMCs. Methods: Human PBMCs were used to reconstitute the immune system in NOG mice implanted subcutaneously with HT-29 human colon cancer cells. Mice were monitored for survival, body weight, and tumor size during the treatment phase of two weeks. Results: None of the mice in the control group died and no significant body weight loss was observed. Six of ten (60%) mice in the CD137 antibody group showed strong signs of graft vs. host disease and either died or reached the termination criterion of ≥20% body weight loss and were sacrificed. One of 30 (3%) mice died in the DARPin drug candidate groups but none of the animals showed body weight loss of ≥20% (p < 0.001, Log-rank test). Tumor growth inhibition was comparable for all treatment groups (around 20-30% at Day 18, p < 0.05 vs. control, Mann Whitney Test). Conclusions: This study confirms the hypothesis that systemic toxicities caused by the urelumab mode of action can be circumvented by FAP-targeting of a CD137 agonistic DARPin drug candidate while achieving comparable tumor growth inhibition. Consequently, higher clinical doses of tumor stroma-targeted agonistic DARPin drug candidates might be possible, and may result in stronger tumor growth inhibition.

Synthetic enzyme inhibitor: a novel targeting ligand for nanotherapeutic drug delivery inhibiting tumor growth without systemic toxicity

2011 ◽  
Vol 7 (6) ◽  
pp. 665-673 ◽  
Author(s):  
Debbie Liao ◽  
Ze Liu ◽  
Wolfgang Wrasidlo ◽  
Tingmei Chen ◽  
Yunping Luo ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Tumor Growth ◽  
Enzyme Inhibitor ◽  
Systemic Toxicity

Examples of Tumor Growth Inhibition Properties of Liposomal Formulations of pH-Sensitive Histidinylated Cationic Amphiphiles

2015 ◽  
Vol 1 (8) ◽  
pp. 646-655 ◽  
Author(s):  
Arup Garu ◽  
Gopikrishna Moku ◽  
Suresh Kumar Gulla ◽  
Dipankar Pramanik ◽  
Bharat K. Majeti ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Growth Inhibition ◽  
Ph Sensitive ◽  
Tumor Growth Inhibition ◽  
Cationic Amphiphiles ◽  
Liposomal Formulations

pH-sensitive micelles with charge-reversible property for tumor growth inhibition and anti-metastasis

2018 ◽  
Vol 6 (3) ◽  
pp. 458-468 ◽  
Author(s):  
Yu Sun ◽  
Yuling Bao ◽  
Xue Jiang ◽  
Songwei Tan ◽  
Mingxing Yin ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Growth Inhibition ◽  
Ph Sensitive ◽  
Tumor Growth Inhibition

Biocompatible VE-based micelles with charge-reversible property for PTX delivery demonstrating effective antitumor and anti-metastasis effects.

Doxorubicin-loaded pH-sensitive dextran-retinal nanoparticles suppress tumor growth by inducing both apoptosis and cell senescence

2015 ◽  
Vol 213 ◽  
pp. e88-e89 ◽  
Author(s):  
Ping Li ◽  
Yijuan Zhang ◽  
Hong Pan ◽  
Manyi Ji ◽  
Nan Sheng ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Ph Sensitive ◽  
Cell Senescence

scholarly journals Conditionally Activated IL-12 or IFNα Indukine™ Molecules Inhibit Syngeneic Lymphoma Tumor Growth in Mice, Induce Anti-Tumor Immune Responses and Are Tolerated in Non-Human Primates

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2258-2258
Author(s):  
Philipp Steiner ◽  
Heather Brodkin ◽  
Josue Canales ◽  
Daniel Hicklin ◽  
Randi Isaacs ◽  
...  
Keyword(s):  
Immune Responses ◽  
Tumor Growth ◽  
Half Life ◽  
B Cell Lymphoma ◽  
Systemic Toxicity ◽  
Lymphoid Cells ◽  
Type I ◽  
Wild Type ◽  
Wide Range ◽  
Anti Tumor Activity

Abstract Systemic therapy with proinflammatory immune modulators to activate anti-tumor immunity is a promising approach to treat cancer. However, poor pharmacokinetic properties and dose-limiting toxicities such as inflammation, cytokine release syndrome, and tissue damage have prevented or limited the clinical use of cytokines such as interleukin 12 (IL-12) and interferon α (IFNα). Previous clinical development of rhIL-12 was terminated due to toxicity, and although rIFNα is approved for the treatment of melanoma, lymphoma, and leukemia, its use has been limited by systemic toxicity and modest efficacy. INDUKINE™ molecules, engineered using Werewolf Therapeutics' Predator™ discovery platform, are novel, systemically delivered cytokine pro-drugs which prevent systemic toxicity and deliver cytokines to the tumor microenvironment (TME) where they are activated. Several INDUKINE™ molecules using Werewolf's proprietary linkers have been previously shown to be cleaved by a wide range of human solid tumors but have yet to be tested in primary human lymphoma samples or syngeneic mouse lymphoma models. IL-12 is a potent, pleiotropic cytokine for immune-mediated killing of cancer cells, whose mechanism of action (MOA) includes activation of both cytotoxic T and NK cells. The WTX-330 INDUKINE™ molecule, a wild-type IL-12 pro-drug, contains a half-life extension (HLE) domain to support infrequent dosing and a high affinity anti-IL-12 neutralizing antibody domain to maintain the molecule in its inactive state in the periphery. Both the HLE and blocking domains are tethered to IL-12 via two identical tumor protease-sensitive linkers. Linker cleavage in the TME removes the HLE domain and the blocker, resulting in active IL-12 within the TME with wild-type IL-12 biologic and PK profiles. IFNα is a member of the type-I IFN family and activates innate immune responses either directly by engaging IFNα receptors (IFNAR) ubiquitously expressed on immune cells or indirectly by inducing chemokines that attract myeloid and lymphoid cells to the tumor site. The WTX-613 INDUKINE™ molecule is an inactive IFNα2b pro-drug with two identical HLE domains tethered to IFNα2b via two identical tumor protease-sensitive linkers. The HLE domains sterically block binding of WTX-613 to IFNAR until cleavage of the linkers in the TME releases active IFNα. Since human IL-12 and IFNα2b are not cross reactive in mice, surrogate WTX-330 and WTX-613 INDUKINE™ molecules were created, consisting of a mouse/human chimeric IL-12 or a mouse IFNα1 to explore anti-tumor responses in syngeneic hematologic cancer models. In the subcutaneously (s.c.) A20 B cell lymphoma model, the WTX-330 surrogate showed dose-dependent anti-tumor activity with 4 out of 10 tumor-free mice at the top dose. The WTX-613 surrogate demonstrated tumor stasis lasting beyond the treatment phase. Utilizing the s.c. EG7.OVA T lymphoblast line, tumor growth was efficiently blocked by the WTX-613 surrogate while the WTX-330 surrogate inhibited tumor growth during the dosing period. Both treatments were well tolerated by the mice at active dose levels. The WTX-330 and WTX-613 surrogates strongly activated NK and CD8+ cell responses and induced APC and effector cell markers in the MC38 syngeneic tumor model supporting a MOA as described for wild-type IL-12 and IFNα. Similar studies are on-going in lymphoma models. PK analysis in mice revealed extended half-life (T1/2) for both WTX-330 and WTX-613 surrogates compared to the short T1/2 of native IL-12 or IFNα1. Finally, WTX-330 and WTX-613 were well tolerated in non-human primates (NHP), resulting in plasma exposure levels for INDUKINE™ molecules that exceeded those needed for anti-tumor activity in mice. In addition, plasma levels of free IL-12 after dosing with WTX-330 were very low compared to tolerated levels of wild-type IL-12. Similar studies for WTX-613 are on-going. Preclinical data obtained so far for both programs support the continued development and future evaluation of these innovative and differentiated therapies in hematologic malignancies, both as monotherapies and in multiple combinations with standard of care. Disclosures Isaacs: Werewolf Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Seidel-Dugan: Werewolf Therapeutics: Current Employment, Other: current shareholder .

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