- |||||||||| evofosfamide (IMGS-101) / Molecular Templates, ImmunoGenesis
Journal, Checkpoint inhibition, Checkpoint block: [18F]FMISO-PET imaging reveals the role of hypoxia severity in checkpoint blockade response. (Pubmed Central) - Jun 16, 2024
Non-invasive hypoxia quantification through molecular imaging evaluating hypoxia severity may be an effective tool in guiding treatment planning, predicting therapy response, and ultimately improving patient outcomes across diverse cancer types and tumor microenvironments. It sets the stage for the translation of these findings into clinical practice, facilitating the optimization of immunotherapy regimens by addressing tumor hypoxia and thereby enhancing the efficacy of cancer treatments.
- |||||||||| IDO1 inhibition enables IFN?-elicited responsiveness of pulmonary breast cancer metastases to hypoxia-directed tumoricidal agents (Section 29) - Mar 5, 2024 - Abstract #AACR2024AACR_2573;
In WT (wild type) mice with established 4T1 lung metastases, administration of the IDO1 inhibitors epacadostat, navoximod or indoximod each similarly resulted in rapid collapse of the metastatic tumor neovasculature and concomitantly increased intratumoral hypoxia and sensitivity to PERK inhibition...Combining chemotherapy with immune checkpoint blockade (ICB) is recognized as an effective strategy for treating lung cancer, with first-line therapy for some patients including the alkylating agent carboplatin in conjunction with pembrolizumab...Elevated intratumoral hypoxia has also previously been linked to increased expression levels of PDL1, a favorable indicator of ICB responsiveness, and we have confirmed the upregulation of PDL1 in 4T1 lung metastases following IDO1 inhibitor administration. Our data in the lung metastasis model support future studies to evaluate whether IDO1 inhibition can be effectively combined with evofosfamide and anti-PD1 treatment to improve therapeutic outcomes.
- |||||||||| evofosfamide (IMGS-101) / Molecular Templates, ImmunoGenesis
Biomarker, Journal: Clinical relevance and therapeutic predictive ability of hypoxia biomarkers in head and neck cancer tumour models. (Pubmed Central) - Mar 1, 2024
Hypoxia or proliferation status alone could not determine HAP sensitivity across our 20 HNSCC and two non-HNSCC tumour models by either tumour growth inhibition or killing of hypoxia cells in an ex vivo clonogenic assay. In summary, our tumour models provide clinically relevant HNSCC models that are suitable for evaluating hypoxia-targeting therapies; however, additional biomarkers to hypoxia are required to accurately predict drug sensitivity.
- |||||||||| evofosfamide (IMGS-101) / Molecular Templates, ImmunoGenesis
Journal: Exploring chronic and transient tumor hypoxia for predicting the efficacy of hypoxia-activated pro-drugs. (Pubmed Central) - Jan 10, 2024
The three-compound combination had three local optima, depending on the HAPs clearance from the tissue interstitium, each two-fold more effective than baseline HAP treatment. Our study indicates that the three-compound therapy administered in the defined order will improve cancer response and that designing complex schedules could benefit from the use of mathematical modeling.
- |||||||||| evofosfamide (IMGS-101) / Molecular Templates, ImmunoGenesis
Preclinical, Journal: In Vitro Characterization of the Bacteria-derived Hypoxia-selective Cytotoxin BE-43547. (Pubmed Central) - Nov 30, 2023
BE-43547 is highly hypoxia-selective, and unlike TH-302, displayed minimal variability between cell lines, suggesting that BE-43547 targets a fundamental feature/target that is only present, or of survival importance, during hypoxia. Spheroid experiments suggested inadequate tissue penetrability, which may be overcome by designing novel drug analogs.
- |||||||||| evofosfamide (IMGS-101) / Molecular Templates, ImmunoGenesis
Journal, Myeloid-derived suppressor cells: Hypoxia-activated prodrug and anti-angiogenic therapy cooperatively treat pancreatic cancer but elicit immunosuppressive G-MDSC infiltration. (Pubmed Central) - Nov 21, 2023
Blockade of the CCL9-CCR1 axis could limit G-MDSC migration, and depletion of Ly6G-positive cells could sensitize tumors to the combination of TH-302 and anti-VEGFR-2 with ICB. Together, these data suggest that pancreatic tumors modulate G-MDSC migration as an adaptive response to vascular normalization, and that these immunosuppressive myeloid cells act in a setting of persistent hypoxia to maintain adaptive immune resistance.
- |||||||||| Zolinza (vorinostat) / Merck (MSD), evofosfamide (IMGS-101) / Molecular Templates, ImmunoGenesis
Review, Journal: Enhancing radiotherapy outcomes in rectal cancer: A systematic review of targeting hypoxia-induced radioresistance. (Pubmed Central) - Nov 14, 2023
Vorinostat, atovaquone, and evofosfamide showed promising preclinical evidence that they can overcome hypoxia-induced radioresistance...This systematic review highlights the importance of further research to fully understand the mechanism behind this radioresistance. There are promising targets identified in this systematic review however, substantially more pre-clinical and clinical research as a priority for future research is needed.
- |||||||||| evofosfamide (IMGS-101) / Molecular Templates, ImmunoGenesis
Journal, Metastases: Radiomic-Based Prediction of Lesion-Specific Systemic Treatment Response in Metastatic Disease. (Pubmed Central) - Oct 3, 2023
P3
Lesion-specific radiomic models indicate a 2 to 3-fold increase in predictive capacity in comparison to a no-skill classifier. These models, although preliminary, achieved a strong predictive value and could be used to predict lesion-specific treatment response.
- |||||||||| Evofosfomide potentiates the efficacy of a novel anti-PD-L1/PD-L2 monoclonal antibody against immune excluded tumors (Exhibit Hall B) - Sep 27, 2023 - Abstract #SITC2023SITC_1180;
Background Evofosfamide (Evo) is a hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard...1 Moreover, in a phase 1 clinical trial, the combination of Evo with the anti-CTLA-4 Ipilimumab resulted in objective responses in patients with cold tumors...Conclusions These data indicate that Evo and IMGS-001 in combination improves upon the efficacy of either treatment alone, and those improvements are not observed for Evo in combination with anti-PD-1 treatment. This novel combination treatment will continue to be tested in preclinical models and has potential to be tested in a clinical trial.
- |||||||||| evofosfamide (TH 302) / Molecular Templates, ImmunoGenesis
Radiomic-Based Prediction of Lesion-Specific Systemic Treatment Response in Metastatic Disease (Hall B2; In Person Only; Screen: 5) - Aug 22, 2023 - Abstract #ASTRO2023ASTRO_1722;
Lesion-specific radiomic models indicate a 2 to 3-fold increase in predictive capacity in comparison to a no-skill classifier. These models, although preliminary, achieved a strong predictive value and could be used to predict lesion-specific treatment response.
- |||||||||| Yondelis (trabectedin) / Otsuka, PharmaMar, Valeo Pharma
Journal: Doxorubicin combined with Trabectedin in systemic first-line M+/recurrent leiomyosarcoma patients. (Pubmed Central) - Jun 9, 2023
These models, although preliminary, achieved a strong predictive value and could be used to predict lesion-specific treatment response. In the first-line setting, the results of this trial were pivotal for numerous reasons; Doxorubicin-Trabectedin is the first combination that has been proven to be more effective in terms of PFS, ORR and trend of OS compared with doxorubicin alone; moreover, it is clear that trials regarding soft tissue sarcoma should strive to be histology-driven.
- |||||||||| IDO1 inhibition sensitizes metastatic lung tumors to hypoxia/ER stress targeting agent-induced cell death (Section 20; Poster Board #16) - Mar 14, 2023 - Abstract #AACR2023AACR_2435;
This contrasts with results obtained with the non-targeted cytotoxic agent Carboplatin that elicited comparable levels of metastatic tumor cell death regardless of Epacadostat co-administration. Altogether, these data establish the potential to benefit treatment in tumor settings where IDO1 inhibition enhances intra-tumoral hypoxia through neovascular regression by facilitating the ability of hypoxia-targeting agents to effectively eliminate tumor cells in a more targeted manner than can be achieved with conventional chemotherapy.
- |||||||||| evofosfamide (TH 302) / Molecular Templates, ImmunoGenesis
Journal: Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma. (Pubmed Central) - Feb 27, 2023
Altogether, these data establish the potential to benefit treatment in tumor settings where IDO1 inhibition enhances intra-tumoral hypoxia through neovascular regression by facilitating the ability of hypoxia-targeting agents to effectively eliminate tumor cells in a more targeted manner than can be achieved with conventional chemotherapy. No abstract available
- |||||||||| Yondelis (trabectedin) / Otsuka, PharmaMar, Valeo Pharma, Votrient (pazopanib) / Novartis, evofosfamide (TH 302) / Molecular Templates, ImmunoGenesis
Clinical, Journal: Keeping up the 'race pace' in a patient with nonuterine leiomyosarcoma. (Pubmed Central) - Oct 22, 2022
Finally, he received fourth-line gemcitabine monotherapy for 5 months until disease progression, which was followed by death. Notably, trabectedin provided long-term disease control and maintained the patient's functional performance throughout treatment.
- |||||||||| evofosfamide (TH 302) / Molecular Templates, ImmunoGenesis
Hypoxia reduction in combination with anti-angiogenic therapy remodels the PDAC microenvironment (Hall C) - Oct 6, 2022 - Abstract #SITC2022SITC_1450;
P1
This combination relieves hypoxic stress and simultaneously reinvigorates T cell function, but may facilitate de novo MDSC infiltration. Future work will determine the underlying factors that shape the tumor immune microenvironment and influence immunotherapy responses.
- |||||||||| evofosfamide (TH 302) / Molecular Templates, ImmunoGenesis, Yervoy (ipilimumab) / Ono Pharma, BMS
Targeting tumor oxidative metabolism to overcome hypoxia-induced immunotherapy resistance in prostate cancer (Hall C) - Oct 6, 2022 - Abstract #SITC2022SITC_1143;
OxPhos inhibition selectively inhibits tumor and myeloid function, while sparing T cell function and responsiveness to ICB. Coordinated remodeling of tumor oxygen metabolism with existing drugs can compromise hypoxia-associated T cell suppression without compromising intrinsic T cell metabolic potential.
- |||||||||| evofosfamide (TH 302) / Molecular Templates, ImmunoGenesis
Preclinical, Journal: Hypoxia-targeting therapy for intestinal T-cell lymphoma in dogs: Preclinical study using 3D in vitro models. (Pubmed Central) - Sep 3, 2022
We assessed the effects of evofosfamide (Evo; hypoxia-activated prodrug) on cell lines cultured under hypoxic conditions...Additionally, Evo downregulated HIF-1α expression in cell lines cultured under hypoxia, suggesting that Evo might inhibit cell growth by inactivating HIF-1α-dependent cell signalling. Our results revealed the preclinical antitumor activity of Evo and provide a rationale for treatment strategies for dogs with ITL.
- |||||||||| evofosfamide (TH 302) / Molecular Templates, ImmunoGenesis
TH302. Finding Allyship in the American College of Surgeons (SDCC - 1B - Upper) - Aug 21, 2022 - Abstract #ACSCLINCON2022ACS_CLINCON_2374;
Our results revealed the preclinical antitumor activity of Evo and provide a rationale for treatment strategies for dogs with ITL. This open forum for all College members will provide a venue for surgeons representing groups historically underrepresented in the surgical workforce to shed light on the barriers to their professional safety and career advancement and for they peers to stand as allies rising up to help dismantle these barriers.
- |||||||||| Tirazone (tirapazamine) / Teclison, SRI International, evofosfamide (TH 302) / Molecular Templates, ImmunoGenesis
Journal, IO biomarker: Detection and impact of hypoxic regions in multicellular tumor spheroid cultures formed by head and neck squamous cell carcinoma cells lines. (Pubmed Central) - May 6, 2022
Cells in solid tumors and MCTSs experience three distinct O microenvironments dictated by their distances from blood vessels or MCTS surfaces, respectively; oxic, hypoxic, or intermediate levels of hypoxia. These studies support the application of more physiologically relevant in vitro 3D models that recapitulate the heterogeneous microenvironments of solid tumors for preclinical cancer drug discovery.
- |||||||||| evofosfamide (TH 302) / Molecular Templates, ImmunoGenesis
Preclinical, Journal: Multicellular tumor spheroids of LNCaP-Luc prostate cancer cells as in vitro screening models for cytotoxic drugs. (Pubmed Central) - Apr 13, 2022
For docetaxel, this resistance increased with the spheroid growth stage, whereas the activity of TH-302 was potentiated by the hypoxic environment. In conclusion, the development of LNCaP-Luc cell MCTS provides a simple model mimicking a microtumor; it appears to be particularly well-suited to the validation of new therapeutic approaches targeting proliferation and the microenvironment.
- |||||||||| evofosfamide (TH 302) / Molecular Templates, ImmunoGenesis
Clinical, Journal: AI-Radiomics Can Improve Inclusion Criteria and Clinical Trial Performance. (Pubmed Central) - Mar 25, 2022
The study presents a first of its kind clinical-radiomic approach for patient enrichment in clinical trials. We show that, had an appropriate model been used for selective patient inclusion, SARC021 trial could have met its primary survival objective for patients with metastatic STS.
- |||||||||| evofosfamide (TH 302) / Molecular Templates, ImmunoGenesis, Yervoy (ipilimumab) / Ono Pharma, BMS
Clinical, P1 data, Journal, Combination therapy, IO biomarker: A Phase I Dose Escalation Study to Evaluate the Safety and Tolerability of Evofosfamide in Combination with Ipilimumab in Advanced Solid Malignancies. (Pubmed Central) - Mar 23, 2022
P1
We show that, had an appropriate model been used for selective patient inclusion, SARC021 trial could have met its primary survival objective for patients with metastatic STS. No new or unexpected safety signals were observed from combining evofosfamide and ipilimumab, and evidence of therapeutic activity was noted.
- |||||||||| evofosfamide (TH 302) / Molecular Templates, ImmunoGenesis
Journal: Mitochondria-targeting multifunctional nanoplatform for cascade phototherapy and hypoxia-activated chemotherapy. (Pubmed Central) - Mar 23, 2022
Polydopamine coated hollow copper sulfide nanoparticles were used as the photothermal nanoagents and thermosensitive drug carriers for loading the hypoxia-activated prodrug, TH302, in our study...Both in vitro and in vivo studies demonstrated the greatly improved anti-cancer activity compared to conventional hypoxia-associated chemotherapy. This work highlights the potential of using a combination of hypoxia-activated prodrugs plus phototherapy for synergistic cancer treatment.
- |||||||||| evofosfamide (TH 302) / Molecular Templates, ImmunoGenesis
Circulating tumor DNA is associated with response and survival in patients with advanced leiomyosarcoma (Section 31) - Mar 9, 2022 - Abstract #AACR2022AACR_5315;
Detection of ctDNA is associated with outcome and objective response to chemotherapy in patients with advanced LMS. These results suggest that liquid biopsy assays could be used to inform treatment decisions by recognizing patients who are likely and unlikely to benefit from chemotherapy.Ongoing work focuses on identification of ctDNA features, such as copy-number alterations or changes in ctDNA levels over time, that may also be associated with disease progression or response to therapy.
- |||||||||| Nexavar (sorafenib) / Bayer, Amgen
Biomarker, Review, Journal: New frontiers against sorafenib resistance in renal cell carcinoma: From molecular mechanisms to predictive biomarkers. (Pubmed Central) - Feb 10, 2022
Herein, we comprehensively summarize the underlying mechanisms of sorafenib resistance and molecular biomarkers for predicting sorafenib responsiveness. Moreover, we outline strategies suitable for overcoming sorafenib resistance and prospect potential approaches for identifying biomarkers associated with sorafenib resistance in RCC, which contributes to guide individualized and precision drug therapy.
- |||||||||| CP-506 / Convert Pharma, Tarlox (tarloxotinib bromide) / Molecular Templates, Proacta, Rain Therap, Signpath Pharma, evofosfamide (TH 302) / Molecular Templates, ImmunoGenesis
Review, Journal: Tumour Hypoxia-Mediated Immunosuppression: Mechanisms and Therapeutic Approaches to Improve Cancer Immunotherapy. (Pubmed Central) - Nov 10, 2021
Accumulating evidence suggests that tumour hypoxia, a pervasive feature of many solid cancers, is a critical phenomenon involved in suppressing the anti-tumour immune response generated by checkpoint inhibitors. In this review, we discuss the mechanisms associated with hypoxia-mediate immunosuppression and focus on modulating tumour hypoxia as an approach to improve immunotherapy responsiveness.
- |||||||||| evofosfamide (TH 302) / Molecular Templates, ImmunoGenesis
Journal: Chitosan oligosaccharide decorated liposomes combined with TH302 for photodynamic therapy in triple negative breast cancer. (Pubmed Central) - Nov 10, 2021
In this review, we discuss the mechanisms associated with hypoxia-mediate immunosuppression and focus on modulating tumour hypoxia as an approach to improve immunotherapy responsiveness. The impressive synergistic antitumor effects, together with the superior fluorescence imaging capability, good biocompatibility and minor side effects confers the liposomes with potential for future translational research in the diagnosis and CD44-overexpressing cancer therapy, especially TNBC.
- |||||||||| evofosfamide (TH 302) / Molecular Templates, ImmunoGenesis, Yervoy (ipilimumab) / Ono Pharma, BMS
Disrupted oxygen supply and tumor hyper- oxygen consumption contribute independently to prostate cancer immune privilege (Poster Hall) - Oct 1, 2021 - Abstract #SITC2021SITC_1046;
In a Phase I clinical trial, the combination of Evofosfamide and anti CTLA-4 (Ipilimumab) elicited both objective responses and prolonged disease stabilization in late-stage ”cold” tumor patients...Heightened tumor oxidative metabolism has been shown to generate hypoxic zones that resist PD-1 blockade therapy [6] and treatment with Metformin, a mitochondrial complex I inhibitor may reduce hypoxia and improve responses [7]...Complex I inhibition selectively inhibits tumor and myeloid cell function, while sparing T cells. This provides opportunities to craft synergistic immuno-metabolic therapies with the potential to treat ”cold” tumor patients refractory to current FDA approved immunotherapeutics.
- |||||||||| Review: Targeting Hypoxia: Hypoxia-Activated Prodrugs in Cancer Therapy. (Pubmed Central) - Aug 17, 2021
Both single-agent and combined use with other drugs have shown promising antitumor effects. In this review, we discuss the mechanism of action and the current preclinical and clinical progress of several of the most widely used HAPs, summarize their existing problems and shortcomings, and discuss future research prospects.
- |||||||||| evofosfamide (TH 302) / Molecular Templates
Journal: Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma. (Pubmed Central) - Jul 31, 2021
Combined treatment with a CREB inhibitor and the hypoxia-activated prodrug TH-302 (evofosfamide) significantly reduced MM-induced bone destruction in vivo. Taken together, our findings reveal that hypoxia and a cytogenetic abnormality regulate DKK1 expression in myeloma cells, and provide an additional rationale for the development of therapeutic strategies that interrupt DKK1 to cure MM.
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