A5055969186- Veterinary Oncology Research
- Cancer Research and Treatments
- Sarcoma Diagnosis and Treatment
- Virus-based gene therapy research
- Cell Adhesion Molecules Research
- Immunotherapy and Immune Responses
- Angiogenesis and VEGF in Cancer
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Cancer Immunotherapy and Biomarkers
- Phagocytosis and Immune Regulation
- Chemokine receptors and signaling
- Retinal Diseases and Treatments
- CAR-T cell therapy research
- Nanoplatforms for cancer theranostics
- Monoclonal and Polyclonal Antibodies Research
- Immune cells in cancer
- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Vitamin C and Antioxidants Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Glycosylation and Glycoproteins Research
- Cancer Cells and Metastasis
- Cancer Genomics and Diagnostics
- Anesthesia and Neurotoxicity Research
- Cancer, Hypoxia, and Metabolism
Massachusetts Institute of Technology
2022-2024
Anti-CTLA-4 antibodies have successfully elicited durable tumor regression in the clinic; however, long-term benefit is limited to a subset of patients for select cancer indications. The incomplete understanding their mechanism action has hindered efforts at improvement, with conflicting hypotheses proposing either antagonism CTLA-4:B7 axis or Fc effector-mediated regulatory T cell (Treg) depletion governing efficacy. Here, we report engineering nonantagonistic CTLA-4 binding domain (b1s1e2)...
Effective antitumor immunity in mice requires activation of the type I interferon (IFN) response pathway. IFNα and IFNβ therapies have proven promising humans, but suffer from limited efficacy high toxicity. Intratumoral IFN retention ameliorates systemic toxicity, given complexity signaling, it was unclear whether long-term intratumoral IFNs would promote or inhibit responses. To this end, we compared that exhibit either brief sustained after injection syngeneic mouse tumor models....
<div>Abstract<p>Although heightened intratumoral levels of reactive oxygen species (ROS) are typically associated with a suppressive tumor microenvironment, under certain conditions ROS contribute to elimination. Treatment approaches, including some chemotherapy and radiation protocols, increase cancer cell that influence their mechanism death subsequent recognition by the immune system. Furthermore, activated myeloid cells rapidly generate upon encounter pathogens or infected...
<p>Fluorescence intensities of OT-I phenotypic markers from the cross-presentation assay with IFNa</p>
<p>Bolus hydrogen peroxide is cytotoxic but rapidly cleared by cancer cells</p>
<p>Cross-presentation assay T-cell gating strategy</p>
<p>Comparison of OT-I phenotypes in cross-presentation assay after treatment with immunogenic cell stress-inducing chemotherapy</p>
<p>Cross-presentation assay myeloid cell gating strategy</p>
<p>2.5F-GOX and MSA-IFNa do not cause toxicity in mice but fail to generate anti-tumor memory</p>
<p>Characterization of recombinant glucose oxidase fusions</p>
<p>Protein sequences</p>
<p>Additional flow analysis of 2.5F-GOX dose escalation study</p>
Abstract Confining cytokine exposure to the tumors would greatly enhance cancer immunotherapy safety and efficacy. Immunocytokines, cytokines fused tumor-targeting antibodies, have been developed with this intention, but without significant clinical success date. A critical limitation is uptake by receptor-expressing cells in blood, that decreases dose at tumor engenders toxicity. Small-format immunocytokines, constructed antibody fragments, are hypothesized improve specificity due rapid...
Engineered cytokine-based approaches for immunotherapy of cancer are poised to enter the clinic, with IL-12 being at forefront. However, little is known about potential mechanisms resistance cytokine therapies. We found that orthotopic murine lung tumors were resistant systemically delivered fused serum albumin (MSA, IL12-MSA) because low receptor (IL-12R) expression on tumor-reactive CD8+ T cells. IL2-MSA increased binding IL12-MSA by cells, and combined administration led enhanced cell...
Cytokine therapies such as IL2 and IL12 suffer from impractically small therapeutic windows driven by their on-target, off-tumor activity, limiting clinical potential despite potent antitumor effects. We previously engineered cytokines that bind anchor to tumor collagen following intratumoral injection, sought test safety biomarker activity in spontaneous canine soft-tissue sarcomas (STS).Collagen-binding were canine-ized minimize immunogenicity used a rapid dose-escalation study healthy...
Catalase is an antioxidant enzyme that catalyzes the rapid conversion of hydrogen peroxide to water and oxygen. Use catalase as a cancer therapeutic has been proposed reduce oxidative stress hypoxia in tumor microenvironment, both activities which are hypothesized growth. Furthermore, exposing murine tumors exogenous was previously reported have benefit. We studied effect tumor-localized catalases with aim further elucidate mechanism action. To do this, we engineered two approaches maximize...
Cytokines IL2 and IL12 exhibit potent anticancer activity but suffer a narrow therapeutic window due to off-tumor immune cell activation. Engineering cytokines with the ability bind associate tumor collagen after intratumoral injection potentiated response without toxicity in mice was previously safe pet dogs sarcoma. Here, we sought test efficacy of this approach advanced melanoma.
Monoclonal antibodies targeting the programmed cell death protein 1 (PD-1) remain most prevalent cancer immunotherapy both as a monotherapy and in combination with additional therapies. Despite extensive success of anti-PD-1 monoclonal clinic, experimental relationship between binding affinity functional potency for vivo has not been reported. Anti-PD-1 higher lower than nivolumab or pembrolizumab are entering clinic show varied preclinical efficacy. Here, we explore role broad-ranging...
Abstract Background Genetically engineered mouse models (GEMMs) of cancer are powerful tools to study mechanisms disease progression and therapy response, yet little is known about how these respond multimodality used in patients. Radiation (RT) frequently treat localized cancers with curative intent, delay oligometastases, palliate symptoms metastatic disease. Methods Here we report the development, testing, validation a platform immobilize target tumors mice stereotactic ablative RT...
ABSTRACT The clinical use of interleukin-2 and -12 cytokines against cancer is limited by their narrow therapeutic windows due to on-target, off-tumor activation immune cells when delivered systemically. Engineering IL-2 IL-12 bind extracellular matrix collagen allows these be retained within tumors after intralesional injection, overcoming safety challenges. While this approach has potentiated responses in syngeneic mouse without toxicity, the complex tumor-immune interactions human cancers...
<p>Supplemental Data S1. Supplemental File containing raw data generated in this study.</p>
<p>Supplemental Figure S1. Local RT causes transient lymphodepletion in murine melanomas.</p>
<p>Supplemental Data S1. Supplemental File containing raw data generated in this study.</p>
<p>Supplemental Figure S3. IL2/IL12 cytokine dose does not appear to correlate with tumor response or survival.</p>