A5000659687- Immunotherapy and Immune Responses
- Cancer Immunotherapy and Biomarkers
- CAR-T cell therapy research
- T-cell and B-cell Immunology
- vaccines and immunoinformatics approaches
- Monoclonal and Polyclonal Antibodies Research
- Glycosylation and Glycoproteins Research
- Immune Cell Function and Interaction
- RNA Interference and Gene Delivery
- Immune cells in cancer
Massachusetts Institute of Technology
2019-2024
IIT@MIT
2021
Allen Institute
2021
Koch Institute for Integrative Cancer Research At MIT
2021
Molecular Sciences Institute
2015
Bioengineering (Switzerland)
2015
The clinical application of cytokine therapies for cancer treatment remains limited due to severe adverse reactions and insufficient therapeutic effects. Although localization by intratumoral administration could address both issues, the rapid escape soluble cytokines from tumor invariably subverts this effort. We find that a fused collagen-binding protein lumican prolongs local retention markedly reduces systemic exposure. Combining lumican-cytokine fusions with immunotherapies...
Abstract Direct injection of therapies into tumors has emerged as an administration route capable achieving high local drug exposure and strong anti-tumor response. A diverse array immune agonists ranging in size target are under development immunotherapies. However, due to the relatively recent adoption intratumoral administration, pharmacokinetics locally-injected biologics remains poorly defined, limiting rational design tumor-localized Here we define a pharmacokinetic framework for...
Abstract Although co-stimulation of T cells with agonist antibodies targeting 4-1BB (CD137) improves antitumor immune responses in preclinical studies, clinical success has been limited by on-target, off-tumor activity. Here, we report the development a tumor-anchored ɑ4-1BB (ɑ4-1BB-LAIR), which consists antibody fused to collagen-binding protein LAIR. While combination treatment an (TA99) shows only modest efficacy, simultaneous depletion CD4+ boosts cure rates over 90% mice....
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....
Peptide ligands are used to increase the specificity of drug carriers their target cells and facilitate intracellular delivery. One method identify such peptide ligands, phage display, enables high-throughput screening libraries for binding therapeutic targets interest. However, conventional methods identifying binders in a library by Sanger sequencing low-throughput, labor-intensive, provide limited perspective (<0.01%) complete sequence space. Moreover, small sample space can be dominated...
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...
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...
Molecular vaccines comprising antigen peptides and inflammatory cues make up a class of therapeutics that promote immunity against cancer pathogenic diseases but often exhibit limited efficacy. Here, we engineered an peptide delivery system to enhance vaccine efficacy by targeting dendritic cells mediating cytosolic delivery. The consists the nontoxic anthrax protein, protective (PA), single-chain variable fragment (scFv) recognizes XCR1 receptor on (DCs). Combining these proteins enabled...
<h3>Background</h3> CD8<sup>+</sup> T cell fate decision refers to the differentiation of a naïve into effector, memory, exhausted, or other fates. Evidence from chronic infection and cancer models suggest that signals during priming are especially important in determining thus functional quality response.<sup>1–4</sup> Priming interactions highly complex, requiring integration multiple signals, each which varies strength duration. Thus, we currently do not comprehend combinatorial...
Abstract Although co-stimulation of T cells with agonist antibodies targeting 4-1BB (CD137) improves antitumor immune responses in preclinical studies, clinical development has been hampered by on-target, off-tumor toxicity. Here, we report the a tumor-anchored α4-1BB (α4-1BB-LAIR), which consists an antibody fused to collagen binding protein LAIR. While combination treatment (TA99) displayed only modest efficacy, simultaneous depletion CD4 + boosted cure rates over 90% mice. We elucidated...
<h3>Background</h3> Conventional dendritic cells (cDC) are critical mediators of protective anti-tumor CD8<sup>+</sup> T-cell responses.<sup>1</sup> Batf3-driven DC1 the predominant cDC subset driving immunity due to their specialized ability cross-present antigens for activation.<sup>2–4</sup> However, contribution other tumor-infiltrating DC subsets such as CD11b<sup>+</sup> DC2 remains poorly characterized. Recent studies suggest that under inflammation, can exist in various functional...
<h3>Background</h3> Ovarian cancer is the fifth leading cause of cancer-related death in women United States.<sup>1</sup> To date, checkpoint blockade therapy (CBT) has failed to be effective ovarian cancer.<sup>2</sup> CBT efficacy typically requires a strong pre-existing tumor-specific T cell response.<sup>3 4</sup> However, analysis patient data indicates that tumor-infiltrating cells are often poorly activated.<sup>5</sup> Understanding mechanisms governing this poor activation could...
<h3>Background</h3> Fate decision in CD8<sup>+</sup> T cells refers to the differentiation that occurs when a naïve cell enters into effector, memory, exhausted, or other states. Multiple models of fate have been proposed, but exact determinants are unknown. Evidence from chronic infection and cancer support notion signals during priming especially important determining both functional quality response. Priming interactions highly complex, requiring integration multiple signals, each which...
<h3>Background</h3> Although co-stimulation of T cells with agonist antibodies targeting 4–1BB (CD137) improves antitumor immune responses in preclinical studies, clinical development has been hampered by on-target, off-tumor toxicity. To overcome this, there a large effort to restrict activity these the tumor microenvironment using wide range strategies. Recently, we have demonstrated that fusions cytokines collagen anchoring proteins enables retention microenvironment, simultaneously...
<h3>Background</h3> Fate decision in CD8<sup>+</sup> T cells refers to the process of differentiation that occurs when a naïve cell enters into effector, memory, exhausted, or other states. Multiple models fate have been proposed, but exact determinants are unknown. Evidence LCMV and cancer support notion signals during priming especially important deciding decisions made early process. Priming interactions highly complex, requiring integration multiple signals. Each these can vary strength...