A5066354365- CAR-T cell therapy research
- Cancer Immunotherapy and Biomarkers
- Immunotherapy and Immune Responses
- PI3K/AKT/mTOR signaling in cancer
- Cancer Research and Treatments
- Melanoma and MAPK Pathways
- Cancer Mechanisms and Therapy
- Immune Cell Function and Interaction
- interferon and immune responses
- RNA regulation and disease
- Protein Degradation and Inhibitors
- Nanoplatforms for cancer theranostics
- Extracellular vesicles in disease
- Phagocytosis and Immune Regulation
- Cancer therapeutics and mechanisms
- Monoclonal and Polyclonal Antibodies Research
- T-cell and B-cell Immunology
- Cell Adhesion Molecules Research
- Microtubule and mitosis dynamics
- Cancer-related gene regulation
- CRISPR and Genetic Engineering
- Click Chemistry and Applications
- Viral-associated cancers and disorders
- Mast cells and histamine
- Vascular Tumors and Angiosarcomas
Fate Therapeutics (United States)
2021-2024
The University of Texas MD Anderson Cancer Center
2012-2021
Scripps MD Anderson Cancer Center
2018
The University of Texas Health Science Center at Houston
2013
Massachusetts General Hospital
2012
T cell-mediated immunotherapies are promising cancer treatments. However, most patients still fail to respond these therapies. The molecular determinants of immune resistance poorly understood. We show that loss PTEN in tumor cells preclinical models melanoma inhibits killing and decreases T-cell trafficking into tumors. In patients, correlates with decreased infiltration at sites, reduced likelihood successful expansion from resected tumors, inferior outcomes PD-1 inhibitor therapy....
Abstract Purpose: Treatment of melanoma patients with selective BRAF inhibitors results in objective clinical responses the majority BRAF-mutant tumors. However, resistance to these develops within a few months. In this study, we test hypothesis that inhibition combination adoptive T-cell transfer (ACT) will be more effective at inducing long-term regressions Experimental Design: BRAF-mutated human tumor cell lines transduced express gp100 and H-2Db allow recognition by gp100-specific pmel-1...
T-cell-based immunotherapies are promising treatments for cancer patients. Although durable responses can be achieved in some patients, many patients fail to respond these therapies, underscoring the need improvement with combination therapies. From a screen of 850 bioactive compounds, we identify HSP90 inhibitors as candidates immunotherapy. We show that inhibition ganetespib enhances T-cell-mediated killing patient-derived human melanoma cells by their autologous T vitro and potentiates...
Purpose: Cancer immunotherapy has shown promising clinical outcomes in many patients. However, some patients still fail to respond, and new strategies are needed overcome resistance. The purpose of this study was identify novel genes understand the mechanisms that confer resistance cancer immunotherapy.Experimental Design: To mediating T-cell killing, we performed an open reading frame (ORF) screen a kinome library whether overexpression gene patient-derived melanoma cells could inhibit...
Allogeneic cellular immunotherapies hold promise for broad clinical implementation but face limitations due to potential rejection of donor cells by the host immune system. Silencing beta-2 microglobulin (B2M) expression is commonly employed evade T cell-mediated host, although absence B2M expected trigger missing-self responses natural killer (NK) cells. Here, we demonstrate that genetic deletion adhesion ligands CD54 and CD58 in B2M-deficient chimeric antigen receptor (CAR) multi-edited...
Immunotherapy has increasingly become a staple in cancer treatment. However, substantial limitations the durability of response highlight need for more rational therapeutic combinations. The aim this study is to investigate how make tumor cells sensitive T-cell-based immunotherapy.Two pairs melanoma patient-derived cell lines and their autologous tumor-infiltrating lymphocytes were utilized high-throughput screen 850 compounds identify bioactive agents that could be used combinatorial...
Background Despite approval of immunotherapy for a wide range cancers, the majority patients fail to respond or relapse following initial response. These failures may be attributed immunosuppressive mechanisms co-opted by tumor cells. However, it is challenging use conventional methods systematically evaluate potential intrinsic factors act as immune regulators in with cancer. Methods To identify non-responders cancer an unbiased manner, we performed genome-wide CRISPR screens and integrated...
OX40 agonist-based combinations are emerging as a novel avenue to improve the effectiveness of cancer immunotherapy. To better guide its clinical development, we characterized role pathway in tumor-reactive immune cells. We also evaluated combining agonists with targeted therapy combat resistance immunotherapy.Experimental Design: utilized patient-derived tumor-infiltrating lymphocytes (TILs) and multiple preclinical models determine direct effect anti-OX40 agonistic antibodies on CD8+ T...
Abstract Although immunotherapy has achieved impressive durable clinical responses, many cancers respond only temporarily or not at all to immunotherapy. To find novel, targetable mechanisms of resistance immunotherapy, patient-derived melanoma cell lines were transduced with 576 open reading frames, exposed arrayed libraries 850 bioactive compounds, prior co-culture autologous tumor-infiltrating lymphocytes (TILs). The synergy between the targets and TILs induce apoptosis, inhibiting...
SUMMARY Allogeneic cell therapies hold promise for broad clinical implementation, but face limitations due to potential rejection by the recipient immune system. Silencing of beta-2-microglobulin ( B2M ) expression is commonly employed evade T cell-mediated rejection, although absence triggers missing-self responses natural killer (NK) cells. Here, we demonstrate that deletion adhesion ligands CD54 and CD58 on targets cells robustly dampens NK reactivity across all sub-populations. Genetic...
Abstract T cell-mediated immunotherapies are promising cancer treatments. However, most patients still fail to respond these therapies. The molecular determinants of immune resistance poorly understood. Here, we interrogated the role loss expression tumor suppressor, PTEN, in resistance. In preclinical studies, found that silencing PTEN cells inhibited killing and decreased cell trafficking into tumors. clinical observed tumors with had significantly less CD8+ infiltration than PTEN-present...
Combining immunotherapy with targeted therapy has increasingly become an appealing therapeutic paradigm for cancer treatment due to its great potential generating durable and synergistic antitumor response. In this study, however, we unexpectedly found that two types of CpG-based tumor peptide vaccine treatments consistently negated the activity a selective BRAF inhibitor in tumors mutation rather than showing effect. Our further studies demonstrated CpG alone was sufficient dampen...
<h3>Background</h3> Clinical administration of chimeric antigen receptor (CAR) NK cell and CAR T-cell therapies require conditioning chemotherapy (CCT) to deplete the host immune system, maximize access homeostatic cytokines, promote expansion functional persistence. However, CCT also elicits pan-immune cytopenia, increases susceptibility infection malignancy, requires patient hospitalization therapy in costly tertiary healthcare settings. The off-the-shelf patients without requiring has...
<h3>Background</h3> Chimeric antigen receptor (CAR)-T cell therapy has revolutionized cancer treatment, but it is associated with significant dose-limiting toxicities, restricted tumor targeting (limited by specific expression), and, notably, a lack of multi-antigen capability to mitigate immune evasion and heterogeneity. Furthermore, dysfunctional starting material, product inconsistency, small manufacturing lot size limits the application on-demand availability CAR-T therapy....
Abstract OX40 (CD134), a tumor necrosis factor (TNF) receptor family member, plays critical role in initiating signaling cascades required for full activation of tumor-reactive T cells. Due to its distinct mechanism action, the use agonist-based combinations is emerging as novel avenue improve effectiveness cancer treatments. Our recently published studies demonstrate that oncogenic PI3K pathway by loss expression suppressor PTEN, imposes an immunosuppressive microenvironment favor immune...
Abstract Recently, T cell based immunotherapies have moved to the forefront of cancer immunotherapy with success Adoptive therapy (ACT) and Immune checkpoint blockade. ACT, where patients are treated tumor infiltrating cells (TILs), conferred a clinical response rate ∼50%. Treatment anti-CTLA4 therapy, Ipilimumab, rates 10-20%, greatly improving overall survival advanced melanoma. Despite encouraging outcomes, there relatively low coupled delay weeks months before shrinkage can be...
Abstract Melanoma is a highly aggressive form of skin cancer, whose rates morbidity and mortality are continuously increasing. The development immunotherapeutic agents like anti-PDL1 anti-CTLA4 antibodies has resulted in fundamental advances the treatment melanoma. However, long lasting responses only observed small subset immunotherapy-treated melanoma patients. This shortfall highlights need for better understanding molecular mechanisms that govern tumor sensitivity or resistance to...