ORCID Profile
0000-0002-6491-7278
Current Organisations
Genentech
,
UW Medicine
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Publisher: Springer Science and Business Media LLC
Date: 04-01-2021
DOI: 10.1038/S41408-020-00405-Z
Abstract: Chimeric antigen receptor T (CAR-T) cell therapy is a transformative approach to cancer eradication. CAR-T is expensive partly due to the restricted use of each CAR construct for specific tumors. Thus, a CAR construct with broad antitumor activity can be advantageous. We identified that CD126 is expressed by many hematologic and solid tumors, including multiple myeloma, lymphoma, acute myeloid leukemia, pancreatic and prostate adenocarcinoma, non-small cell lung cancer, and malignant melanoma among others. CAR-T cells targeting CD126 were generated and shown to kill many tumor cells in an antigen-specific manner and with efficiency directly proportional to CD126 expression. Soluble CD126 did not interfere with CAR-T cell killing. The CAR-T constructs bind murine CD126 but caused no weight loss or hepatotoxicity in mice. In multiple myeloma and prostate adenocarcinoma xenograft models, intravenously injected CD126 CAR-T cells infiltrated within, expanded, and killed tumor cells without toxicity. Binding of soluble interleukin-6 receptor (sIL-6R) by CAR-T cells could mitigate cytokine release syndrome. Murine SAA-3 levels were lower in mice injected with CD126 CAR-T compared to controls, suggesting that binding of sIL-6R by CAR-T cells could mitigate cytokine release syndrome. CD126 provides a novel therapeutic target for CAR-T cells for many tumors with a low risk of toxicity.
Publisher: Research Square Platform LLC
Date: 31-01-2023
DOI: 10.21203/RS.3.RS-2518935/V1
Abstract: Chimeric antigen receptor (CAR-T) cell therapy has shown rapid, frequent and deep responses in patients with relapsed, refractory multiple myeloma (RRMM). However, relapse following CAR-T is frequently observed and the cause for resistance is not well defined. Among the potential mechanism of resistance, T cell intrinsic factors may be an important source of failure. Here, we used spectral flow cytometry to identify the change in T cell phenotypes in bone marrow aspirates at different stages of multiple myeloma progression, including cases that relapsed after anti-BCMA CAR-T therapies. We identified completely different T cell phenotypes in RRMM and post CAR-T relapse cases compared to healthy donors and earlier stages of multiple myeloma, a novel double negative CD3 + T cells in RRMM and CAR-T relapsed cases, and difference in CD8 T cell phenotype at the baseline between peripheral blood and bone marrow from healthy donors. We found that the majority of T cells in RRMM, and significant subset of T cells in post CAR-T relapsed cases, expressed multiple co-inhibitory markers including PD1, TIGIT, 2B4 and KLRG1.
Publisher: Impact Journals, LLC
Date: 09-11-2016
Publisher: Springer New York
Date: 2013
Publisher: Public Library of Science (PLoS)
Date: 25-05-2017
Publisher: Springer Science and Business Media LLC
Date: 15-04-2019
DOI: 10.1038/S41375-019-0470-4
Abstract: IL-6 signaling plays a crucial role in the pathogenesis of a number of diseases, including multiple myeloma, primary amyloidosis, cytokine release syndrome and other inflammatory conditions. It is central for the growth and survival of malignant plasma cells. IL-6R and IL-6ST receptors transduce IL-6 signaling. Molecular mechanisms regulating expression of IL-6R are not well understood and current therapies are based on monoclonal antibody to target IL-6 signaling. Small molecule inhibitors targeting IL-6 signaling are highly desirable. Metformin specifically decreased IL-6R expression which is mediated via AMPK, mTOR, and miR34a. This is a novel finding and adds to existing therapies targeting IL-6 signaling.
Publisher: Springer Science and Business Media LLC
Date: 21-10-2016
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 07-12-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-03-2023
DOI: 10.34067/KID.0000000000000113
Abstract: Ixazomib treatment resulted in decreases in B-cell subsets and bone marrow lymphocytes. Ixazomib treatment resulted in modest decreases in certain anti-HLA antibody specificities. Ixazomib treatment was tolerated, with modest adverse events. Ixazomib is a second-generation oral proteasome inhibitor approved for treatment of refractory multiple myeloma. We conducted an open-label phase II trial, IXAzomib for DESensitization (IXADES), testing the safety of ixazomib treatment as an approach to decreasing the level and ersity of specificities of anti-HLA antibodies in subjects awaiting kidney transplantation. The trial (NCT03213158) enrolled highly sensitized kidney transplant candidates, defined as subjects with calculated panel reactive antibodies (cPRA) %, awaiting kidney transplantation months. The subjects were treated with 12 monthly cycles of ixazomib 3 mg+dexamethasone 20 mg. Efficacy was defined as a decrease of cPRA % or kidney transplantation. The safety end point was tolerability. In ten enrolled subjects, no grade IV, five grade III, 11 grade II, and 43 grade I adverse events were noted. The adverse events included infection, transient paresthesia, nausea, vomiting, and diarrhea. The IXADES regimen was not associated with significant change in levels or ersity of anti-HLA antibodies (cPRA). Although the IXADES regimen did not exhibit a clear impact on levels and ersity of anti-HLA antibodies in this small cohort, the prolonged half-life of IgG could necessitate a longer duration of treatment for accurate evaluation of efficacy. In conclusion, treatment with ixazomib/dexamethasone engendered mild-to-moderate toxicity. The impact on anti-HLA was modest and paradoxical in the case of anti-HLA-DR. Clinical trials combining ixazomib with other immunosuppressive agents may be more effective in addressing antibody-mediated processes in kidney transplantation.
Publisher: Impact Journals, LLC
Date: 28-07-2016
Location: United States of America
No related grants have been discovered for Ameet Mishra.