Publications by authors named "Katherine Cummins"

12 Publications

  • Page 1 of 1

Human chimeric antigen receptor macrophages for cancer immunotherapy.

Nat Biotechnol 2020 08 23;38(8):947-953. Epub 2020 Mar 23.

Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.

Chimeric antigen receptor (CAR) T cell therapy has shown promise in hematologic malignancies, but its application to solid tumors has been challenging. Given the unique effector functions of macrophages and their capacity to penetrate tumors, we genetically engineered human macrophages with CARs to direct their phagocytic activity against tumors. We found that a chimeric adenoviral vector overcame the inherent resistance of primary human macrophages to genetic manipulation and imparted a sustained pro-inflammatory (M1) phenotype. CAR macrophages (CAR-Ms) demonstrated antigen-specific phagocytosis and tumor clearance in vitro. In two solid tumor xenograft mouse models, a single infusion of human CAR-Ms decreased tumor burden and prolonged overall survival. Characterization of CAR-M activity showed that CAR-Ms expressed pro-inflammatory cytokines and chemokines, converted bystander M2 macrophages to M1, upregulated antigen presentation machinery, recruited and presented antigen to T cells and resisted the effects of immunosuppressive cytokines. In humanized mouse models, CAR-Ms were further shown to induce a pro-inflammatory tumor microenvironment and boost anti-tumor T cell activity.
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http://dx.doi.org/10.1038/s41587-020-0462-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883632PMC
August 2020

Oncogene-independent BCR-like signaling adaptation confers drug resistance in Ph-like ALL.

J Clin Invest 2020 07;130(7):3637-3653

Division of Oncology, and.

Children and adults with Philadelphia chromosome-like B cell acute lymphoblastic leukemia (Ph-like B-ALL) experience high relapse rates despite best-available conventional chemotherapy. Ph-like ALL is driven by genetic alterations that activate constitutive cytokine receptor and kinase signaling, and early-phase trials are investigating the potential of the addition of tyrosine kinase inhibitors (TKIs) to chemotherapy to improve clinical outcomes. However, preclinical studies have shown that JAK or PI3K pathway inhibition is insufficient to eradicate the most common cytokine receptor-like factor 2-rearranged (CRLF2-rearranged) Ph-like ALL subset. We thus sought to define additional essential signaling pathways required in Ph-like leukemogenesis for improved therapeutic targeting. Herein, we describe an adaptive signaling plasticity of CRLF2-rearranged Ph-like ALL following selective TKI pressure, which occurs in the absence of genetic mutations. Interestingly, we observed that Ph-like ALL cells have activated SRC, ERK, and PI3K signaling consistent with activated B cell receptor (BCR) signaling, although they do not express cell surface μ-heavy chain (μHC). Combinatorial targeting of JAK/STAT, PI3K, and "BCR-like" signaling with multiple TKIs and/or dexamethasone prevented this signaling plasticity and induced complete cell death, demonstrating a more optimal and clinically pragmatic therapeutic strategy for CRLF2-rearranged Ph-like ALL.
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http://dx.doi.org/10.1172/JCI134424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324172PMC
July 2020

Chimeric antigen receptor T-cell therapy for acute myeloid leukemia: how close to reality?

Haematologica 2019 07 20;104(7):1302-1308. Epub 2019 Jun 20.

Division of Hematology-Oncology and Center for Cellular Immunotherapies, University of Pennsylvania, PA, USA

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http://dx.doi.org/10.3324/haematol.2018.208751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601074PMC
July 2019

The natural history of vascular and other complications in patients treated with nilotinib for chronic myeloid leukemia.

Blood Adv 2019 04;3(7):1084-1091

Department of Clinical Haematology, Austin Hospital, Melbourne, Australia.

Although second-generation tyrosine kinase inhibitors (TKIs) show superiority in achieving deep molecular responses in chronic myeloid leukemia in chronic phase (CML-CP) compared with imatinib, the differing adverse effect (AE) profiles need consideration when deciding the best drug for individual patients. Long-term data from randomized trials of nilotinib demonstrate an increased risk of vascular AEs (VAEs) compared with other TKIs, although the natural history of these events in response to dose modifications or cessation has not been fully characterized. We retrospectively reviewed the incidence of nilotinib-associated AEs in 220 patients with CML-CP at 17 Australian institutions. Overall, AEs of any grade were reported in 95 patients (43%) and prompted nilotinib cessation in 46 (21%). VAEs occurred in 26 patients (12%), with an incidence of 4.1 events per 100 patient-years. Multivariate analysis identified age ( = .022) and dyslipidemia ( = .007) as independent variables for their development. There was 1 fatal first VAE, whereas the remaining patients either continued nilotinib (14 patients) or stopped it immediately (11 patients). Recurrent VAEs were associated with ongoing therapy in 7 of 14 who continued (with 2 fatal VAEs) vs 1 of 11 who discontinued ( = .04). Nineteen of the 23 evaluable patients surviving a VAE ultimately stopped nilotinib, of whom 14 received an alternative TKI. Dose reduction or cessation because of VAEs did not adversely affect maintenance of major molecular response. These findings demonstrate that in contrast to other AEs, VAEs are ideally managed with nilotinib cessation because of the increased risk of additional events with its ongoing use.
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http://dx.doi.org/10.1182/bloodadvances.2018028035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457217PMC
April 2019

Will CAR T cell therapy have a role in AML? Promises and pitfalls.

Semin Hematol 2019 04 29;56(2):155-163. Epub 2018 Aug 29.

Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA; Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Center for Cellular Immunotherapies, The University of Pennsylvania, Philadelphia, PA. Electronic address:

Relapsed and/or refractory acute myeloid leukemia (RR AML) has a dismal prognosis. While chimeric antigen receptor T cells (CART) have been successful in improving treatment outcomes for B-lineage acute lymphoblastic leukemia by targeting CD19, the success of this strategy necessitates a cell surface antigen whose depletion can be clinically tolerated. The primary barrier currently preventing the use of CART therapy for AML is the lack of a myeloid equivalent to CD19-that is, an "expendable" antigen. All currently known cell surface targets on leukemic blasts are shared with healthy hematopoietic stem and progenitor cells or their progeny. Hence, while targeting CD19-expressing cells leads to prolonged B-cell aplasia which is clinically benign, targeting myeloid antigens would lead to prolonged myeloablation which is not clinically tolerable. Creative solutions are being developed to try to circumvent these challenges, using not only CART but a range of adoptive cellular immunotherapy modalities and novel transplant-related approaches to try to extend the successes of CART therapy to patients with AML.
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http://dx.doi.org/10.1053/j.seminhematol.2018.08.008DOI Listing
April 2019

A High-Throughput Workflow to Study Remodeling of Extracellular Matrix-Based Microtissues.

Tissue Eng Part C Methods 2019 01 28;25(1):25-36. Epub 2018 Dec 28.

Department of Biomedical Engineering, University of Minnesota-Twin Cities, Minneapolis, Minnesota.

Impact Statement: The described microtissue-microwell workflow is uniquely suited for high-throughput study of extracellular matrix (ECM) remodeling at the molecular, cellular, and tissue levels and demonstrates possibilities of studying progressive, heterogeneous diseases in a way that is meaningful for drug discovery and development. We outline several assays that can be utilized in studying tissue-level diseases and functions that involve cell-ECM interactions and ECM remodeling (e.g., cancer, fibrosis, wound healing) in pursuit of an improved three-dimensional cell culturing system. Finally, we demonstrate the ability to cryopreserve cells encapsulated in microtissue constructs while remaining highly viable, proliferative, and retaining cell functions that are involved in ECM remodeling.
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http://dx.doi.org/10.1089/ten.TEC.2018.0290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352510PMC
January 2019

A high-throughput microtissue platform to probe endothelial function in vitro.

Integr Biol (Camb) 2018 09;10(9):555-565

Department of Biomedical Engineering, University of Minnesota, Twin Cities, USA.

A critical role of vascular endothelium is as a semi-permeable barrier, dynamically regulating the flux of solutes between blood and the surrounding tissue. Existing platforms that quantify endothelial function in vitro are either significantly throughput limited or overlook physiologically relevant extracellular matrix (ECM) interactions and thus do not recapitulate in vivo function. Leveraging droplet microfluidics, we developed a scalable platform to measure endothelial function in nanoliter-volume, ECM-based microtissues. In this study, we describe our high-throughput method for fabricating endothelial-coated collagen microtissues that incorporate physiologically relevant cell-ECM interactions. We showed that the endothelial cells had characteristic morphology, expressed tight junction proteins, and remodeled the ECM via compaction and deposition of basement membrane. We also measured macromolecular permeability using two optical modalities, and found the cell layers: (1) had permeability values comparable to in vivo measurements and (2) were responsive to physiologically-relevant modulators of endothelial permeability (TNF-α and TGF-β). This is the first demonstration, to the authors' knowledge, of high-throughput assessment (n > 150) of endothelial permeability on natural ECM. Additionally, this technology is compatible with standard cell culture equipment (e.g. multi-well plates) and could be scaled up further to be integrated with automated liquid handling systems and automated imaging platforms. Overall, this platform recapitulates the functions of traditional transwell inserts, but extends application to high-throughput studies and introduces new possibilities for interrogating cell-cell and cell-matrix interactions.
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http://dx.doi.org/10.1039/c8ib00111aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558661PMC
September 2018

Genetic Inactivation of CD33 in Hematopoietic Stem Cells to Enable CAR T Cell Immunotherapy for Acute Myeloid Leukemia.

Cell 2018 05 31;173(6):1439-1453.e19. Epub 2018 May 31.

Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. Electronic address:

The absence of cancer-restricted surface markers is a major impediment to antigen-specific immunotherapy using chimeric antigen receptor (CAR) T cells. For example, targeting the canonical myeloid marker CD33 in acute myeloid leukemia (AML) results in toxicity from destruction of normal myeloid cells. We hypothesized that a leukemia-specific antigen could be created by deleting CD33 from normal hematopoietic stem and progenitor cells (HSPCs), thereby generating a hematopoietic system resistant to CD33-targeted therapy and enabling specific targeting of AML with CAR T cells. We generated CD33-deficient human HSPCs and demonstrated normal engraftment and differentiation in immunodeficient mice. Autologous CD33 KO HSPC transplantation in rhesus macaques demonstrated long-term multilineage engraftment of gene-edited cells with normal myeloid function. CD33-deficient cells were impervious to CD33-targeting CAR T cells, allowing for efficient elimination of leukemia without myelotoxicity. These studies illuminate a novel approach to antigen-specific immunotherapy by genetically engineering the host to avoid on-target, off-tumor toxicity.
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http://dx.doi.org/10.1016/j.cell.2018.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003425PMC
May 2018

The incidence and natural history of dasatinib complications in the treatment of chronic myeloid leukemia.

Blood Adv 2017 May 15;1(13):802-811. Epub 2017 May 15.

Austin Hospital, Melbourne, Australia.

Dasatinib has shown superiority over imatinib in achieving molecular responses (MRs) in chronic phase chronic myeloid leukemia but with a different toxicity profile, which may impact its overall benefit. Reported toxicities include pleural effusions and pulmonary hypertension, and although the incidence of these events is well described, response to therapy and impact of dose modifications on toxicity has not been comprehensively characterized in a real-world setting. We retrospectively reviewed the incidence of dasatinib adverse events in 212 chronic phase chronic myeloid leukemia patients at 17 Australian institutions. Adverse events were reported in 116 patients (55%), most commonly pleural effusions (53 patients, 25%), which was the predominant cause of permanent drug cessation. Age and dose were risk factors for pleural effusion ( < .01 and .047, respectively). Recurrence rates were higher in those who remained on 100 mg compared with those who dose reduced ( = .041); however, recurrence still occurred at 50 mg. Patients who developed pleural effusions were more likely to have achieved MR4.5 after 6 months of dasatinib than those without effusions ( = .008). Pulmonary hypertension occurred in 5% of patients, frequently in association with pleural effusion, and was reversible upon dasatinib cessation in 6 of 7 patients. Dose reductions and temporary cessations had minimal impact on MR rates. Our observations suggest that by using the lowest effective dose in older patients to minimize the effusion risk, dose modification for cytopenias, and care with concomitant antiplatelet therapy, the necessity for permanent dasatinib cessation due to toxicity is likely to be minimal in immunologically competent patients.
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http://dx.doi.org/10.1182/bloodadvances.2016003889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727806PMC
May 2017

Anti-CD123 chimeric antigen receptor T-cells (CART): an evolving treatment strategy for hematological malignancies, and a potential ace-in-the-hole against antigen-negative relapse.

Leuk Lymphoma 2018 07 13;59(7):1539-1553. Epub 2017 Sep 13.

a Center for Cellular Immunotherapies, Perelman School of Medicine , University of Pennsylvania , Philadelphia , PA , USA.

Chimeric antigen receptor-modified T-cells (CART) are a potent and targeted immunotherapy which have induced remissions in some patients with chemotherapy refractory or relapsed (RR) hematologic malignancies. Hundreds of patients have now been treated worldwide with anti-CD19 CART cells, with complete response rates of up to 90%. CART therapy has a unique toxicity profile, and unfortunately not all responses are durable. Treatment failure occurs via two main routes - by loss of the CART cell population, or relapse with antigen loss. Emerging data indicate that targeting an alternative antigen instead of, or as well as CD19, could improve CART cell efficacy and reduce antigen-negative relapse. Other strategies include the addition of other immune-based therapies. This review explores the rationale, pre-clinical data and currently investigative strategies underway for CART therapy targeting the myeloid and lymphoid stem/progenitor antigen CD123.
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http://dx.doi.org/10.1080/10428194.2017.1375107DOI Listing
July 2018

PAX5-expressing ALK-negative anaplastic large cell lymphoma with extensive extranodal and nodal involvement.

BMJ Case Rep 2015 Jul 17;2015. Epub 2015 Jul 17.

Alfred Pathology Service, Alfred Health, Melbourne, Victoria, Australia Department of Haematology, Monash Health, Clayton, Victoria, Australia.

A 55-year-old man with a history of well controlled HIV infection was admitted with acute renal impairment, peripheral oedema, constitutional symptoms, deranged liver function and hypercalcaemia. Core biopsies of a retroperitoneal mass demonstrated anaplastic lymphoma kinase (ALK) negative anaplastic large cell lymphoma (ALCL) with unusual Paired box 5 (PAX5) positivity. The same malignant cells were identifiable on urine cytology. Staging investigations revealed extensive nodal and extranodal disease including ALK negative ALCL involving the kidney and prostate, which has not previously been reported in the published literature.
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http://dx.doi.org/10.1136/bcr-2015-211159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513530PMC
July 2015

Numerous Howell-Jolly bodies in a patient with idiopathic splenic calcification.

Br J Haematol 2015 Jun 28;169(6):767. Epub 2015 Apr 28.

Department of Pathology (Haematology) and Clinical Haematology, Alfred Health, Melbourne, Vic., Australia.

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http://dx.doi.org/10.1111/bjh.13454DOI Listing
June 2015