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Article ; Online: Engineering strategies to optimise adoptive cell therapy in ovarian cancer.

Guerra, Catarina / Kalaitsidou, Milena / Kueberuwa, Gray / Hawkins, Robert / Edmondson, Richard

2023 Volume 121, Page(s) 102632

Abstract: Ovarian cancer is amongst the ten most common cancer types in women, and it is one of the leading causes of death. Despite the promising results of targeted therapies, including anti-angiogenic agents and poly (ADP-ribose) polymerase inhibitors (PARPi), ... ...

Abstract	Ovarian cancer is amongst the ten most common cancer types in women, and it is one of the leading causes of death. Despite the promising results of targeted therapies, including anti-angiogenic agents and poly (ADP-ribose) polymerase inhibitors (PARPi), the majority of patients will relapse and develop treatment resistance, implying that novel therapeutic strategies are required. Adoptive cell therapy (ACT) refers to the process by which autologous immune cells are used to eliminate cancer. Examples include tumour infiltrating lymphocytes (TILs), T cells genetically engineered with T cell receptors (TCR), or chimeric antigen receptor (CAR)-T cells. Recently, ACT has revealed promising results in the treatment of haematological malignancies, however, its application to solid tumours is still limited due to lack of functionality and persistence of T cells, prevalence of an exhausted phenotype and impaired trafficking towards the tumour microenvironment (TME). In this review we explore the potential of ACT for the treatment of ovarian cancer and strategies to overcome its principal limitations.
MeSH term(s)	Humans ; Female ; Immunotherapy, Adoptive/methods ; Neoplasm Recurrence, Local ; Ovarian Neoplasms/therapy ; Neoplasms/therapy ; T-Lymphocytes ; Receptors, Antigen, T-Cell ; Tumor Microenvironment
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2023-10-05
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	125102-8
ISSN	1532-1967 ; 0305-7372
ISSN (online)	1532-1967
ISSN	0305-7372
DOI	10.1016/j.ctrv.2023.102632
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Article: Transgenic T-cell receptor immunotherapy for cancer: building on clinical success.

Oppermans, Natasha / Kueberuwa, Gray / Hawkins, Robert E / Bridgeman, John S

Therapeutic advances in vaccines and immunotherapy

2020 Volume 8, Page(s) 2515135520933509

Abstract: With the advent of immunotherapy as a realistic and promising option for cancer treatment, adoptive cellular therapies are gaining significant interest in the clinic. Whilst the recent successes of chimeric antigen receptor T-cell therapies for ... ...

Abstract	With the advent of immunotherapy as a realistic and promising option for cancer treatment, adoptive cellular therapies are gaining significant interest in the clinic. Whilst the recent successes of chimeric antigen receptor T-cell therapies for haematological malignancies are widely known, they have yet to show great success in solid cancers. However, immune cells transduced with T-cell receptors have been shown to traffic to and exert anti-cancer effects on solid tumour cells with some great successes. In this review, we explore the field of transgenic T-cell receptor immunotherapy, highlighting some of the key clinical trials which have paved the way for this type of cellular immunotherapy. Some trials have shown amazing clinical results, including long-term remissions and minimal toxicity, and can be looked at as an exemplar for this adoptive cell therapy. There have also been key trials where unexpected, fatal, off-tumour toxicity has occurred, and these trials have also been instrumental in shaping safer clinical trials, particularly regarding preclinical testing. In addition to previous trials, we analysed the current clinical trial space for T-cell receptor T-cell therapy, showing which trials are dominating in the clinic and which targets are being prioritised by researchers around the world. By looking at both past and current trials, we have been able to identify key drivers in developing transgenic T-cell receptor immunotherapy for the future.
Keywords	covid19
Language	English
Publishing date	2020-06-22
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2970613-0
ISSN	2515-1363 ; 2515-1355
ISSN (online)	2515-1363
ISSN	2515-1355
DOI	10.1177/2515135520933509
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Article ; Online: Optogenetic control of iPS cell-derived neurons in 2D and 3D culture systems using channelrhodopsin-2 expression driven by the synapsin-1 and calcium-calmodulin kinase II promoters.

Lee, Si-Yuen / George, Julian H / Nagel, David A / Ye, Hua / Kueberuwa, Gray / Seymour, Leonard W

Journal of tissue engineering and regenerative medicine

2019 Volume 13, Issue 3, Page(s) 369–384

Abstract: Development of an optogenetically controllable human neural network model in three-dimensional (3D) cultures can provide an investigative system that is more physiologically relevant and better able to mimic aspects of human brain function. Light- ... ...

Abstract	Development of an optogenetically controllable human neural network model in three-dimensional (3D) cultures can provide an investigative system that is more physiologically relevant and better able to mimic aspects of human brain function. Light-sensitive neurons were generated by transducing channelrhodopsin-2 (ChR2) into human induced pluripotent stem cell (hiPSC) derived neural progenitor cells (Axol) using lentiviruses and cell-type specific promoters. A mixed population of human iPSC-derived cortical neurons, astrocytes and progenitor cells were obtained (Axol-ChR2) upon neural differentiation. Pan-neuronal promoter synapsin-1 (SYN1) and excitatory neuron-specific promoter calcium-calmodulin kinase II (CaMKII) were used to drive reporter gene expression in order to assess the differentiation status of the targeted cells. Expression of ChR2 and characterisation of subpopulations in differentiated Axol-ChR2 cells were evaluated using flow cytometry and immunofluorescent staining. These cells were transferred from 2D culture to 3D alginate hydrogel functionalised with arginine-glycine-aspartate (RGD) and small molecules (Y-27632). Improved RGD-alginate hydrogel was physically characterised and assessed for cell viability to serve as a generic 3D culture system for human pluripotent stem cells (hPSCs) and neuronal cells. Prior to cell encapsulation, neural network activities of Axol-ChR2 cells and primary neurons were investigated using calcium imaging. Results demonstrate that functional activities were successfully achieved through expression of ChR2- by both the CaMKII and SYN1 promoters. The RGD-alginate hydrogel system supports the growth of differentiated Axol-ChR2 cells whilst allowing detection of ChR2 expression upon light stimulation. This allows precise and non-invasive control of human neural networks in 3D.
MeSH term(s)	Alginates/pharmacology ; Animals ; Calcium/metabolism ; Calcium-Calmodulin-Dependent Protein Kinases/genetics ; Calcium-Calmodulin-Dependent Protein Kinases/metabolism ; Cell Culture Techniques/methods ; Cell Differentiation/drug effects ; Cell Line ; Cell Survival/drug effects ; Channelrhodopsins/metabolism ; Human Embryonic Stem Cells/cytology ; Human Embryonic Stem Cells/drug effects ; Humans ; Induced Pluripotent Stem Cells/cytology ; Induced Pluripotent Stem Cells/drug effects ; Induced Pluripotent Stem Cells/metabolism ; Lentivirus/metabolism ; Mice ; Neural Stem Cells/cytology ; Neural Stem Cells/metabolism ; Neurons/cytology ; Neurons/drug effects ; Neurons/metabolism ; Optogenetics ; Promoter Regions, Genetic/genetics ; Rheology ; Synapsins/genetics ; Synapsins/metabolism
Chemical Substances	Alginates ; Channelrhodopsins ; Synapsins ; Calcium-Calmodulin-Dependent Protein Kinases (EC 2.7.11.17) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2019-01-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2316155-3
ISSN	1932-7005 ; 1932-6254
ISSN (online)	1932-7005
ISSN	1932-6254
DOI	10.1002/term.2786
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Article: A syngeneic mouse b-cell lymphoma model for pre-clinical evaluation of cd19 car t cells

Kueberuwa, Gray / Zheng, Weiming / Kalaitsidou, Milena / Gilham, David E / Hawkins, Robert E

Journal of visualized experiments. 2018 Oct. 16, , no. 140

2018

Abstract: The astonishing clinical success of CD19 chimeric antigen receptor (CAR) T-cell therapy has led to the approval of two second generation chimeric antigen receptors (CARs) for acute lymphoblastic leukemia (ALL) andnon-Hodgkin lymphoma (NHL). The focus of ... ...

Abstract	The astonishing clinical success of CD19 chimeric antigen receptor (CAR) T-cell therapy has led to the approval of two second generation chimeric antigen receptors (CARs) for acute lymphoblastic leukemia (ALL) andnon-Hodgkin lymphoma (NHL). The focus of the field is now on emulating these successes in other hematological malignancies where less impressive complete response rates are observed. Further engineering of CAR T cells or co-administration of other treatment modalities may successfully overcome obstacles to successful therapy in other cancer settings. We therefore present a model in which others can conduct pre-clinical testing of CD19 CAR T cells. Results in this well tested B-cell lymphoma model are likely to be informative CAR T-cell therapy in general. This protocol allows the reproducible production of mouse CAR T cells through calcium phosphate transfection of Plat-E producer cells with MP71 retroviral constructs and pCL-Eco packaging plasmid followed by collection of secreted retroviral particles and transduction using recombinant human fibronectin fragment and centrifugation. Validation of retroviral transduction, and confirmation of the ability of CAR T cells to kill target lymphoma cells ex vivo, through the use of flow cytometry, luminometry and enzyme-linked immunosorbent assay (ELISA), is also described. Protocols for testing CAR T cells in vivo in lymphoreplete and lymphodepleted syngeneic mice, bearing established, systemic lymphoma are described. Anti-cancer activity is monitored by in vivo bioluminescence and disease progression. We show typical results of eradication of established B-cell lymphoma when utilizing 1st or 2nd generation CARs in combination with lymphodepleting pre-conditioning and a minority of mice achieving long term remissions when utilizing CAR T cells expressing IL-12 in lymphoreplete mice. These protocols can be used to evaluate CD19 CAR T cells with different additional modification, combinations of CAR T cells and other therapeutic agents or adapted for the use of CAR T cells against different target antigens.
Keywords	B-cell lymphoma ; T-lymphocytes ; antigens ; antineoplastic activity ; bioluminescence ; calcium phosphates ; centrifugation ; disease course ; engineering ; enzyme-linked immunosorbent assay ; fibronectins ; flow cytometry ; humans ; interleukin-12 ; lymphocytic leukemia ; mice ; models ; neoplasm cells ; packaging ; plasmids ; receptors ; therapeutics ; transfection
Language	English
Dates of publication	2018-1016
Size	p. e58492.
Publishing place	Journal of Visualized Experiments
Document type	Article
ZDB-ID	2259946-0
ISSN	1940-087X
ISSN	1940-087X
DOI	10.3791/58492
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Signaling via a CD28/CD40 chimeric costimulatory antigen receptor (CoStAR™), targeting folate receptor alpha, enhances T cell activity and augments tumor reactivity of tumor infiltrating lymphocytes.

Kalaitsidou, Milena / Moon, Owen R / Sykorova, Martina / Bao, Leyuan / Qu, Yun / Sukumaran, Sujita / Valentine, Michael / Zhou, Xingliang / Pandey, Veethika / Foos, Kay / Medvedev, Sergey / Powell, Daniel J / Udyavar, Akshata / Gschweng, Eric / Rodriguez, Ruben / Dudley, Mark E / Hawkins, Robert E / Kueberuwa, Gray / Bridgeman, John S

Frontiers in immunology

2023 Volume 14, Page(s) 1256491

Abstract: Transfer of autologous tumor infiltrating lymphocytes (TIL) to patients with refractory melanoma has shown clinical efficacy in a number of trials. However, extending the clinical benefit to patients with other cancers poses a challenge. Inefficient ... ...

Abstract	Transfer of autologous tumor infiltrating lymphocytes (TIL) to patients with refractory melanoma has shown clinical efficacy in a number of trials. However, extending the clinical benefit to patients with other cancers poses a challenge. Inefficient costimulation in the tumor microenvironment can lead to T cell anergy and exhaustion resulting in poor anti-tumor activity. Here, we describe a chimeric costimulatory antigen receptor (CoStAR) comprised of FRα-specific scFv linked to CD28 and CD40 intracellular signaling domains. CoStAR signaling alone does not activate T cells, while the combination of TCR and CoStAR signaling enhances T cell activity resulting in less differentiated T cells, and augmentation of T cell effector functions, including cytokine secretion and cytotoxicity. CoStAR activity resulted in superior T cell proliferation, even in the absence of exogenous IL-2. Using an
MeSH term(s)	Humans ; T-Lymphocytes ; CD28 Antigens ; Lymphocytes, Tumor-Infiltrating ; Folate Receptor 1 ; Receptors, Chimeric Antigen/genetics ; Melanoma ; CD40 Antigens ; Tumor Microenvironment
Chemical Substances	CD28 Antigens ; Folate Receptor 1 ; Receptors, Chimeric Antigen ; CD40 Antigens
Language	English
Publishing date	2023-11-07
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1256491
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Article: Clinical feasibility and treatment outcomes with nonselected autologous tumor-infiltrating lymphocyte therapy in patients with advanced cutaneous melanoma.

Pillai, Manon / Jiang, Yizhou / Lorigan, Paul C / Thistlethwaite, Fiona C / Thomas, Martine / Kirillova, Natalia / Bridgeman, John S / Kueberuwa, Gray / Biswas, Sunetra / Velazquez, Peter / Chonzi, David / Guest, Ryan D / Roberts, Zachary J / Hawkins, Robert E

American journal of cancer research

2022 Volume 12, Issue 8, Page(s) 3967–3984

Abstract: Nonselected autologous tumor-infiltrating lymphocytes (TILs) may provide advantages over other treatments for solid tumors, including checkpoint inhibitor-refractory melanoma. This retrospective analysis reports a single-center experience of nonselected ... ...

Abstract	Nonselected autologous tumor-infiltrating lymphocytes (TILs) may provide advantages over other treatments for solid tumors, including checkpoint inhibitor-refractory melanoma. This retrospective analysis reports a single-center experience of nonselected autologous TILs derived from digested tumors for compassionate use treatment of advanced cutaneous melanoma, including after programmed cell death protein 1 (PD-1) inhibition. Patients with histologically confirmed metastatic cutaneous melanoma and no standard-of-care treatment options underwent tumor resection for TIL product manufacturing. Patients received lymphodepleting chemotherapy with cyclophosphamide for 2 days and fludarabine for 5 days, followed by a single TIL infusion and post-TIL high-dose interleukin (IL)-2. Safety assessments included clinically significant adverse events (AEs). Efficacy assessments included overall response rate (ORR), complete response (CR) rate, disease control rate (DCR), and overall survival. Between October 2011 and August 2019, 21 patients underwent treatment (median follow-up time, 52.2 months from TIL infusion). Among all treated patients, median age was 45 years, median number of disease sites was 4, 100% had M1c or M1d disease, and 90% received prior checkpoint inhibitor. Twelve patients received TILs after prior PD-1 inhibition. The safety profile among all treated patients and the prior PD-1 inhibitor subgroup was generally consistent with lymphodepletion and high-dose IL-2. No treatment-related deaths occurred. Among all patients, the ORR was 67%, CR rate was 19%, and the DCR was 86%, which was consistent with that observed in the prior PD-1 inhibitor subgroup (58%, 8%, and 75%, respectively). Median overall survival in all treated patients and the prior PD-1 inhibitor subgroup was 21.3 months. In total, 5 patients (24%) had durable ongoing responses (>30 months post-TIL infusion) at data cutoff, and all patients who achieved CR remained alive and disease free. To further illustrate how TIL therapy may integrate into established treatment paradigms, several case studies of patients treated in this series were included. Overall, these data demonstrate that manufacturing of nonselected autologous TILs from tumor digests is feasible and resulted in high rates of durable response in poor-risk patient populations, which may address significant unmet medical need.
Language	English
Publishing date	2022-08-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2589522-9
ISSN	2156-6976
ISSN	2156-6976
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Article ; Online: A Syngeneic Mouse B-Cell Lymphoma Model for Pre-Clinical Evaluation of CD19 CAR T Cells.

Kueberuwa, Gray / Zheng, Weiming / Kalaitsidou, Milena / Gilham, David E / Hawkins, Robert E

Journal of visualized experiments : JoVE

2018 , Issue 140

Abstract	The astonishing clinical success of CD19 chimeric antigen receptor (CAR) T-cell therapy has led to the approval of two second generation chimeric antigen receptors (CARs) for acute lymphoblastic leukemia (ALL) andnon-Hodgkin lymphoma (NHL). The focus of the field is now on emulating these successes in other hematological malignancies where less impressive complete response rates are observed. Further engineering of CAR T cells or co-administration of other treatment modalities may successfully overcome obstacles to successful therapy in other cancer settings. We therefore present a model in which others can conduct pre-clinical testing of CD19 CAR T cells. Results in this well tested B-cell lymphoma model are likely to be informative CAR T-cell therapy in general. This protocol allows the reproducible production of mouse CAR T cells through calcium phosphate transfection of Plat-E producer cells with MP71 retroviral constructs and pCL-Eco packaging plasmid followed by collection of secreted retroviral particles and transduction using recombinant human fibronectin fragment and centrifugation. Validation of retroviral transduction, and confirmation of the ability of CAR T cells to kill target lymphoma cells ex vivo, through the use of flow cytometry, luminometry and enzyme-linked immunosorbent assay (ELISA), is also described. Protocols for testing CAR T cells in vivo in lymphoreplete and lymphodepleted syngeneic mice, bearing established, systemic lymphoma are described. Anti-cancer activity is monitored by in vivo bioluminescence and disease progression. We show typical results of eradication of established B-cell lymphoma when utilizing 1
MeSH term(s)	Animals ; Antigens, CD19/immunology ; Disease Models, Animal ; Immunotherapy, Adoptive/methods ; Lymphoma, B-Cell/immunology ; Lymphoma, B-Cell/therapy ; Mice ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/immunology ; Receptors, Chimeric Antigen/immunology ; T-Lymphocytes/immunology ; T-Lymphocytes/transplantation ; Treatment Outcome
Chemical Substances	Antigens, CD19 ; Receptors, Antigen, T-Cell ; Receptors, Chimeric Antigen
Language	English
Publishing date	2018-10-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Video-Audio Media
ISSN	1940-087X
ISSN (online)	1940-087X
DOI	10.3791/58492
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Article: CD19 CAR T Cells Expressing IL-12 Eradicate Lymphoma in Fully Lymphoreplete Mice through Induction of Host Immunity.

Kueberuwa, Gray / Kalaitsidou, Milena / Cheadle, Eleanor / Hawkins, Robert Edward / Gilham, David Edward

Molecular therapy oncolytics

2017 Volume 8, Page(s) 41–51

Abstract: Chimeric antigen receptor (CAR) T cell therapy represents a significant advancement in cancer therapy. Larger studies have shown ∼90% complete remission rates against chemoresistant and/or refractory ... ...

Abstract	Chimeric antigen receptor (CAR) T cell therapy represents a significant advancement in cancer therapy. Larger studies have shown ∼90% complete remission rates against chemoresistant and/or refractory CD19
Language	English
Publishing date	2017-12-19
Publishing country	United States
Document type	Journal Article
ISSN	2372-7705
ISSN	2372-7705
DOI	10.1016/j.omto.2017.12.003
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Article ; Online: CAR T-cell therapy: toxicity and the relevance of preclinical models.

Kalaitsidou, Milena / Kueberuwa, Gray / Schütt, Antje / Gilham, David Edward

Immunotherapy

2015 Volume 7, Issue 5, Page(s) 487–497

Abstract: Chimeric antigen receptor (CAR) T cells form part of a broad wave of immunotherapies that are showing promise in early phase cancer clinical trials. This clinical delivery has been based upon preclinical efficacy testing that confirmed the proof of ... ...

Abstract	Chimeric antigen receptor (CAR) T cells form part of a broad wave of immunotherapies that are showing promise in early phase cancer clinical trials. This clinical delivery has been based upon preclinical efficacy testing that confirmed the proof of principle of the therapy. However, CAR T-cell therapy does not exist alone as T cells are generally given in combination with patient preconditioning, most commonly in the form of chemotherapy, and may also include systemic cytokine support, both of which are associated with toxicity. Consequently, complete CAR T-cell therapy includes elements where the toxicity profile is well known, but also includes the CAR T cell itself, for which toxicity profiles are largely unknown. With recent reports of adverse events associated with CAR T-cell therapy, there is now concern that current preclinical models may not be fit for purpose with respect to CAR T-cell toxicity profiling. Here, we explore the preclinical models used to validate CAR T-cell function and examine their potential to predict CAR T-cell driven toxicities for the future.
MeSH term(s)	Animals ; Cytokines/immunology ; Humans ; Immunotherapy, Adoptive/methods ; Receptors, Antigen, T-Cell/immunology ; Recombinant Fusion Proteins/immunology ; T-Lymphocytes/immunology ; T-Lymphocytes/transplantation
Chemical Substances	Cytokines ; Receptors, Antigen, T-Cell ; Recombinant Fusion Proteins
Language	English
Publishing date	2015
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ISSN	1750-7448
ISSN (online)	1750-7448
DOI	10.2217/imt.14.123
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Article ; Online: Tissue-specific attenuation of oncolytic sindbis virus without compromised genetic stability.

Kueberuwa, Gray / Cawood, Ryan / Tedcastle, Alison / Seymour, Leonard W

Human gene therapy methods

2014 Volume 25, Issue 2, Page(s) 154–165

Abstract: Wild-type Sindbis virus (SV) shows promise as an oncolytic agent, although potential off-target replication is a safety concern. To remove possible pathology reflecting virus replication in liver, muscle, and/or hematopoietic cells, microRNA (miR)- ... ...

Abstract	Wild-type Sindbis virus (SV) shows promise as an oncolytic agent, although potential off-target replication is a safety concern. To remove possible pathology reflecting virus replication in liver, muscle, and/or hematopoietic cells, microRNA (miR)-response elements (MREs) to liver-specific miR122, muscle-specific miR133a and miR206, or hematopoietic-specific miR142-3p were inserted into the Sindbis viral genome. We compared the effectiveness of MREs in two distinct genomic locations and found better tissue-specific attenuation when they were inserted into the structural polyprotein coding region (up to 6000-fold selectivity with miR142-3p) rather than into the 3' untranslated region (up to 850-fold with miR142-3p). While this degree of tissue-specific attenuation may be effective for relieving pathology in vivo, genetic instability of RNA viruses raises concerns over the mutation or loss of MREs conferring safety. Genetically modified SVs containing a reporter transgene, used as a surrogate for virus replication, mutated quickly in vitro, losing 50% transgene sequence within 6.2 passages. Using a shorter insert containing MREs but no transgene, complete genetic stability was observed over at least 10 passages. We conclude that SV may be genetically modified to improve clinical properties, but attention must be paid to ensure that genetic stability is sufficient for intended applications.
MeSH term(s)	3' Untranslated Regions ; Animals ; Cell Line ; Cricetinae ; Genome, Viral ; Genomic Instability ; Green Fluorescent Proteins/genetics ; Green Fluorescent Proteins/metabolism ; HEK293 Cells ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/metabolism ; Humans ; Liver/metabolism ; Liver/virology ; Mice ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Muscles/metabolism ; Muscles/virology ; Oncolytic Viruses/genetics ; Response Elements/genetics ; Sindbis Virus/genetics ; Sindbis Virus/physiology
Chemical Substances	3' Untranslated Regions ; MicroRNAs ; enhanced green fluorescent protein ; Green Fluorescent Proteins (147336-22-9)
Language	English
Publishing date	2014-02-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2654800-8
ISSN	1946-6544 ; 1946-6536
ISSN (online)	1946-6544
ISSN	1946-6536
DOI	10.1089/hgtb.2013.202
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