scholarly journals Cell therapies in ovarian cancer

2021 ◽  
Vol 13 ◽  
pp. 175883592110083
Author(s):  
Apostolos Sarivalasis ◽  
Matteo Morotti ◽  
Arthur Mulvey ◽  
Martina Imbimbo ◽  
George Coukos
Keyword(s):  
Ovarian Cancer ◽  
T Cell ◽  
Cell Therapy ◽  
Ex Vivo ◽  
Gynecological Cancer ◽  
Adoptive Cell Therapy ◽  
Survival Rates ◽  
Tumor Infiltrating Lymphocytes ◽  
T Cell Therapy ◽  
Cell Therapies

Epithelial ovarian cancer (EOC) is the most important cause of gynecological cancer-related mortality. Despite improvements in medical therapies, particularly with the incorporation of drugs targeting homologous recombination deficiency, EOC survival rates remain low. Adoptive cell therapy (ACT) is a personalized form of immunotherapy in which autologous lymphocytes are expanded, manipulated ex vivo, and re-infused into patients to mediate cancer rejection. This highly promising novel approach with curative potential encompasses multiple strategies, including the adoptive transfer of tumor-infiltrating lymphocytes, natural killer cells, or engineered immune components such as chimeric antigen receptor (CAR) constructs and engineered T-cell receptors. Technical advances in genomics and immuno-engineering have made possible neoantigen-based ACT strategies, as well as CAR-T cells with increased cell persistence and intratumoral trafficking, which have the potential to broaden the opportunity for patients with EOC. Furthermore, dendritic cell-based immunotherapies have been tested in patients with EOC with modest but encouraging results, while the combination of DC-based vaccination as a priming modality for other cancer therapies has shown encouraging results. In this manuscript, we provide a clinically oriented historical overview of various forms of cell therapies for the treatment of EOC, with an emphasis on T-cell therapy.

scholarly journals High-affinity oligoclonal TCRs define effective adoptive T cell therapy targeting mutant KRAS-G12D

2020 ◽  
Vol 117 (23) ◽  
pp. 12826-12835 ◽  
Author(s):  
Malcolm J. W. Sim ◽  
Jinghua Lu ◽  
Matthew Spencer ◽  
Francis Hopkins ◽  
Eric Tran ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Ex Vivo ◽  
Human Leukocyte ◽  
Tumor Infiltrating Lymphocytes ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy ◽  
High Affinity ◽  
Successful Case

Complete cancer regression occurs in a subset of patients following adoptive T cell therapy (ACT) of ex vivo expanded tumor-infiltrating lymphocytes (TILs). However, the low success rate presents a great challenge to broader clinical application. To provide insight into TIL-based immunotherapy, we studied a successful case of ACT where regression was observed against tumors carrying the hotspot mutation G12D in the KRAS oncogene. Four T cell receptors (TCRs) made up the TIL infusion and recognized two KRAS-G12D neoantigens, a nonamer and a decamer, all restricted by human leukocyte antigen (HLA) C*08:02. Three of them (TCR9a, 9b, and 9c) were nonamer-specific, while one was decamer-specific (TCR10). We show that only mutant G12D but not the wild-type peptides stabilized HLA-C*08:02 due to the formation of a critical anchor salt bridge to HLA-C. Therapeutic TCRs exhibited high affinities, ranging from nanomolar to low micromolar. Intriguingly, TCR binding affinities to HLA-C inversely correlated with their persistence in vivo, suggesting the importance of antigenic affinity in the function of therapeutic T cells. Crystal structures of TCR–HLA-C complexes revealed that TCR9a to 9c recognized G12D nonamer with multiple conserved contacts through shared CDR2β and CDR3α. This allowed CDR3β variation to confer different affinities via a variable HLA-C contact, generating an oligoclonal response. TCR10 recognized an induced and distinct G12D decamer conformation. Thus, this successful case of ACT included oligoclonal TCRs of high affinity recognizing distinct conformations of neoantigens. Our study revealed the potential of a structural approach to inform clinical efforts in targeting KRAS-G12D tumors by immunotherapy and has general implications for T cell-based immunotherapies.

scholarly journals Immune Escape Mechanisms and Future Prospects for Immunotherapy in Neuroblastoma

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Thitinee Vanichapol ◽  
Somchai Chutipongtanate ◽  
Usanarat Anurathapan ◽  
Suradej Hongeng
Keyword(s):  
Immune System ◽  
T Cell ◽  
Cell Therapy ◽  
Cell Function ◽  
Immune Cell ◽  
Immune Escape ◽  
Adoptive Cell Therapy ◽  
Immune Recognition ◽  
T Cell Therapy ◽  
Cell Therapies

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood with 5-year survival rate of 40% in high-risk patients despite intensive therapies. Recently, adoptive cell therapy, particularly chimeric antigen receptor (CAR) T cell therapy, represents a revolutionary treatment for hematological malignancies. However, there are challenges for this therapeutic strategy with solid tumors, as a result of the immunosuppressive nature of the tumor microenvironment (TME). Cancer cells have evolved multiple mechanisms to escape immune recognition or to modulate immune cell function. Several subtypes of immune cells that infiltrate tumors can foster tumor development, harbor immunosuppressive activity, and decrease an efficacy of adoptive cell therapies. Therefore, an understanding of the dual role of the immune system under the influences of the TME has been crucial for the development of effective therapeutic strategies against solid cancers. This review aims to depict key immune players and cellular pathways involved in the dynamic interplay between the TME and the immune system and also to address challenges and prospective development of adoptive T cell transfer for neuroblastoma.

scholarly journals Developing T-cell therapies for lymphoma without receptor engineering

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 622-631 ◽  
Author(s):  
Melanie Grant ◽  
Catherine M. Bollard
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Ex Vivo ◽  
Disease Stage ◽  
Antigen Receptors ◽  
Chimeric Antigen Receptors ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Cell Therapeutics ◽  
Clinical Responses

AbstractT-cell therapy has emerged from the bench for the treatment of patients with lymphoma. Responses to T-cell therapeutics are regulated by multiple factors, including the patient’s immune system status and disease stage. Outside of engineering of chimeric antigen receptors and artificial T-cell receptors, T-cell therapy can be mediated by ex vivo expansion of antigen-specific T cells targeting viral and/or nonviral tumor-associated antigens. These approaches are contributing to enhanced clinical responses and overall survival. In this review, we summarize the available T-cell therapeutics beyond receptor engineering for the treatment of patients with lymphoma.

scholarly journals Developing T-cell therapies for lymphoma without receptor engineering

2017 ◽  
Vol 1 (26) ◽  
pp. 2579-2590 ◽  
Author(s):  
Melanie Grant ◽  
Catherine M. Bollard
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Ex Vivo ◽  
Disease Stage ◽  
Antigen Receptors ◽  
Chimeric Antigen Receptors ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Cell Therapeutics ◽  
Clinical Responses

Abstract T-cell therapy has emerged from the bench for the treatment of patients with lymphoma. Responses to T-cell therapeutics are regulated by multiple factors, including the patient’s immune system status and disease stage. Outside of engineering of chimeric antigen receptors and artificial T-cell receptors, T-cell therapy can be mediated by ex vivo expansion of antigen-specific T cells targeting viral and/or nonviral tumor-associated antigens. These approaches are contributing to enhanced clinical responses and overall survival. In this review, we summarize the available T-cell therapeutics beyond receptor engineering for the treatment of patients with lymphoma.

scholarly journals AIM Platform: A Novel Nano Artificial Antigen-Presenting Cell-Based Clinical System Designed to Consistently Produce Multi-Antigen-Specific T-Cell Products with Potent and Durable Anti-Tumor Properties

2020 ◽  
Vol 47 (6) ◽  
pp. 464-471
Author(s):  
Lauren Suarez ◽  
Ruipeng Wang ◽  
Scott Carmer ◽  
Daniel Bednarik ◽  
Han Myint ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Cell Therapy ◽  
Ex Vivo ◽  
Adoptive Cell Therapy ◽  
Tumor Infiltrating Lymphocytes ◽  
Genetically Engineered ◽  
Alternative Methods ◽  
Cell Repertoire

Over the last decade, tremendous progress has been made in the field of adoptive cell therapy. The two prevailing modalities include endogenous non-engineered approaches and genetically engineered T-cell approaches. Endogenous non-engineered approaches include dendritic cell-based systems and tumor-infiltrating lymphocytes (TIL) that are used to produce multi-antigen-specific T-cell products. Genetically engineered approaches, such as T-cell receptor engineered cells and chimeric antigen receptor T cells are used to produce single antigen-specific T-cell products. It is noted by the authors that there are alternative methods to sort for antigen-specific T cells such as peptide multimer sorting or cytokine secretion assay-based sorting, both of which are potentially challenging for broad development and commercialization. In this review, we are focusing on a novel nanoparticle technology that generates a non-engineered product from the endogenous T-cell repertoire. The most common approaches for ex vivo activation and expansion of endogenous, non-genetically engineered cell therapy products rely on dendritic cell-based systems or IL-2 expanded TIL. Hurdles remain in developing efficient, consistent, controlled processes; thus, these processes still have limited access to broad patient populations. Here, we describe a novel approach to produce cellular therapies at clinical scale, using proprietary nanoparticles combined with a proprietary manufacturing process to enrich and expand antigen-specific CD8<sup>+</sup> T-cell products with consistent purity, identity, and composition required for effective and durable anti-tumor response.

scholarly journals Nanoparticles for Enhanced Adoptive T Cell Therapies and Future Perspectives for CNS Tumors

2021 ◽  
Vol 12 ◽  
Author(s):  
Preethi Bala Balakrishnan ◽  
Elizabeth E. Sweeney
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Ex Vivo ◽  
Clinical Success ◽  
Hematologic Malignancies ◽  
Adoptive T Cell Therapy ◽  
Cns Tumors ◽  
T Cell Therapy ◽  
Cell Therapies

Adoptive T cell therapy has emerged as a revolutionary immunotherapy for treating cancer. Despite immense promise and clinical success in some hematologic malignancies, limitations remain that thwart its efficacy in solid tumors. Particularly in tumors of the central nervous system (CNS), T cell therapy is often restricted by the difficulty in intratumoral delivery across anatomical niches, suboptimal T cell specificity or activation, and intratumoral T cell dysfunction due to immunosuppressive tumor microenvironments (TMEs). Nanoparticles may offer several advantages to overcome these limitations of T cell therapy, as they can be designed to robustly and specifically activate T cells ex vivo prior to adoptive transfer, to encapsulate T cell stimulating agents for co-localized stimulation, and to be conjugated onto T cells for added functionality. This perspective highlights recent preclinical advances in using nanoparticles to enhance T cell therapy, and discusses the potential applicability and constraints of nanoparticle-enhanced T cells as a new platform for treating CNS tumors.

scholarly journals IMMU-41. HIGH-THROUGHPUT RETRIEVAL OF THERAPEUTIC T CELL RECEPTORS FROM GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii113-ii113
Author(s):  
Katharina Lindner ◽  
Chin Leng Tan ◽  
Matthias Bozza ◽  
Khwab Sanghvi ◽  
Isabel Poschke ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Single Cell ◽  
High Throughput ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Adoptive Cell Therapy ◽  
Expression Vectors ◽  
T Cell Therapy ◽  
Single Cell Sequencing

Abstract Gliomas are tumors with low mutational burden with the majority of them being resistant to checkpoint inhibition due to few immunogenic antigens. Multicenter vaccine trials targeting personalized neoantigens in gliomas demonstrated feasibility and illustrated the challenges of retrieving neoepitope-specific T cells based on the prediction of immunogenic neoepitopes. Here we took an entirely different T cell-centric approach and established a single cell sequencing-based high-throughput T cell receptor (TCR) retrieval platform, exploiting the therapeutic potential of spontaneous intratumoral T cell clonotypes for the development of adoptive cell therapy. We conducted direct ex vivo TCR single cell sequencing from freshly sorted human glioma-infiltrating T cell samples. High fidelity PCR was established to clone TCRs from single cell libraries directly into episomal expression vectors further optimized for T cell therapy. In parallel to standard therapy, patient-derived xenografts were developed and characterized. Tumor-reactivity of retrieved TCRs was demonstrated against patient-derived cell lines. Collectively, we provide a novel sequencing-based platform for high-throughput identification and validation of endogenous glioma-targeting TCRs and demonstrate their therapeutic applicability.

scholarly journals Cell Therapy With TILs: Training and Taming T Cells to Fight Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Amrendra Kumar ◽  
Reese Watkins ◽  
Anna E. Vilgelm
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cancer Immunotherapy ◽  
Immune Cells ◽  
Data Science ◽  
Tumor Regression ◽  
Ex Vivo ◽  
Adoptive Cell Therapy ◽  
Tumor Infiltrating Lymphocytes

The rationale behind cancer immunotherapy is based on the unequivocal demonstration that the immune system plays an important role in limiting cancer initiation and progression. Adoptive cell therapy (ACT) is a form of cancer immunotherapy that utilizes a patient’s own immune cells to find and eliminate tumor cells, however, donor immune cells can also be employed in some cases. Here, we focus on T lymphocyte (T cell)-based cancer immunotherapies that have gained significant attention after initial discoveries that graft-versus-tumor responses were mediated by T cells. Accumulating knowledge of T cell development and function coupled with advancements in genetics and data science has enabled the use of a patient’s own (autologous) T cells for ACT (TIL ACTs). In TIL ACT, tumor-infiltrating lymphocytes (TILs) are collected from resected tumor material, enhanced and expanded ex-vivo, and delivered back to the patient as therapeutic agents. ACT with TILs has been shown to cause objective tumor regression in several types of cancers including melanoma, cervical squamous cell carcinoma, and cholangiocarcinoma. In this review, we provide a brief history of TIL ACT and discuss the current state of TIL ACT clinical development in solid tumors. We also discuss the niche of TIL ACT in the current cancer therapy landscape and potential strategies for patient selection.

scholarly journals 'Off-the-shelf’ allogeneic antigen-specific adoptive T-cell therapy for the treatment of multiple EBV-associated malignancies

2021 ◽  
Vol 9 (2) ◽  
pp. e001608
Author(s):  
Debottam Sinha ◽  
Sriganesh Srihari ◽  
Kirrliee Beckett ◽  
Laetitia Le Texier ◽  
Matthew Solomon ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Adoptive T Cell Therapy ◽  
Nuclear Antigen ◽  
T Cell Therapy ◽  
In Vivo Models ◽  
Hla Alleles ◽  
Cell Therapies ◽  
Wide Range

BackgroundEpstein-Barr virus (EBV), an oncogenic human gammaherpesvirus, is associated with a wide range of human malignancies of epithelial and B-cell origin. Recent studies have demonstrated promising safety and clinical efficacy of allogeneic ‘off-the-shelf’ virus-specific T-cell therapies for post-transplant viral complications.MethodsTaking a clue from these studies, we developed a highly efficient EBV-specific T-cell expansion process using a replication-deficient AdE1-LMPpoly vector that specifically targets EBV-encoded nuclear antigen 1 (EBNA1) and latent membrane proteins 1 and 2 (LMP1 and LMP2), expressed in latency II malignancies.ResultsThese allogeneic EBV-specific T cells efficiently recognized human leukocyte antigen (HLA)-matched EBNA1-expressing and/or LMP1 and LMP2-expressing malignant cells and demonstrated therapeutic potential in a number of in vivo models, including EBV lymphomas that emerged spontaneously in humanized mice following EBV infection. Interestingly, we were able to override resistance to T-cell therapy in vivo using a ‘restriction-switching’ approach, through sequential infusion of two different allogeneic T-cell therapies restricted through different HLA alleles. Furthermore, we have shown that inhibition of the programmed cell death protein-1/programmed death-ligand 1 axis in combination with EBV-specific T-cell therapy significantly improved overall survival of tumor-bearing mice when compared with monotherapy.ConclusionThese findings suggest that restriction switching by sequential infusion of allogeneic T-cell therapies that target EBV through distinct HLA alleles may improve clinical response.

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