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 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 Advances in Adoptive Cell Therapy Using Induced Pluripotent Stem Cell-Derived T Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Ratchapong Netsrithong ◽  
Methichit Wattanapanitch
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cell Biology ◽  
Ex Vivo ◽  
Adoptive Cell Therapy ◽  
Basic Knowledge ◽  
Car T Cells ◽  
Car T ◽  
Induced Pluripotent

Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR) T cells holds impressive clinical outcomes especially in patients who are refractory to other kinds of therapy. However, many challenges hinder its clinical applications. For example, patients who undergo chemotherapy usually have an insufficient number of autologous T cells due to lymphopenia. Long-term ex vivo expansion can result in T cell exhaustion, which reduces the effector function. There is also a batch-to-batch variation during the manufacturing process, making it difficult to standardize and validate the cell products. In addition, the process is labor-intensive and costly. Generation of universal off-the-shelf CAR T cells, which can be broadly given to any patient, prepared in advance and ready to use, would be ideal and more cost-effective. Human induced pluripotent stem cells (iPSCs) provide a renewable source of cells that can be genetically engineered and differentiated into immune cells with enhanced anti-tumor cytotoxicity. This review describes basic knowledge of T cell biology, applications in ACT, the use of iPSCs as a new source of T cells and current differentiation strategies used to generate T cells as well as recent advances in genome engineering to produce next-generation off-the-shelf T cells with improved effector functions. We also discuss challenges in the field and future perspectives toward the final universal off-the-shelf immunotherapeutic products.

scholarly journals Chimeric Antigen Receptor-T Cells: A Pharmaceutical Scope

2021 ◽  
Vol 12 ◽  
Author(s):  
Alejandrina Hernández-López ◽  
Mario A. Téllez-González ◽  
Paul Mondragón-Terán ◽  
Angélica Meneses-Acosta
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Adoptive Cell Therapy ◽  
Genetically Engineered ◽  
First Line ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Advanced Therapy ◽  
Car T

Cancer is among the leading causes of death worldwide. Therefore, improving cancer therapeutic strategies using novel alternatives is a top priority on the contemporary scientific agenda. An example of such strategies is immunotherapy, which is based on teaching the immune system to recognize, attack, and kill malignant cancer cells. Several types of immunotherapies are currently used to treat cancer, including adoptive cell therapy (ACT). Chimeric Antigen Receptors therapy (CAR therapy) is a kind of ATC where autologous T cells are genetically engineered to express CARs (CAR-T cells) to specifically kill the tumor cells. CAR-T cell therapy is an opportunity to treat patients that have not responded to other first-line cancer treatments. Nowadays, this type of therapy still has many challenges to overcome to be considered as a first-line clinical treatment. This emerging technology is still classified as an advanced therapy from the pharmaceutical point of view, hence, for it to be applied it must firstly meet certain requirements demanded by the authority. For this reason, the aim of this review is to present a global vision of different immunotherapies and focus on CAR-T cell technology analyzing its elements, its history, and its challenges. Furthermore, analyzing the opportunity areas for CAR-T technology to become an affordable treatment modality taking the basic, clinical, and practical aspects into consideration.

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.

773 Adoptive Cell Therapy Response in Melanoma is Mediated by Stem-like CD8 T cells

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A822-A822
Author(s):  
Sri Krishna ◽  
Frank Lowery ◽  
Amy Copeland ◽  
Stephanie Goff ◽  
Grégoire Altan-Bonnet ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Single Cell ◽  
Cd8 T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
High Dimensional ◽  
Tumor Control ◽  
Intrinsic Factors ◽  
Infiltrating Lymphocytes

BackgroundAdoptive T cell therapy (ACT) utilizing ex vivo-expanded autologous tumor infiltrating lymphocytes (TILs) can result in complete regression of human cancers.1 Successful immunotherapy is influenced by several tumor-intrinsic factors.2 3 Recently, T cell-intrinsic factors have been associated with immunotherapy response in murine and human studies.4 5 Analyses of tumor-reactive TILs have concluded that anti-tumor neoantigen-specific TILs are enriched in subsets defined by the expression of PD-1 or CD39.6 7 Thus, there is a lack of consensus regarding the tumor-reactive TIL subset that is directly responsible for successful immunotherapies such as ICB and ACT. In this study, we attempted to define the fitness landscape of TIL-enriched infusion products to specifically understand its phenotypic impact on human immunotherapy responses.MethodsWe compared the phenotypic differences that could distinguish bulk ACT infusion products (I.P.) administered to patients who had complete response to therapy (complete responders, CRs, N = 24) from those whose disease progressed following ACT (non-responders, NRs, N = 30) by high dimensional single cell protein and RNA analysis of the I.P. We further analyzed the phenotypic states of anti-tumor neoantigen specific TILs from patient I.P (N = 26) by flow cytometry and single cell transcriptomics.ResultsWe identified two CD8+ TIL populations associated with clinical outcomes: a memory-progenitor CD39-negative stem-like TIL (CD39-CD69-) in the I.P. associated with complete cancer regression (overall survival, P < 0.0001, HR = 0.217, 95% CI 0.101 to 0.463) and TIL persistence, and a terminally differentiated CD39-positive TIL (CD39+CD69+) population associated with poor TIL persistence post-treatment. Although the majority (>65%) of neoantigen-reactive TILs in both responders and non-responders to ACT were found in the differentiated CD39+ state, CR infusion products also contained a pool of CD39- stem-like neoantigen-specific TILs (median = 8.8%) that was lacking in NR infusion products (median = 23.6%, P = 1.86 x 10-5). Tumor-reactive stem-like T cells were capable of self-renewal, expansion, and persistence, and mediated superior anti-tumor response in vivo.ConclusionsOur results support the hypothesis that responders to ACT received infusion products containing a pool of stem-like neoantigen-specific TILs that are able to undergo prolific expansion, give rise to differentiated subsets, and mediate long-term tumor control and T cell persistence, in line with recent murine ICB studies mediated by TCF+ progenitor T cells.4 5 Our data also suggest that TIL subsets mediating ACT-response (stem-like CD39-) might be distinct from TIL subsets enriched for anti-tumor-reactivity (terminally differentiated CD39+) in human TIL.6 7AcknowledgementsWe thank Don White for curating the melanoma patient cohort, and J. Panopoulos (Flowjo) for helpful discussions on high-dimensional analysis, and NCI Surgery Branch members for helpful insights and suggestions. S. Krishna acknowledges funding support from NCI Director’s Innovation Award from the National Cancer Institute.Trial RegistrationNAEthics ApprovalThe study was approved by NCI’s IRB ethics board.ReferencesGoff SL, et al. Randomized, prospective evaluation comparing intensity of lymphodepletion before adoptive transfer of tumor-infiltrating lymphocytes for patients with metastatic melanoma. J Clin Oncol 2016;34:2389–2397.Snyder A, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 2014;371:2189–2199.McGranahan N, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016;351:1463–1469.Sade-Feldman M, et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 2019;176:404.Miller BC, et al. Subsets of exhausted CD8 T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol 2019;20:326–336.Simoni Y, et al. Bystander CD8 T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 2018;557:575–579.Gros A, et al. PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors. J Clin Invest 2014;124:2246–2259.

scholarly journals 764 Expansion with IL-15 increases cytotoxicity of Vγ9Vδ2 T cells and is associated with higher levels of cytotoxic molecules and T-bet

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A812-A812
Author(s):  
Pia Aehnlich ◽  
Per Thor Straten ◽  
Ana Micaela Carnaz Simoes ◽  
Signe Skadborg ◽  
Gitte Olofsson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Expansion ◽  
Ex Vivo ◽  
Adoptive Cell Therapy ◽  
Hematological Cancers ◽  
Cytotoxic Molecules ◽  
Vγ9vδ2 T Cells ◽  
T Cell Expansion

BackgroundAdoptive cell therapy (ACT) is an approved treatment option for certain hematological cancers and has also shown success for some solid cancers. Still, benefit and eligibility do not extend to all patients. ACT with Vγ9Vδ2 T cells is a promising approach to overcome this hurdle.MethodsIn this study, we explored the effect of different cytokine conditions on the expansion of Vγ9Vδ2 T cells in vitro.ResultsWe could show that Vγ9Vδ2 T cell expansion is feasible with two different cytokine conditions: (a) 1000U/ml interleukin (IL)-2 and (b) 100U/ml IL-2+100U/ml IL-15. We did not observe differences in expansion rate or Vγ9Vδ2 T cell purity between the conditions; however, IL-2/IL-15-expanded Vγ9Vδ2 T cells displayed enhanced cytotoxicity against tumor cells, also in hypoxia. While this increase in killing capacity was not reflected in phenotype, we demonstrated that IL-2/IL-15-expanded Vγ9Vδ2 T cells harbor increased amounts of perforin, granzyme B and granulysin in a resting state and release more upon activation. IL-2/IL-15-expanded Vγ9Vδ2 T cells also showed higher levels of transcription factor T-bet, which could indicate that T-bet and cytotoxic molecule levels confer the increased cytotoxicity.ConclusionsThese results advocate the inclusion of IL-15 into ex vivo Vγ9Vδ2 T cell expansion protocols in future clinical studies.

scholarly journals CAR T Cell Therapy’s Potential for Pediatric Brain Tumors

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5445
Author(s):  
Pauline Thomas ◽  
Natacha Galopin ◽  
Emma Bonérandi ◽  
Béatrice Clémenceau ◽  
Sophie Fougeray ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Cell Therapy ◽  
Pediatric Brain Tumors ◽  
Genetically Engineered ◽  
Molecular Techniques ◽  
Car T Cell ◽  
Cell Immunotherapy ◽  
Car T ◽  
Engineered T Cells

Malignant central nervous system tumors are the leading cause of cancer death in children. Progress in high-throughput molecular techniques has increased the molecular understanding of these tumors, but the outcomes are still poor. Even when efficacious, surgery, radiation, and chemotherapy cause neurologic and neurocognitive morbidity. Adoptive cell therapy with autologous CD19 chimeric antigen receptor T cells (CAR T) has demonstrated remarkable remission rates in patients with relapsed refractory B cell malignancies. Unfortunately, tumor heterogeneity, the identification of appropriate target antigens, and location in a growing brain behind the blood–brain barrier within a specific suppressive immune microenvironment restrict the efficacy of this strategy in pediatric neuro-oncology. In addition, the vulnerability of the brain to unrepairable tissue damage raises important safety concerns. Recent preclinical findings, however, have provided a strong rationale for clinical trials of this approach in patients. Here, we examine the most important challenges associated with the development of CAR T cell immunotherapy and further present the latest preclinical strategies intending to optimize genetically engineered T cells’ efficiency and safety in the field of pediatric neuro-oncology.

An Update on Adoptive T-Cell Therapy and Neoantigen Vaccines

2019 ◽  
pp. e70-e78 ◽  
Author(s):  
Patrick A. Ott ◽  
Gianpietro Dotti ◽  
Cassian Yee ◽  
Stephanie L. Goff
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Adoptive Cell Therapy ◽  
Adoptive T Cell Therapy ◽  
Clinical Activity ◽  
Single Chain ◽  
T Cell Therapy ◽  
Substantial Impact ◽  
Mhc Molecules

Adoptive T-cell therapy using tumor-infiltrating lymphocytes (TILs) has demonstrated long-lasting antitumor activity in select patients with advanced melanoma. Cancer vaccines have been used for many decades and have shown some promise but overall relatively modest clinical activity across cancers. Technological advances in genome sequencing capabilities and T-cell engineering have had substantial impact on both adoptive cell therapy and the cancer vaccine field. The ability to identify neoantigens—a class of tumor antigens that is truly tumor specific and encoded by tumor mutations through rapid and relatively inexpensive next-generation sequencing—has already demonstrated the critical importance of these antigens as targets of antitumor-specific T-cell responses in the context of immune checkpoint blockade and other immunotherapies. Therapeutically targeting these antigens with either adoptive T-cell therapy or vaccine approaches has demonstrated early promise in the clinic in patients with advanced solid tumors. Chimeric antigen receptor (CAR) T cells, which are engineered by fusing an antigen-specific, single-chain antibody (scFv) with signaling molecules of the T-cell receptor (TCR)/CD3 complex creating an antibody-like structure on T cells that recognizes antigens independently of major histocompatibility complex (MHC) molecules, have demonstrated remarkable clinical activity in patients with advanced B-cell malignancies, leading to several approvals by the U.S. Food and Drug Administration (FDA).

scholarly journals Deciphering and predicting CD4+ T cell immunodominance of influenza virus hemagglutinin

2020 ◽  
Vol 217 (10) ◽  
Author(s):  
Antonino Cassotta ◽  
Philipp Paparoditis ◽  
Roger Geiger ◽  
Ramgopal R. Mettu ◽  
Samuel J. Landry ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Processing ◽  
Ex Vivo ◽  
Influenza Pandemic ◽  
Cd4 T Cell ◽  
Cytotoxic T Cell ◽  
Cell Repertoire ◽  
Th Cells ◽  
Cytotoxic T Cell Responses

The importance of CD4+ T helper (Th) cells is well appreciated in view of their essential role in the elicitation of antibody and cytotoxic T cell responses. However, the mechanisms that determine the selection of immunodominant epitopes within complex protein antigens remain elusive. Here, we used ex vivo stimulation of memory T cells and screening of naive and memory T cell libraries, combined with T cell cloning and TCR sequencing, to dissect the human naive and memory CD4+ T cell repertoire against the influenza pandemic H1 hemagglutinin (H1-HA). We found that naive CD4+ T cells have a broad repertoire, being able to recognize naturally processed as well as cryptic peptides spanning the whole H1-HA sequence. In contrast, memory Th cells were primarily directed against just a few immunodominant peptides that were readily detected by mass spectrometry–based MHC-II peptidomics and predicted by structural accessibility analysis. Collectively, these findings reveal the presence of a broad repertoire of naive T cells specific for cryptic H1-HA peptides and demonstrate that antigen processing represents a major constraint determining immunodominance.

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