scholarly journals Inducible gene switches with memory in human T cells for cellular immunotherapy

2018 ◽  
Author(s):  
Deboki Chakravarti ◽  
Leidy D Caraballo ◽  
Benjamin H. Weinberg ◽  
Wilson W. Wong
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Activity ◽  
Adoptive T Cell Therapy ◽  
Cellular Immunotherapy ◽  
Antigen Receptors ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Gene Switches ◽  
Engineered T Cells

AbstractCell-based therapies that employ engineered T cells—including the expression of chimeric antigen receptors (CARs)—to target cancer cells have demonstrated promising responses in clinical trials. However, engineered T cell responses must be regulated to prevent severe side effects such as cytokine storms and off-target responses. Here we present a class of recombinase-based gene circuits that will enable inducible switching between two states of adoptive T cell therapy using an FDA-approved drug, creating a generalizable platform that can be used to control when and how strongly a gene is expressed. These circuits exhibit memory such that induced T cells will maintain any changes made even when the drug inducer is removed. This memory feature avoids prolonged drug inducer exposure, thus reducing the complexity and potential side effect associated with the drug inducer. We have utilized these circuits to control the expression of an anti-Her2-CAR, demonstrating the ability of these circuits to regulate CAR expression and T cell activity. We envision this platform can be extended to regulate other genes in T cell behavior for various adoptive T cell therapies.

scholarly journals Modular Chimeric Antigen Receptor Systems for Universal CAR T Cell Retargeting

2020 ◽  
Vol 21 (19) ◽  
pp. 7222
Author(s):  
Ashley R. Sutherland ◽  
Madeline N. Owens ◽  
C. Ronald Geyer
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Activity ◽  
Cellular Immunotherapy ◽  
Antigen Receptors ◽  
Antigen Specificity ◽  
Precise Control ◽  
Car T Cells ◽  
Multiple Antigen ◽  
Car T

The engineering of T cells through expression of chimeric antigen receptors (CARs) against tumor-associated antigens (TAAs) has shown significant potential for use as an anti-cancer therapeutic. The development of strategies for flexible and modular CAR T systems is accelerating, allowing for multiple antigen targeting, precise programming, and adaptable solutions in the field of cellular immunotherapy. Moving beyond the fixed antigen specificity of traditional CAR T systems, the modular CAR T technology splits the T cell signaling domains and the targeting elements through use of a switch molecule. The activity of CAR T cells depends on the presence of the switch, offering dose-titratable response and precise control over CAR T cells. In this review, we summarize developments in universal or modular CAR T strategies that expand on current CAR T systems and open the door for more customizable T cell activity.

Tumor Specific T Cells Modified to Secrete IL-12 Eradicate Systemic Tumors in the Absence of Prior Toxic Chemotherapy Conditioning Regimens

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3120-3120
Author(s):  
Hollie J. Pegram ◽  
James Lee ◽  
Erik Hayman ◽  
Gavin H Imperato ◽  
Thomas J. Tedder ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Cell Activity ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy ◽  
Tumor Bearing ◽  
Conditioning Regimens ◽  
Ifn Γ

Abstract Abstract 3120 T cells may be genetically modified to target tumor-associated antigens through the retroviral transduction of genes encoding chimeric antigen receptors (CARs). We have previously generated a series of CARs specific to the CD19 antigen expressed on most B cell tumors. In xenotransplant models of disease we have shown that human T cells expressing CD19 targeted CARs successfully eradicate established B cell tumors in immune compromised SCID-Beige mice. To further our understanding of the in vivo biology of CAR modified T cells, we generated a more clinically relevant syngeneic, immune competent tumor model utilizing CD19 knock out (mCD19−/−) human CD19 knock in (hCD19+/−) C57BL6 transgenic mice (C57BL6(mCD19−/− hCD19+/−)) bearing systemic syngeneic EL4(hCD19+) thymoma tumors. Treatment of tumor bearing mice with syngeneic T cells modified to express the CD19 targeted 19m ζ CAR alone failed to either eradicate tumor or induce predicted B cell aplasias. However, prior lymphodepletion with cyclophosphamide followed by infusion of 19m ζ+ T cells successfully eradicated tumor in 83% of treated mice and induced long term B cell aplasias. Translation of this therapy to the clinic has also revealed that optimal responses require pre-conditioning regimens. Given the toxicity of pre-conditioning treatments, these therapies are largely restricted to younger, healthier patients able to tolerate such intensive regimens. To further understand the mechanisms of action of improved therapy following prior cyclophosphamide therapy, we demonstrated markedly enhanced serum levels of the IL-12 and IFN γ cytokines as well as a marked reduction of endogenous CD4+ regulatory T cells. We postulated that IL-12, which induces IFN γ secretion, may in part explain the enhanced anti-tumor efficacy following prior lymphodepletion, and may potentially obviate the need for toxic conditioning pre-treatments. To address this hypothesis, we modified CAR+ T cells to constitutively secrete IL-12. Subsequent adoptive therapy of EL4(hCD19+) tumor bearing C57BL6(mCD19−/− hCD19+/−) mice with hCD19 targeted IL-12 secreting T cells successfully eradicated disease in 75% of treated mice and induced predicted B cell aplasias in the absence of prior lymphodepletion. Significantly, we found that this enhanced hCD19 targeted T cell activity required the infusion of both CD4+ and CD8+ gene modified T cells, and was further dependent upon autocrine IL-12 stimulation of the modified tumor targeted T cells as well as modified T cell IFN γ secretion and stimulation. To our knowledge, this is the first time adoptive T cell transfer has been demonstrated to successfully eradicate tumor in the absence of prior conditioning regimens. Therefore, these data support the rapid translation of this adoptive T cell therapy to the clinic, as it may enhance the anti-tumor efficacy of this therapy and further expand the patient population eligible for adoptive T cells therapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Chimeric Antigen Receptors Expand the Repertoire of Antigenic Macromolecules for Cellular Immunity

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3356
Author(s):  
John T. Keane ◽  
Avery D. Posey
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cellular Therapy ◽  
Antigen Receptors ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Car T Cell Therapy ◽  
Car T ◽  
Specific Receptors ◽  
Tumor Specificity

T-cell therapies have made significant improvements in cancer treatment over the last decade. One cellular therapy utilizing T-cells involves the use of a chimeric MHC-independent antigen-recognition receptor, typically referred to as a chimeric antigen receptor (CAR). CAR molecules, while mostly limited to the recognition of antigens on the surface of tumor cells, can also be utilized to exploit the diverse repertoire of macromolecules targetable by antibodies, which are incorporated into the CAR design. Leaning into this expansion of target macromolecules will enhance the diversity of antigens T-cells can target and may improve the tumor-specificity of CAR T-cell therapy. This review explores the types of macromolecules targetable by T-cells through endogenous and synthetic antigen-specific receptors.

scholarly journals Engineered T Cell Therapy for Gynecologic Malignancies: Challenges and Opportunities

2021 ◽  
Vol 12 ◽  
Author(s):  
Yifan Xu ◽  
Jin Jiang ◽  
Yutong Wang ◽  
Wei Wang ◽  
Haokun Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Gynecologic Cancer ◽  
B Cell Lymphoma ◽  
Adoptive T Cell Therapy ◽  
Gynecologic Malignancies ◽  
T Cell Therapy ◽  
Incidence And Mortality ◽  
Engineered T Cells

Gynecologic malignancies, mainly including ovarian cancer, cervical cancer and endometrial cancer, are leading causes of death among women worldwide with high incidence and mortality rate. Recently, adoptive T cell therapy (ACT) using engineered T cells redirected by genes which encode for tumor-specific T cell receptors (TCRs) or chimeric antigen receptors (CARs) has demonstrated a delightful potency in B cell lymphoma treatment. Researches impelling ACT to be applied in treating solid tumors like gynecologic tumors are ongoing. This review summarizes the preclinical research and clinical application of engineered T cells therapy for gynecologic cancer in order to arouse new thoughts for remedies of this disease.

scholarly journals Application of Adoptive T-Cell Therapy Using Tumor Antigen-Specific T-Cell Receptor Gene Transfer for the Treatment of Human Leukemia

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Toshiki Ochi ◽  
Hiroshi Fujiwara ◽  
Masaki Yasukawa
Keyword(s):  
T Cells ◽  
T Cell ◽  
Gene Transfer ◽  
Cell Receptor ◽  
Adoptive T Cell Therapy ◽  
Human Leukemia ◽  
Cancer Antigen ◽  
T Cell Therapy ◽  
Engineered T Cells ◽  
Leukemia Antigen

The last decade has seen great strides in the field of cancer immunotherapy, especially the treatment of melanoma. Beginning with the identification of cancer antigens, followed by the clinical application of anti-cancer peptide vaccination, it has now been proven that adoptive T-cell therapy (ACT) using cancer antigen-specific T cells is the most effective option. Despite the apparent clinical efficacy of ACT, the timely preparation of a sufficient number of cancer antigen-specific T cells for each patient has been recognized as its biggest limitation. Currently, therefore, attention is being focused on ACT with engineered T cells produced using cancer antigen-specific T-cell receptor (TCR) gene transfer. With regard to human leukemia, ACT using engineered T cells bearing the leukemia antigen-specific TCR gene still remains in its infancy. However, several reports have provided preclinical data on TCR gene transfer using Wilms' tumor gene product 1 (WT1), and also preclinical and clinical data on TCR gene transfer involving minor histocompatibility antigen, both of which have been suggested to provide additional clinical benefit. In this review, we examine the current status of anti-leukemia ACT with engineered T cells carrying the leukemia antigen-specific TCR gene, and discuss the existing barriers to progress in this area.

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 Enabling T Cell Recruitment to Tumours as a Strategy for Improving Adoptive T Cell Therapy

2017 ◽  
Vol 13 (01) ◽  
pp. 66 ◽  
Author(s):  
Bruno Cadilha ◽  
Klara Dorman ◽  
Felicitas Rataj ◽  
Stefan Endres ◽  
Sebastian Kobold ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Therapeutic Potential ◽  
Cell Activity ◽  
Cell Lineage ◽  
Solid Tumours ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy

Immunotherapy has successfully been implemented as the standard of care in a number of oncologic indications. A hallmark of cancer immunotherapy is the successful activation of T cells against cancer cells, leading to unparalleled efficacy for some tumour entities. However, current approved approaches are not specific, limiting both their activity and their safety. A more tailored way of using the therapeutic potential of T cells is adoptive T cell therapy, which encompasses ex vivo T cell manipulation and reinfusion to patients suffering from cancer. In haematologic malignancies such as acute lymphatic leukaemia of the B cell lineage, T cells modified with a chimeric antigen receptor against the B cell lineage antigen CD19 induce remissions in a high proportion of patients. In contrast, patients suffering from advanced solid tumours have shown little benefit from cell-based approaches. This is partly due to limited access of T cells to the tumour tissue, consequently restricting T cell activity. In this review, we focus on the limitations of T cell trafficking towards solid tumours. We summarise the existing knowledge on lymphocyte migration to understand how this pathway may be used to open therapeutic approaches for a broader range of indications. We also review new strategies targeting the tumour site that aid naturally occurring or gene-engineered T cells to migrate to solid tumours. Finally, we discuss how guiding T cells towards the tumour might contribute in harnessing their full cytolytic potential.

98 ATA3271: an armored, next-generation off-the-shelf, allogeneic, mesothelin-CAR T cell therapy for solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A109-A109
Author(s):  
Jiangyue Liu ◽  
Xianhui Chen ◽  
Jason Karlen ◽  
Alfonso Brito ◽  
Tiffany Jheng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Next Generation ◽  
Phase 3 ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Car T Cells ◽  
Car T

BackgroundMesothelin (MSLN) is a glycosylphosphatidylinositol (GPI)-anchored membrane protein with high expression levels in an array of malignancies including mesothelioma, ovaria, non-small cell lung cancer, and pancreatic cancers and is an attractive target antigen for immune-based therapies. Early clinical evaluation of autologous MSLN-targeted chimeric antigen receptor (CAR)-T cell therapies for malignant pleural mesothelioma has shown promising acceptable safety1 and have recently evolved with incorporation of next-generation CAR co-stimulatory domains and armoring with intrinsic checkpoint inhibition via expression of a PD-1 dominant negative receptor (PD1DNR).2 Despite the promise that MSLN CAR-T therapies hold, manufacturing and commercial challenges using an autologous approach may prove difficult for widespread application. EBV T cells represent a unique, non-gene edited approach toward an off-the-shelf, allogeneic T cell platform. EBV-specific T cells are currently being evaluated in phase 3 trials [NCT03394365] and, to-date, have demonstrated a favorable safety profile including limited risks for GvHD and cytokine release syndrome.3 4 Clinical proof-of-principle studies for CAR transduced allogeneic EBV T cell therapies have also been associated with acceptable safety and durable response in association with CD19 targeting.5 Here we describe the first preclinical evaluation of ATA3271, a next-generation allogeneic CAR EBV T cell therapy targeting MSLN and incorporating PD1DNR, designed for the treatment of solid tumor indications.MethodsWe generated allogeneic MSLN CAR+ EBV T cells (ATA3271) using retroviral transduction of EBV T cells. ATA3271 includes a novel 1XX CAR signaling domain, previously associated with improved signaling and decreased CAR-mediated exhaustion. It is also armored with PD1DNR to provide intrinsic checkpoint blockade and is designed to retain functional persistence.ResultsIn this study, we characterized ATA3271 both in vitro and in vivo. ATA3271 show stable and proportional CAR and PD1DNR expression. Functional studies show potent antitumor activity of ATA3271 against MSLN-expressing cell lines, including PD-L1-high expressors. In an orthotopic mouse model of pleural mesothelioma, ATA3271 demonstrates potent antitumor activity and significant survival benefit (100% survival exceeding 50 days vs. 25 day median for control), without evident toxicities. ATA3271 maintains persistence and retains central memory phenotype in vivo through end-of-study. Additionally, ATA3271 retains endogenous EBV TCR function and reduced allotoxicity in the context of HLA mismatched targets. ConclusionsOverall, ATA3271 shows potent anti-tumor activity without evidence of allotoxicity, both in vitro and in vivo, suggesting that allogeneic MSLN-CAR-engineered EBV T cells are a promising approach for the treatment of MSLN-positive cancers and warrant further clinical investigation.ReferencesAdusumilli PS, Zauderer MG, Rusch VW, et al. Abstract CT036: A phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CAR T cells: Safety and efficacy. Cancer Research 2019;79:CT036-CT036.Kiesgen S, Linot C, Quach HT, et al. Abstract LB-378: Regional delivery of clinical-grade mesothelin-targeted CAR T cells with cell-intrinsic PD-1 checkpoint blockade: Translation to a phase I trial. Cancer Research 2020;80:LB-378-LB-378.Prockop S, Doubrovina E, Suser S, et al. Off-the-shelf EBV-specific T cell immunotherapy for rituximab-refractory EBV-associated lymphoma following transplantation. J Clin Invest 2020;130:733–747.Prockop S, Hiremath M, Ye W, et al. A Multicenter, Open Label, Phase 3 Study of Tabelecleucel for Solid Organ Transplant Subjects with Epstein-Barr Virus-Driven Post-Transplant Lymphoproliferative Disease (EBV+PTLD) after Failure of Rituximab or Rituximab and Chemotherapy. Blood 2019; 134: 5326–5326.Curran KJ, Sauter CS, Kernan NA, et al. Durable remission following ‘Off-the-Shelf’ chimeric antigen receptor (CAR) T-Cells in patients with relapse/refractory (R/R) B-Cell malignancies. Biology of Blood and Marrow Transplantation 2020;26:S89.

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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