scholarly journals Hypoxia in cancer chemo- and immunotherapy: foe or friend?

2019 ◽  
Author(s):  
Noemi Vitos ◽  
Shannon Chen ◽  
Shreya Mathur ◽  
Ibrahim Chamseddine ◽  
Katarzyna A. Rejniak
Keyword(s):  
T Cell ◽  
Oxygen Demand ◽  
Optimization Techniques ◽  
Adoptive T Cell Therapy ◽  
Tumor Resistance ◽  
Treatment Protocols ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Computational Optimization

AbstractHypoxia, a low level of oxygen in the tissue, is a feature of most solid tumors. It arises due to an imbalance between the oxygen supply from the abnormal vasculature and oxygen demand by the large number of tumor and stromal cells. Hypoxia has been implicated in the development of aggressive tumors and tumor resistance to various therapies. This makes hypoxia a negative marker of patients’ survival. However, recent advances in designing new hypoxia-activated pro-drugs and adoptive T cell therapies provide an opportunity for exploiting hypoxia in order to improve cancer treatment. We used novel mathematical models of micro-pharmacology and computational optimization techniques for determining the most effective treatment protocols that take advantage of heterogeneous and dynamically changing oxygenation in in vivo tumors. These models were applied to design schedules for a combination of three therapeutic compounds in pancreatic cancers and determine the most effective adoptive T cell therapy protocols in melanomas.

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.

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 IMMU-31. QUANTITATIVE EVALUATION OF ROUTES OF ADMINISTRATION OF IMMUNOTHERAPEUTIC T CELLS TO ORTHOTOPIC GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii111-ii111
Author(s):  
Lan Hoang-Minh ◽  
Angelie Rivera-Rodriguez ◽  
Fernanda Pohl-Guimarães ◽  
Seth Currlin ◽  
Christina Von Roemeling ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Ex Vivo ◽  
Adoptive T Cell Therapy ◽  
Whole Body ◽  
T Cell Therapy ◽  
Clinical Responses

Abstract SIGNIFICANCE Adoptive T cell therapy (ACT) has emerged as the most effective treatment against advanced malignant melanoma, eliciting remarkable objective clinical responses in up to 75% of patients with refractory metastatic disease, including within the central nervous system. Immunologic surrogate endpoints correlating with treatment outcome have been identified in these patients, with clinical responses being dependent on the migration of transferred T cells to sites of tumor growth. OBJECTIVE We investigated the biodistribution of intravenously or intraventricularly administered T cells in a murine model of glioblastoma at whole body, organ, and cellular levels. METHODS gp100-specific T cells were isolated from the spleens of pmel DsRed transgenic C57BL/6 mice and injected intravenously or intraventricularly, after in vitro expansion and activation, in murine KR158B-Luc-gp100 glioma-bearing mice. To determine transferred T cell spatial distribution, the brain, lymph nodes, heart, lungs, spleen, liver, and kidneys of mice were processed for 3D imaging using light-sheet and multiphoton imaging. ACT T cell quantification in various organs was performed ex vivo using flow cytometry, 2D optical imaging (IVIS), and magnetic particle imaging (MPI) after ferucarbotran nanoparticle transfection of T cells. T cell biodistribution was also assessed in vivo using MPI. RESULTS Following T cell intravenous injection, the spleen, liver, and lungs accounted for more than 90% of transferred T cells; the proportion of DsRed T cells in the brains was found to be very low, hovering below 1%. In contrast, most ACT T cells persisted in the tumor-bearing brains following intraventricular injections. ACT T cells mostly concentrated at the periphery of tumor masses and in proximity to blood vessels. CONCLUSIONS The success of ACT immunotherapy for brain tumors requires optimization of delivery route, dosing regimen, and enhancement of tumor-specific lymphocyte trafficking and effector functions to achieve maximal penetration and persistence at sites of invasive tumor growth.

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 Synthetic Antigen-Presenting Cells for Adoptive T Cell Therapy

2021 ◽  
Author(s):  
Shreyas N. Dahotre ◽  
Anna M. Romanov ◽  
Fang-Yi Su ◽  
Gabriel A. Kwong
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antigen Presenting Cells ◽  
Adoptive T Cell Therapy ◽  
Target Antigen ◽  
T Cell Therapy ◽  
Promising Alternative ◽  
Cell Therapies ◽  
Antigen Presenting

AbstractAdoptive T cell therapies are transforming the treatment of solid and liquid tumors, yet their widespread adoption is limited in part by the challenge of generating functional cells. T cell activation and expansion using conventional antigen-presenting cells (APCs) is unreliable due to the variable quality of donor-derived APCs. As a result, engineered approaches using nanomaterials presenting T cell activation signals are a promising alternative due to their ability to be robustly manufactured with precise control over stimulation cues. In this work, we design synthetic APCs that consist of liposomes surface-functionalized with peptide-major histocompatibility complexes (pMHC). Synthetic APCs selectively target and activate antigen-specific T cell populations to levels similar to conventional protocols using non-specific αCD3 and αCD28 antibodies without the need for costimulation signals. T cells treated with synthetic APCs produce effector cytokines and demonstrate cytotoxic activity when co-cultured with tumor cells presenting target antigen in vitro. Following adoptive transfer into tumor-bearing mice, activated cells control tumor growth and improve overall survival compared to untreated mice. Synthetic APCs could potentially be used in the future to improve the accessibility of adoptive T cell therapies by removing the need for conventional APCs during manufacturing.

scholarly journals In vitro proteasome processing of neo-splicetopes does not predict their presentation in vivo

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Gerald Willimsky ◽  
Christin Beier ◽  
Lena Immisch ◽  
Georgios Papafotiou ◽  
Vivian Scheuplein-Schlosser ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Response ◽  
Adoptive T Cell Therapy ◽  
Prediction Algorithm ◽  
General Applicability ◽  
T Cell Therapy ◽  
Tcr Repertoire ◽  
Peptide Prediction

Proteasome catalyzed peptide splicing (PCPS) of cancer-driving antigens could generate attractive neoepitopes to be targeted by TCR-based adoptive T cell therapy. Based on a spliced peptide prediction algorithm TCRs were generated against putative KRASG12V and RAC2P29L derived neo-splicetopes with high HLA-A*02:01 binding affinity. TCRs generated in mice with a diverse human TCR repertoire specifically recognized the respective target peptides with high efficacy. However, we failed to detect any neo-splicetope specific T cell response when testing the in vivo neo-splicetope generation and obtained no experimental evidence that the putative KRASG12V- and RAC2P29L-derived neo-splicetopes were naturally processed and presented. Furthermore, only the putative RAC2P29L-derived neo-splicetopes was generated by in vitro PCPS. The experiments pose severe questions on the notion that available algorithms or the in vitro PCPS reaction reliably simulate in vivo splicing and argue against the general applicability of an algorithm-driven 'reverse immunology' pipeline for the identification of cancer-specific neo-splicetopes.

Phase I/II study of adoptive T-cell therapy following in vivo priming with a HER2/neu vaccine in patients with advanced-stage HER2+ breast cancer.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 615-615
Author(s):  
Mary L. Disis ◽  
Andrew L Coveler ◽  
Doreen Higgins ◽  
Leonard A D'Amico ◽  
Chihiro Morishima ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Cell Therapy ◽  
Phase I ◽  
Adoptive T Cell Therapy ◽  
Advanced Stage ◽  
T Cell Therapy ◽  
Her2 Breast Cancer

A Novel Bioluminescent Mouse Model for Optimization of Adoptive T Cell Therapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2162-2162
Author(s):  
Martin Szyska ◽  
Stefanie Herda ◽  
Stefanie Althoff ◽  
Andreas Heimann ◽  
Tra My Dang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Tumor Model ◽  
Effector Function ◽  
Tumor Rejection ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy ◽  
The Impact

Abstract Adoptive T cell therapy (ATT) is a promising option for the treatment of solid cancers. However, various defense mechanisms acquired by the tumor during evolution prevent transferred T cells (TC) to unfold their full potential. A combination of ATT with accessory therapeutic approaches including checkpoint inhibition and targeted therapy could lift TC inhibition and efficiently shift the immune balance towards tumor rejection. An in-vivo analysis of the impact of combination strategies on the outcome of ATT would greatly enhance the search for an optimal accessory to ATT therapy. We generated the transgenic mouse line BLITC (bioluminescence imaging of T cells) expressing an NFAT (nuclear factor of activated T cell)-dependent Click-beetle luciferase (Na et. al, 2010) and a constitutive Renilla Luciferase, allowing us to monitor migration and activation of transferred TCs in vivo. In order to analyze crucial ATT parameters in a clinically relevant tumor model, BLITC mice were crossed to the two HY-TCR transgenic mice Marilyn (CD4: H-2Ab-Dby) and MataHari (CD8: H-2Db-Uty) to generate TCs that could be monitored for in-vivo infiltration, local activation and rejection of established (> 0,5 cm x 0,5 cm / ≥10 days growth) H-Y expressing MB49 tumors. In order to better reflect the clinical situation, we lymphodepleted tumor-bearing immunocompetent albino B6 mice with fludarabine (FLu) and/or cyclophosphamide (CTX) prior to ATT. Transferred TCs were FACSorted and injected after an optional culture expansion phase. As shown before for freshly injected tumor cells (Perez-Diez, 2007), we observed a superior response of tumor-antigen specific CD4+ TCs compared to CD8+ TCs against established tumors. Whereas 5*106 CD8+ T cells hardly attenuated tumor growth, even as few as 5000 H-Y TCR-transgenic CD4+ T cells rejected tumors in most mice, depending on the lymphodepleting treatment (Figure A - remission rates in parentheses). Tumor infiltration and activation of adoptively transferred TCs was monitored in-vivo by the respective bioluminescent reporters. Around day 4 and 6, CD4+ TCs migrated from tumor-draining lymph nodes into the tumor environment and persisted until rejection. Interestingly, activation of CD4+ TCs was only transient (between days 4 and 7) in all mice, independent of therapy outcome (in Figure B shown for refractory tumor). Whereas loss of activation signal during remission was correlated with tumor clearance and decline of effector function, in refractory tumors it suggests a rapid inactivation of infiltrating TCs by the tumor microenvironment. Our data indicate that the failure of tumor rejection is not caused by impaired peripheral expansion or tumor homing but rather by inhibition of TC effector function. Responsible mechanisms and counter-acting therapeutic interventions are the focus of ongoing studies. In summary, the BLITC reporter system facilitates analysis of therapeutic parameters for ATT in a well-established solid tumor model. Using BLITC mice for transduction with TCR or CAR expression cassettes could allow rapid monitoring of on-target as well as undesired off-target effects in virtually any tumor setting. Future experiments will focus on the beneficial effects of combination treatments on the activation of adoptively transferred TCs. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

scholarly journals Engraftment of human central memory-derived effector CD8+ T cells in immunodeficient mice

Blood ◽  
2011 ◽  
Vol 117 (6) ◽  
pp. 1888-1898 ◽  
Author(s):  
Xiuli Wang ◽  
Carolina Berger ◽  
ChingLam W. Wong ◽  
Stephen J. Forman ◽  
Stanley R. Riddell ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Effector T Cells ◽  
Central Memory ◽  
Model Systems ◽  
Adoptive T Cell Therapy ◽  
Effector Memory ◽  
T Cell Therapy ◽  
Effector Cells

Abstract In clinical trials of adoptive T-cell therapy, the persistence of transferred cells correlates with therapeutic efficacy. However, properties of human T cells that enable their persistence in vivo are poorly understood, and model systems that enable investigation of the fate of human effector T cells (TE) have not been described. Here, we analyzed the engraftment of adoptively transferred human cytomegalovirus pp65-specific CD8+ TE cells derived from purified CD45RO+CD62L+ central memory (TCM) or CD45RO+CD62L− effector memory (TEM) precursors in an immunodeficient mouse model. The engraftment of TCM-derived effector cells (TCM/E) was dependent on human interleukin-15, and superior in magnitude and duration to TEM-derived effector cells (TEM/E). T-cell receptor Vβ analysis of persisting cells demonstrated that CD8+ TCM/E engraftment was polyclonal, suggesting that the ability to engraft is a general feature of TCM/E. CD8+ TEM/E proliferated extensively after transfer but underwent rapid apoptosis. In contrast, TCM/E were less prone to apoptosis and established a persistent reservoir of functional T cells in vivo characterized by higher CD28 expression. These studies predict that human CD8+ effector T cells derived from TCM precursors may be preferred for adoptive therapy based on superior engraftment fitness.

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