bims-adocet Biomed News
on Adoptive cell therapy
Issue of 2024–09–01
twelve papers selected by
Shani Kassia Lyskov, Tel Aviv University
  1. Fate induction in CD8 CAR T cells through asymmetric cell division.
  2. FGFR4-specific CAR-T cells with inducible caspase-9 suicide gene as an approach to treat rhabdomyosarcoma.
  3. Pharmacologic HIF stabilization activates costimulatory receptor expression to increase antitumor efficacy of adoptive T cell therapy.
  4. CAR T cells engineered to secrete IFN-κ induce tumor ferroptosis via an IFNAR/STAT1/ACSL4 axis.
  5. Sodium chloride in the tumor microenvironment enhances T cell metabolic fitness and cytotoxicity.
  6. NaCl enhances CD8+ T cell effector functions in cancer immunotherapy.
  7. Complementary dual-virus strategy drives synthetic target and cognate T-cell engager expression for endogenous-antigen agnostic immunotherapy.
  8. Activation and antitumor immunity of CD8+ T cells are supported by the glucose transporter GLUT10 and disrupted by lactic acid.
  9. A novel bispecific T-cell engager using the ligand-target csGRP78 against acute myeloid leukemia.
  10. Cbl-b inhibition promotes less differentiated phenotypes of T cells with enhanced cytokine production.
  11. LSD1 inhibition improves efficacy of adoptive T cell therapy by enhancing CD8+ T cell responsiveness.
  12. Age-associated contraction of tumor-specific T cells impairs antitumor immunity.
  1. Nature. 2024 Aug 28.
    Fate induction in CD8 CAR T cells through asymmetric cell division.
    Casey S Lee, Sisi Chen, Corbett T Berry, Andre R Kelly, Patrick J Herman, Sangwook Oh, Roddy S O'Connor, Aimee S Payne, Christoph T Ellebrecht.
      Early expansion and long-term persistence predict efficacy of chimeric antigen receptor T cells (CARTs)1-7, but mechanisms governing effector versus memory CART differentiation and whether asymmetric cell division induces differential fates in human CARTs remain unclear. Here we show that target-induced proximity labelling enables isolation of first-division proximal-daughter and distal-daughter CD8 CARTs that asymmetrically distribute their surface proteome and transcriptome, resulting in divergent fates. Target-engaged CARs remain on proximal daughters, which inherit a surface proteome resembling activated-undivided CARTs, whereas the endogenous T cell receptor and CD8 enrich on distal daughters, whose surface proteome resembles resting CARTs, correlating with glycolytic and oxidative metabolism, respectively. Despite memory-precursor phenotype and in vivo longevity, distal daughters demonstrate transient potent cytolytic activity similar to proximal daughters, uncovering an effector-like state in distal daughters destined to become memory CARTs. Both partitioning of pre-existing transcripts and changes in RNA velocity contribute to asymmetry of fate-determining factors, resulting in diametrically opposed transcriptional trajectories. Independent of naive, memory or effector surface immunophenotype, proximal-daughter CARTs use core sets of transcription factors known to support proliferation and effector function. Conversely, transcription factors enriched in distal daughters restrain differentiation and promote longevity, evidenced by diminished long-term in vivo persistence and function of distal-daughter CARTs after IKZF1 disruption. These studies establish asymmetric cell division as a framework for understanding mechanisms of CART differentiation and improving therapeutic outcomes.
    DOI:  https://doi.org/10.1038/s41586-024-07862-7
  2. Cancer Gene Ther. 2024 Aug 25.
    FGFR4-specific CAR-T cells with inducible caspase-9 suicide gene as an approach to treat rhabdomyosarcoma.
    Wei Xiao, Liping Xu, Jinghua Wang, Kuai Yu, Bushu Xu, Yi Que, Jingjing Zhao, Qiuzhong Pan, Chengqi Gao, Penghui Zhou, Xing Zhang.
      Metastatic rhabdomyosarcoma is associated with poor survival and unsatisfactory treatment outcomes. Therefore, new immunotherapeutic methods are urgently required. Fibroblast growth factor receptor 4 (FGFR4), a new therapeutic target for rhabdomyosarcoma, plays a crucial role in its onset and development. This study aimed to generate FGFR4 single-chain variable fragment-based chimeric antigen receptor (CAR) T cells without causing evident toxicity and incorporating an inducible caspase-9 (iCasp9) suicide gene system to enhance their safety. FGFR4 antigen expression was evaluated in normal murine tissues, normal human tissues, and specimens from patients with rhabdomyosarcoma. Combined with a 4-1BB co-stimulatory domain, a CD3ζ signaling domain, and an iCasp9 suicide gene, CAR-T cells with an FGFR4-specific single-chain variable fragment were developed. The specific cytotoxic effects, T-cell proliferation, cytokine secretion, apoptosis induction by chemical dimerization (AP20187), and toxicity of FGFR4 CAR-T cells were investigated in vitro and in vivo. FGFR4 CAR-T cells generated a variety of immune-promoting cytokines, including tumor necrosis factor α, interleukin 2, and interferon γ, and displayed effective cytotoxic activity against FGFR4-overexpressing rhabdomyosarcoma cells in vitro. FGFR4 CAR-T cells were relatively effective against FGFR4-overexpressing rhabdomyosarcoma, with tumor regression and poor survival in a subcutaneous xenograft model. The iCasp9 gene was incorporated into FGFR4 CAR-T cells and it was demonstrated that effective and reliable suicide gene activity depends on the administration of AP20187. By making use of the cross-reaction of FGFR4 CAR-T cells with murine FGFR4 in a syngeneic tumor model, this study found that FGFR4 CAR-T cells could regulate the growth of tumors without evident toxicity. Our study demonstrates that FGFR4 is a prospective target for CAR-T cell therapy in rhabdomyosarcoma without serious on-target off-tumor toxicity. FGFR4 CAR-T cells with the iCasp9 suicide gene system as a safety switch to limit toxicity may broaden the clinical applications of cellular therapy.
    DOI:  https://doi.org/10.1038/s41417-024-00823-2
  3. Sci Adv. 2024 Aug 30. 10(35): eadq2366
    Pharmacologic HIF stabilization activates costimulatory receptor expression to increase antitumor efficacy of adoptive T cell therapy.
    Walter Jackson Iii, Yongkang Yang, Shaima Salman, Dominic Dordai, Yajing Lyu, Emmanuel Datan, Daiana Drehmer, Tina Yi-Ting Huang, Yousang Hwang, Gregg L Semenza.
      Adoptive cell transfer (ACT) is a therapeutic strategy to augment antitumor immunity. Here, we report that ex vivo treatment of mouse CD8+ T cells with dimethyloxalylglycine (DMOG), a stabilizer of hypoxia-inducible factors (HIFs), induced HIF binding to the genes encoding the costimulatory receptors CD81, GITR, OX40, and 4-1BB, leading to increased expression. DMOG treatment increased T cell killing of melanoma cells, which was further augmented by agonist antibodies targeting each costimulatory receptor. In tumor-bearing mice, ACT using T cells treated ex vivo with DMOG and agonist antibodies resulted in decreased tumor growth compared to ACT using control T cells and increased intratumoral markers of CD8+ T cells (CD7, CD8A, and CD8B1), natural killer cells (NCR1 and KLRK1), and cytolytic activity (perforin-1 and tumor necrosis factor-α). Costimulatory receptor gene expression was also induced when CD8+ T cells were treated with three highly selective HIF stabilizers that are currently in clinical use.
    DOI:  https://doi.org/10.1126/sciadv.adq2366
  4. Cancer Immunol Res. 2024 Aug 26.
    CAR T cells engineered to secrete IFN-κ induce tumor ferroptosis via an IFNAR/STAT1/ACSL4 axis.
    Yaoxin Gao, Shasha Liu, Yifan Huang, Hui Wang, Yuyu Zhao, Xuyang Cui, Yajing Peng, Feng Li, Yi Zhang.
      Ferroptosis is an iron-dependent form of cell death that influences cancer immunity. Therapeutic modulation of ferroptosis is considered a potential strategy to enhance the efficacy of other cancer therapies, including immunotherapies such as chimeric antigen receptor (CAR) T cell therapy. In this study, we demonstrated that IFN-κ influenced the induction of ferroptosis. IFN-κ could enhance the sensitivity of tumor cells to ferroptosis induced by the small molecule compound erastin and the polyunsaturated fatty acid arachidonic acid. Mechanistically, IFN-κ in combination with arachidonic acid induced immunogenic tumor ferroptosis via an IFNAR/STAT1/ACSL4 axis. Moreover, CAR T cells engineered to express IFN-κ showed increased antitumor efficiency against H460 cells (antigen positive) and H322 cells (antigen negative) both in vitro and in vivo. We conclude that IFN-κ is a potential cytokine that could be harnessed to enhance the antitumor function of CAR T cells by inducing tumor ferroptosis.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-24-0130
  5. Nat Immunol. 2024 Aug 28.
    Sodium chloride in the tumor microenvironment enhances T cell metabolic fitness and cytotoxicity.
    Dominik Soll, Chang-Feng Chu, Shan Sun, Veronika Lutz, Mahima Arunkumar, Mariam Gachechiladze, Sascha Schäuble, Maha Alissa-Alkhalaf, Trang Nguyen, Michelle-Amirah Khalil, Ignacio Garcia-Ribelles, Michael Mueller, Katrin Buder, Bernhard Michalke, Gianni Panagiotou, Kai Ziegler-Martin, Pascal Benz, Philipp Schatzlmaier, Karsten Hiller, Hannes Stockinger, Maik Luu, Kilian Schober, Carolin Moosmann, Wolfgang W Schamel, Magdalena Huber, Christina E Zielinski.
      The efficacy of antitumor immunity is associated with the metabolic state of cytotoxic T cells, which is sensitive to the tumor microenvironment. Whether ionic signals affect adaptive antitumor immune responses is unclear. In the present study, we show that there is an enrichment of sodium in solid tumors from patients with breast cancer. Sodium chloride (NaCl) enhances the activation state and effector functions of human CD8+ T cells, which is associated with enhanced metabolic fitness. These NaCl-induced effects translate into increased tumor cell killing in vitro and in vivo. Mechanistically, NaCl-induced changes in CD8+ T cells are linked to sodium-induced upregulation of Na+/K+-ATPase activity, followed by membrane hyperpolarization, which magnifies the electromotive force for T cell receptor (TCR)-induced calcium influx and downstream TCR signaling. We therefore propose that NaCl is a positive regulator of acute antitumor immunity that might be modulated for ex vivo conditioning of therapeutic T cells, such as CAR T cells.
    DOI:  https://doi.org/10.1038/s41590-024-01918-6
  6. Nat Immunol. 2024 Aug 28.
    NaCl enhances CD8+ T cell effector functions in cancer immunotherapy.
    Caterina Scirgolea, Rosa Sottile, Marco De Luca, Alberto Susana, Silvia Carnevale, Simone Puccio, Valentina Ferrari, Veronica Lise, Giorgia Contarini, Alice Scarpa, Eloise Scamardella, Simona Feno, Chiara Camisaschi, Gabriele De Simone, Gianluca Basso, Desiree Giuliano, Emilia Maria Cristina Mazza, Luca Gattinoni, Rahul Roychoudhuri, Emanuele Voulaz, Diletta Di Mitri, Matteo Simonelli, Agnese Losurdo, Davide Pozzi, Carlson Tsui, Axel Kallies, Sara Timo, Giuseppe Martano, Elettra Barberis, Marcello Manfredi, Maria Rescigno, Sebastien Jaillon, Enrico Lugli.
      CD8+ T cells control tumors but inevitably become dysfunctional in the tumor microenvironment. Here, we show that sodium chloride (NaCl) counteracts T cell dysfunction to promote cancer regression. NaCl supplementation during CD8+ T cell culture induced effector differentiation, IFN-γ production and cytotoxicity while maintaining the gene networks responsible for stem-like plasticity. Accordingly, adoptive transfer of tumor-specific T cells resulted in superior anti-tumor immunity in a humanized mouse model. In mice, a high-salt diet reduced the growth of experimental tumors in a CD8+ T cell-dependent manner by inhibiting terminal differentiation and enhancing the effector potency of CD8+ T cells. Mechanistically, NaCl enhanced glutamine consumption, which was critical for transcriptional, epigenetic and functional reprogramming. In humans, CD8+ T cells undergoing antigen recognition in tumors and predicting favorable responses to checkpoint blockade immunotherapy resembled those induced by NaCl. Thus, NaCl metabolism is a regulator of CD8+ T cell effector function, with potential implications for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41590-024-01923-9
  7. Nat Commun. 2024 Aug 23. 15(1): 7267
    Complementary dual-virus strategy drives synthetic target and cognate T-cell engager expression for endogenous-antigen agnostic immunotherapy.
    Zaid Taha, Mathieu Joseph François Crupi, Nouf Alluqmani, Duncan MacKenzie, Sydney Vallati, Jack Timothy Whelan, Faiha Fareez, Akram Alwithenani, Julia Petryk, Andrew Chen, Marcus Mathew Spinelli, Kristy Ng, Judy Sobh, Christiano Tanese de Souza, Priya Rose Bharadwa, Timothy Kit Hin Lee, Dylan Anthony Thomas, Ben Zhen Huang, Omar Kassas, Joanna Poutou, Victoria Heather Gilchrist, Stephen Boulton, Max Thomson, Ricardo Marius, Mohsen Hooshyar, Scott McComb, Rozanne Arulanandam, Carolina Solange Ilkow, John Cameron Bell, Jean-Simon Diallo.
      Targeted antineoplastic immunotherapies have achieved remarkable clinical outcomes. However, resistance to these therapies due to target absence or antigen shedding limits their efficacy and excludes tumours from candidacy. To address this limitation, here we engineer an oncolytic rhabdovirus, vesicular stomatitis virus (VSVΔ51), to express a truncated targeted antigen, which allows for HER2-targeting with trastuzumab. The truncated HER2 (HER2T) lacks signaling capabilities and is efficiently expressed on infected cell surfaces. VSVΔ51-mediated HER2T expression simulates HER2-positive status in tumours, enabling effective treatment with the antibody-drug conjugate trastuzumab emtansine in vitro, ex vivo, and in vivo. Additionally, we combine VSVΔ51-HER2T with an oncolytic vaccinia virus expressing a HER2-targeted T-cell engager. This dual-virus therapeutic strategy demonstrates potent curative efficacy in vivo in female mice using CD3+ infiltrate for anti-tumour immunity. Our findings showcase the ability to tailor the tumour microenvironment using oncolytic viruses, thereby enhancing compatibility with "off-the-shelf" targeted therapies.
    DOI:  https://doi.org/10.1038/s41467-024-51498-0
  8. Sci Transl Med. 2024 Aug 28. 16(762): eadk7399
    Activation and antitumor immunity of CD8+ T cells are supported by the glucose transporter GLUT10 and disrupted by lactic acid.
    Ying Liu, Feng Wang, Dongxue Peng, Dan Zhang, Luping Liu, Jun Wei, Jian Yuan, Luyao Zhao, Huimin Jiang, Tingting Zhang, Yunxuan Li, Chenxi Zhao, Shuhua He, Jie Wu, Yechao Yan, Peitao Zhang, Chunyi Guo, Jiaming Zhang, Xia Li, Huan Gao, Ke Li.
      CD8+ T cell activation leads to the rapid proliferation and differentiation of effector T cells (Teffs), which mediate antitumor immunity. Although aerobic glycolysis is preferentially activated in CD8+ Teffs, the mechanisms that regulate CD8+ T cell glucose uptake in the low-glucose and acidic tumor microenvironment (TME) remain poorly understood. Here, we report that the abundance of the glucose transporter GLUT10 is increased during CD8+ T cell activation and antitumor immunity. Specifically, GLUT10 deficiency inhibited glucose uptake, glycolysis, and antitumor efficiency of tumor-infiltrating CD8+ T cells. Supplementation with glucose alone was insufficient to rescue the antitumor function and glucose uptake of CD8+ T cells in the TME. By analyzing tumor environmental metabolites, we found that high concentrations of lactic acid reduced the glucose uptake, activation, and antitumor effects of CD8+ T cells by directly binding to GLUT10's intracellular motif. Disrupting the interaction of lactic acid and GLUT10 by the mimic peptide PG10.3 facilitated CD8+ T cell glucose utilization, proliferation, and antitumor functions. The combination of PG10.3 and GLUT1 inhibition or anti-programmed cell death 1 antibody treatment showed synergistic antitumor effects. Together, our data indicate that GLUT10 is selectively required for glucose uptake of CD8+ T cells and identify that TME accumulated lactic acid inhibits CD8+ T cell effector function by directly binding to GLUT10 and reducing its glucose transport capacity. Last, our study suggests disrupting lactate-GLUT10 binding as a promising therapeutic strategy to enhance CD8+ T cell-mediated antitumor effects.
    DOI:  https://doi.org/10.1126/scitranslmed.adk7399
  9. Cell Mol Life Sci. 2024 Aug 28. 81(1): 371
    A novel bispecific T-cell engager using the ligand-target csGRP78 against acute myeloid leukemia.
    Xiaozhu Zeng, Hang Zhang, Jing Guo, Dong Yang, Yongjie Zhu, Nan Liu, Jie Tang, Ting Liu, Xudong Zhao.
      Current medical therapies for treating acute myeloid leukemia (AML) remain unmet, and AML patients may benefit from targeted immunotherapy approaches that focus on specific tumor antigens. GRP78, which is upregulated in various malignant tumors such as AML, is partially expressed as cell surface GRP78 (csGRP78) on the cell membrane, making it an ideal target for redirecting T cells, including T-cell engagers. However, considering the conventional approach of using two scFv segments to construct a bispecific T-cell engager (BiTE), we have undertaken the development of a novel BiTE that utilizes a cyclic peptide ligand to specifically target csGRP78, which we refer to as GRP78-CD3/BiTE. We studied the effects of GRP78-CD3/BiTE on treatments for AML in vitro and in vivo and assessed the pharmacokinetics of this engager. Our findings demonstrated that GRP78-CD3/BiTE could not only effectively mediate the cytotoxicity of T cells against csGRP78-expressing AML cells but also specifically eliminate primary AML tumor cells in vitro. Furthermore, GRP78-CD3/BiTE exhibited a longer half-life despite having a lower molecular weight than CD19-CD3/BiTE. In a xenograft mouse model of AML, treatment with GRP78-CD3/BiTE prolonged the survival time of the mice. Our findings demonstrate that GRP78-CD3/BiTE is effective and selective for eliminating csGRP78-expressing AML cells and suggest that this approach to targeted immunotherapy could lead to effective new treatments for AML.
    Keywords:  AML; Bispecific T-cell engagers; Pep42; csGRP78
    DOI:  https://doi.org/10.1007/s00018-024-05410-0
  10. Cell Immunol. 2024 Aug 23. pii: S0008-8749(24)00066-2. [Epub ahead of print]403-404 104863
    Cbl-b inhibition promotes less differentiated phenotypes of T cells with enhanced cytokine production.
    Junfan Wang, XiaoJian Han, Yanan Hao, Siyin Chen, Bo Pang, Lin Zou, Xiaxia Han, Wang Wang, Li Liu, Meiying Shen, Aishun Jin.
      For adoptive therapy with T cell receptor engineered T (TCR-T) cells, the quantity and quality of the final cell product directly affect their anti-tumor efficacy. The post-transfer efficacy window of TCR-T cells is keen to optimizing attempts during the manufacturing process. Cbl-b is a E3 ubiquitin ligase previously shown with critical negative impact in T cell functions. This study investigated whether strategic inclusion of a commercially available small inhibitor targeting Cbl-b (Cbl-b-IN-1) prior to T cell activation could enhance the quality of the final TCR-T cell product. Examination with both PBMCs and TCR-T cells revealed that Cbl-b-IN-1 treatment promoted TCR expression efficiency, T cell proliferation potential and, specifically, cell survival capability post antigenic stimulation. Cbl-b-IN-1 exposure facilitated T cells in maintaining less differentiated states with enhanced cytokine production. Further, we found that Cbl-b-IN-1 effectively augmented the activation of TCR signaling, shown by increased phosphorylation levels of Zeta-chain-associated protein kinase 70 (ZAP70) and phospholipase c-γ1 (PLCγ1). In conclusion, our results evidence that the inclusion of Cbl-b inhibitor immediately prior to TCR-T cell activation may enhance their proliferation, survival, and function potentials, presenting an applicable optimization strategy for immunotherapy with adoptive cell transfer.
    Keywords:  Cbl-b inhibitor; Differentiation; Proliferation; TCR signaling; TCR-T
    DOI:  https://doi.org/10.1016/j.cellimm.2024.104863
  11. Nat Commun. 2024 Aug 27. 15(1): 7366
    LSD1 inhibition improves efficacy of adoptive T cell therapy by enhancing CD8+ T cell responsiveness.
    Isabella Pallavicini, Teresa Maria Frasconi, Carlotta Catozzi, Elena Ceccacci, Silvia Tiberti, Dorothee Haas, Jule Samson, Christoph Heuser-Loy, Carina B Nava Lauson, Marta Mangione, Elisa Preto, Alberto Bigogno, Eleonora Sala, Matteo Iannacone, Ciro Mercurio, Luca Gattinoni, Ignazio Caruana, Mirela Kuka, Luigi Nezi, Saverio Minucci, Teresa Manzo.
      The lysine-specific histone demethylase 1 A (LSD1) is involved in antitumor immunity; however, its role in shaping CD8 + T cell (CTL) differentiation and function remains largely unexplored. Here, we show that pharmacological inhibition of LSD1 (LSD1i) in CTL in the context of adoptive T cell therapy (ACT) elicits phenotypic and functional alterations, resulting in a robust antitumor immunity in preclinical models in female mice. In addition, the combination of anti-PDL1 treatment with LSD1i-based ACT eradicates the tumor and leads to long-lasting tumor-free survival in a melanoma model, complementing the limited efficacy of the immune or epigenetic therapy alone. Collectively, these results demonstrate that LSD1 modulation improves antitumoral responses generated by ACT and anti-PDL1 therapy, providing the foundation for their clinical evaluation.
    DOI:  https://doi.org/10.1038/s41467-024-51500-9
  12. Cancer Immunol Res. 2024 Aug 24.
    Age-associated contraction of tumor-specific T cells impairs antitumor immunity.
    Peter Georgiev, SeongJun Han, Amy Y Huang, Thao H Nguyen, Jefte M Drijvers, Hannah Creasey, Joseph A Pereira, Cong-Hui Yao, Joon Seok Park, Thomas S Conway, Megan E Fung, Dan Liang, Michael Peluso, Shakchhi Joshi, Jared H Rowe, Brian C Miller, Gordon J Freeman, Arlene H Sharpe, Marcia C Haigis, Alison E Ringel.
      Progressive decline of the adaptive immune system with increasing age coincides with a sharp increase in cancer incidence. In this study, we set out to understand whether deficits in antitumor immunity with advanced age promote tumor progression and/or drive resistance to immunotherapy. We found that multiple syngeneic cancers grew more rapidly in aged versus young adult mice, driven by dysfunctional CD8+ T-cell responses. By systematically mapping immune cell profiles within tumors, we identified loss of tumor antigen-specific CD8+ T cells as a primary feature accelerating the growth of tumors in aged mice and driving resistance to immunotherapy. When antigen-specific T cells from young adult mice were administered to aged mice, tumor outgrowth was delayed and the aged animals became sensitive to PD-1 blockade. These studies reveal how age-associated CD8+ T-cell dysfunction may license tumorigenesis in elderly patients and have important implications for the use of aged mice as pre-clinical models of aging and cancer.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-24-0463
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