bims-adocet Biomed News
on Adoptive cell therapy
Issue of 2024–09–22
seven papers selected by
Shani Kassia Lyskov, Tel Aviv University
  1. Proteasome inhibition enhances the anti-leukemic efficacy of chimeric antigen receptor (CAR) expressing NK cells against acute myeloid leukemia.
  2. Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy.
  3. Natural TCRs targeting KRASG12V display fine specificity and sensitivity to human solid tumors.
  4. Efficient combinatorial adaptor-mediated targeting of acute myeloid leukemia with CAR T-cells.
  5. Targeting BTN2A1 enhances Vγ9Vδ2 T-cell effector functions and triggers tumor cell pyroptosis.
  6. Intratumoral radiation dose heterogeneity augments antitumor immunity in mice and primes responses to checkpoint blockade.
  7. Tumor-reactive T cell clonotype dynamics underlying clinical response to TIL therapy in melanoma.
  1. J Hematol Oncol. 2024 Sep 16. 17(1): 85
    Proteasome inhibition enhances the anti-leukemic efficacy of chimeric antigen receptor (CAR) expressing NK cells against acute myeloid leukemia.
    David Sedloev, Qian Chen, Julia M Unglaub, Nicola Schanda, Yao Hao, Eleni Besiridou, Brigitte Neuber, Anita Schmitt, Simon Raffel, Yi Liu, Maike Janssen, Carsten Müller-Tidow, Michael Schmitt, Tim Sauer.
       BACKGROUND: Relapsed and refractory acute myeloid leukemia (AML) carries a dismal prognosis. CAR T cells have shown limited efficacy in AML, partially due to dysfunctional autologous T cells and the extended time for generation of patient specific CAR T cells. Allogeneic NK cell therapy is a promising alternative, but strategies to enhance efficacy and persistence may be necessary. Proteasome inhibitors (PI) induce changes in the surface proteome which may render malignant cells more vulnerable to NK mediated cytotoxicity. Here, we investigated the potential benefit of combining PIs with CAR-expressing allogeneic NK cells against AML.
    METHODS: We established the IC50 concentrations for Bortezomib and Carfilzomib against several AML cell lines. Surface expression of class-I HLA molecules and stress-associated proteins upon treatment with proteasome inhibitors was determined by multiparameter flow cytometry. Using functional in vitro assays, we explored the therapeutic synergy between pre-treatment with PIs and the anti-leukemic efficacy of NK cells with or without expression of AML-specific CAR constructs against AML cell lines and primary patient samples. Also, we investigated the tolerability and efficacy of a single PI application strategy followed by (CAR-) NK cell infusion in two different murine xenograft models of AML.
    RESULTS: AML cell lines and primary AML patient samples were susceptible to Bortezomib and Carfilzomib mediated cytotoxicity. Conditioned resistance to Azacitidine/Venetoclax did not confer primary resistance to PIs. Treating AML cells with PIs reduced the surface expression of class-I HLA molecules on AML cells in a time-and-dose dependent manner. Stress-associated proteins were upregulated on the transcriptional level and on the cell surface. NK cell mediated killing of AML cells was enhanced in a synergistic manner. PI pre-treatment increased effector-target cell conjugate formation and Interferon-γ secretion, resulting in enhanced NK cell activity against AML cell lines and primary samples in vitro. Expression of CD33- and CD70-specific CARs further improved the antileukemic efficacy. In vivo, Bortezomib pre-treatment followed by CAR-NK cell infusion reduced AML growth, leading to prolonged overall survival.
    CONCLUSIONS: PIs enhance the anti-leukemic efficacy of CAR-expressing allogeneic NK cells against AML in vitro and in vivo, warranting further exploration of this combinatorial treatment within early phase clinical trials.
    DOI:  https://doi.org/10.1186/s13045-024-01604-y
  2. Cell. 2024 Sep 12. pii: S0092-8674(24)00956-5. [Epub ahead of print]
    Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy.
    Jeremy G Baldwin, Christoph Heuser-Loy, Tanmoy Saha, Roland C Schelker, Dragana Slavkovic-Lukic, Nicholas Strieder, Inmaculada Hernandez-Lopez, Nisha Rana, Markus Barden, Fabio Mastrogiovanni, Azucena Martín-Santos, Andrea Raimondi, Philip Brohawn, Brandon W Higgs, Claudia Gebhard, Veena Kapoor, William G Telford, Sanjivan Gautam, Maria Xydia, Philipp Beckhove, Sina Frischholz, Kilian Schober, Zacharias Kontarakis, Jacob E Corn, Matteo Iannacone, Donato Inverso, Michael Rehli, Jessica Fioravanti, Shiladitya Sengupta, Luca Gattinoni.
      Mitochondrial loss and dysfunction drive T cell exhaustion, representing major barriers to successful T cell-based immunotherapies. Here, we describe an innovative platform to supply exogenous mitochondria to T cells, overcoming these limitations. We found that bone marrow stromal cells establish nanotubular connections with T cells and leverage these intercellular highways to transplant stromal cell mitochondria into CD8+ T cells. Optimal mitochondrial transfer required Talin 2 on both donor and recipient cells. CD8+ T cells with donated mitochondria displayed enhanced mitochondrial respiration and spare respiratory capacity. When transferred into tumor-bearing hosts, these supercharged T cells expanded more robustly, infiltrated the tumor more efficiently, and exhibited fewer signs of exhaustion compared with T cells that did not take up mitochondria. As a result, mitochondria-boosted CD8+ T cells mediated superior antitumor responses, prolonging animal survival. These findings establish intercellular mitochondrial transfer as a prototype of organelle medicine, opening avenues to next-generation cell therapies.
    Keywords:  CAR T therapy; CD8(+) T cells; TCR-T therapy; TIL therapy; Talin 2; bone marrow stromal cells; cancer immunotherapy; immune metabolism; mitochondrial transfer; nanotubes
    DOI:  https://doi.org/10.1016/j.cell.2024.08.029
  3. J Clin Invest. 2024 Sep 17. pii: e175790. [Epub ahead of print]
    Natural TCRs targeting KRASG12V display fine specificity and sensitivity to human solid tumors.
    Adham S Bear, Rebecca B Nadler, Mark H O'Hara, Kelsey L Stanton, Chong Xu, Robert J Saporito, Andrew J Rech, Miren L Baroja, Tatiana Blanchard, Maxwell H Elliott, Michael J Ford, Richard C Jones, Shivang Patel, Andrea L Brennan, Zachary O'Neil, Daniel J Powell, Robert H Vonderheide, Gerald P Linette, Beatriz M Carreno.
       BACKGROUND: Neoantigens derived from KRASMUT have been described, but the fine antigen specificity of T cell responses directed against these epitopes are poorly understood. Here, we explore KRASMUT immunogenicity and the properties of 4 TCRs specific for KRASG12V restricted to HLA-A3 superfamily of class I alleles.
    METHODS: A phase I clinical vaccine trial targeting KRASMUT was conducted. TCRs targeting KRASG12V restricted to HLA-A*03:01 or HLA-A*11:01 were isolated from vaccinated patients or healthy individuals. A comprehensive analysis of TCR antigen specificity, affinity, cross-reactivity, and CD8 coreceptor dependence was performed. TCR lytic activity was evaluated, and target antigen density was determined by quantitative immunopeptidomics.
    RESULTS: Vaccination against KRASMUT resulted in the priming of CD8+ and CD4+ T cell responses. KRASG12V -specific natural (not affinity-enhanced) TCRs exhibited exquisite specificity to mutated protein with no discernable reactivity against KRASWT. TCR-recognition motifs were determined and used to identify and exclude cross-reactivity to non-cognate peptides derived from the human proteome. Both HLA-A*03:01 and HLA-A*11:01 restricted TCR-redirected CD8+ T cells exhibited potent lytic activity against KRASG12V cancers, while only HLA-A*11:01 restricted TCR-T CD4+ T cells exhibited anti-tumor effector functions consistent with partial co-receptor dependence. All KRASG12V-specific TCRs displayed high sensitivity for antigen as demonstrated by their ability to eliminate tumor cell lines expressing low levels of of peptide/HLA (4.4 to 242) complexes per cell.
    CONCLUSION: This study identifies KRASG12V-specific TCRs with high therapeutic potential for the development of TCR-T cell therapies.
    TRIAL REGISTRATION:
    CLINICALTRIALS: gov NCT03592888.
    FUNDING: AACR SU2C / Lustgarten Foundation, Parker Institute for Cancer Immunotherapy, and NIH (R01 CA204261, P01 CA217805, P30 CA016520).
    Keywords:  Antigen presentation; Cancer immunotherapy; Immunology; Oncology; T cell receptor
    DOI:  https://doi.org/10.1172/JCI175790
  4. Leukemia. 2024 Sep 18.
    Efficient combinatorial adaptor-mediated targeting of acute myeloid leukemia with CAR T-cells.
    Laura Volta, Renier Myburgh, Christian Pellegrino, Christian Koch, Monique Maurer, Francesco Manfredi, Mara Hofstetter, Anne Kaiser, Florin Schneiter, Jan Müller, Marco M Buehler, Roberto De Luca, Nicholas Favalli, Chiara F Magnani, Timm Schroeder, Dario Neri, Markus G Manz.
      CAR T-cell products targeting lineage-specific cell-of-origin antigens, thereby eliminating both tumor and healthy counterpart cells, are currently clinically approved therapeutics in B- and plasma-cell malignancies. While they represent a major clinical improvement, they are still limited in terms of efficacy by e.g. single, sometimes low-expressed antigen targeting, and in terms of safety by e.g., lack of on-off activity. Successful cell-of-origin non-discriminative targeting of heterogeneous hematopoietic stem and progenitor cell malignancies, such as acute myeloid leukemia (AML), will require antigen-versatile targeting and off-switching of effectors in order to then allow rescue by hematopoietic stem cell transplantation (HSCT), preventing permanent myeloablation. To address this, we developed adaptor-CAR (AdFITC-CAR) T-cells targeting fluoresceinated AML antigen-binding diabody adaptors. This platform enables the use of adaptors matching the AML-antigen-expression profile and conditional activity modulation. Combining adaptors significantly improved lysis of AML cells in vitro. In therapeutic xenogeneic mouse models, AdFITC-CAR T-cells co-administered with single diabody adaptors were as efficient as direct CAR T-cells, and combinatorial use of adaptors further enhanced therapeutic efficacy against both, cell lines and primary AML. Collectively, this study provides proof-of-concept that AdFITC-CAR T-cells and combinations of adaptors can efficiently enhance immune-targeting of AML.
    DOI:  https://doi.org/10.1038/s41375-024-02409-1
  5. Cancer Immunol Res. 2024 Sep 20.
    Targeting BTN2A1 enhances Vγ9Vδ2 T-cell effector functions and triggers tumor cell pyroptosis.
    Anne-Charlotte Le Floch, Caroline Imbert, Nicolas Boucherit, Laurent Gorvel, Stéphane Fattori, Florence Orlanducci, Aude Le Roy, Lorenzo Archetti, Lydie Crescence, Laurence Panicot-Dubois, Christophe Dubois, Norbert Vey, Antoine Briantais, Amandine Anastasio, Carla Cano, Geoffrey Guittard, Mathieu Frechin, Daniel Olive.
      Vγ9Vδ2 T cells are potent but elusive cytotoxic effectors. Butyrophilin subfamily 2 member A1 (BTN2A1) is a surface protein that has recently been shown to bind the Vγ9 chain of the γδ T-cell receptor (TCR) but its precise role in modulating Vγ9Vδ2 T-cell functions remains unknown. Here, we show that 107G3B5, a monoclonal BTN2A1 agonist antibody, was able to significantly enhance Vγ9Vδ2 T-cell functions against hematological or solid cell lines and against primary cells from adult acute lymphoblastic leukemia patients. New computer vision strategies applied to holotomographic microscopy videos showed that 107G3B5 enhanced the interaction between Vγ9Vδ2 T cells and target cells in a quantitative and qualitative manner. In addition, we found that Vγ9Vδ2 T cells activated by 107G3B5 induced caspase 3/7 activation in tumor cells, thereby triggering tumor cell death by pyroptosis. Together, these data demonstrate that targeting BTN2A1 with 107G3B5 enhances the Vγ9Vδ2 T-cell antitumor response by triggering the pyroptosis-induced immunogenic cell death. These new pyroptosis-based therapies have great potential to stimulate the immune system to fight cancer, especially "cold" tumors.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-23-0868
  6. Sci Transl Med. 2024 Sep 18. 16(765): eadk0642
    Intratumoral radiation dose heterogeneity augments antitumor immunity in mice and primes responses to checkpoint blockade.
    Justin C Jagodinsky, Jessica M Vera, Won Jong Jin, Amanda G Shea, Paul A Clark, Raghava N Sriramaneni, Thomas C Havighurst, Ishan Chakravarthy, Raad H Allawi, KyungMann Kim, Paul M Harari, Paul M Sondel, Michael A Newton, Marka R Crittenden, Michael J Gough, Jessica R Miller, Irene M Ong, Zachary S Morris.
      Radiation therapy (RT) activates multiple immunologic effects in the tumor microenvironment (TME), with diverse dose-response relationships observed. We hypothesized that, in contrast with homogeneous RT, a heterogeneous RT dose would simultaneously optimize activation of multiple immunogenic effects in a single TME, resulting in a more effective antitumor immune response. Using high-dose-rate brachytherapy, we treated mice bearing syngeneic tumors with a single fraction of heterogeneous RT at a dose ranging from 2 to 30 gray. When combined with dual immune checkpoint inhibition in murine models, heterogeneous RT generated more potent antitumor responses in distant, nonirradiated tumors compared with any homogeneous dose. The antitumor effect after heterogeneous RT required CD4 and CD8 T cells and low-dose RT to a portion of the tumor. At the 3-day post-RT time point, dose heterogeneity imprinted the targeted TME with spatial differences in immune-related gene expression, antigen presentation, and susceptibility of tumor cells to immune-mediated destruction. At a later 10-day post-RT time point, high-, moderate-, or low-RT-dose regions demonstrated distinct infiltrating immune cell populations. This was associated with an increase in the expression of effector-associated cytokines in circulating CD8 T cells. Consistent with enhanced adaptive immune priming, heterogeneous RT promoted clonal expansion of effector CD8 T cells. These findings illuminate the breadth of dose-dependent effects of RT on the TME and the capacity of heterogeneous RT to promote antitumor immunity when combined with immune checkpoint inhibitors.
    DOI:  https://doi.org/10.1126/scitranslmed.adk0642
  7. Immunity. 2024 Sep 10. pii: S1074-7613(24)00413-8. [Epub ahead of print]
    Tumor-reactive T cell clonotype dynamics underlying clinical response to TIL therapy in melanoma.
    Johanna Chiffelle, David Barras, Rémy Pétremand, Angela Orcurto, Sara Bobisse, Marion Arnaud, Aymeric Auger, Blanca Navarro Rodrigo, Eleonora Ghisoni, Christophe Sauvage, Damien Saugy, Alexandra Michel, Baptiste Murgues, Noémie Fahr, Martina Imbimbo, Maria Ochoa de Olza, Sofiya Latifyan, Isaac Crespo, Fabrizio Benedetti, Raphael Genolet, Lise Queiroz, Julien Schmidt, Krisztian Homicsko, Stefan Zimmermann, Olivier Michielin, Michal Bassani-Sternberg, Lana E Kandalaft, Urania Dafni, Jesus Corria-Osorio, Lionel Trueb, Denarda Dangaj Laniti, Alexandre Harari, George Coukos.
      Adoptive cell therapy (ACT) using in vitro expanded tumor-infiltrating lymphocytes (TILs) has inconsistent clinical responses. To better understand determinants of therapeutic success, we tracked TIL clonotypes from baseline tumors to ACT products and post-ACT blood and tumor samples in melanoma patients using single-cell RNA and T cell receptor (TCR) sequencing. Patients with clinical responses had baseline tumors enriched in tumor-reactive TILs, and these were more effectively mobilized upon in vitro expansion, yielding products enriched in tumor-specific CD8+ cells that preferentially infiltrated tumors post-ACT. Conversely, lack of clinical responses was associated with tumors devoid of tumor-reactive resident clonotypes and with cell products mostly composed of blood-borne clonotypes that persisted in blood but not in tumors post-ACT. Upon expansion, tumor-specific TILs lost tumor-associated transcriptional signatures, including exhaustion, and responders exhibited an intermediate exhausted effector state after TIL engraftment in the tumor, suggesting functional reinvigoration. Our findings provide insight into the nature and dynamics of tumor-specific clonotypes associated with clinical response to TIL-ACT, with implications for treatment optimization.
    Keywords:  adoptive cell transfer; cancer immunotherapy; cell state; clonotype dynamics; exhaustion; expansion; melanoma; tumor engraftment; tumor reactivity; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/j.immuni.2024.08.014
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