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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02717

Universal ready-to-use immunotherapeutic approach for the treatment of cancer: expanded and activated polyclonal γδ memory T cells.

  • 1Department of Onco - Cellular and Genetic Hematology and Therapy, Bambino Gesù Children Hospital (IRCCS), Italy
  • 2Giannina Gaslini Institute (IRCCS), Italy
  • 3Bambino Gesù Children Hospital (IRCCS), Italy
  • 4Department of Immunology, IRCCS Bambino Gesù Children’s Hospital, Italy
  • 5Department of Gynecological Obstetric and Urological Sciences, Faculty of Medicine and Dentistry, Sapienza University of Rome, Italy

Important progress has been registered in the last years in the treatment of patients suffering from oncological/haematological malignancies, but more still needs to be done to reduce toxicity and side-effects, improve outcome and offer new strategies for relapsed or refractory disease. A remarkable part of these clinical benefits is due to advances in immunotherapy. Here, we investigate the generation of a novel, universal and ready-to-use immunotherapeutic product based on γδ-T lymphocytes. These cells are part of the innate immune system exerting potent natural cytotoxicity against bacteria, viruses and tumours. This ability, coupled with their negligible alloreactivity, makes them attractive for adoptive immunotherapy approaches. To achieve a cell product suitable for clinical use, we developed a strategy capable to generate polyclonal γδ-T cells with predominant memory-Vδ1 phenotype and the additional possibility of gene-modification in good manufacturing practice (GMP) procedures. We expand clinically relevant numbers of functional polyclonal memory γδ-T cells under GMP conditions, with the additional possibility of gene-modification to improve anti-tumour activity. Irradiated engineered artificial antigen-presenting cells (aAPCs) expressing CD86/41BBL/CD40L and the cytomegalovirus (CMV)-antigen-pp65 have been used. The presence of CMV-pp65 and CD40L proved to be crucial for expansion of the memory-Vδ1 subpopulation. To allow clinical translation and guarantee patient safety, aAPCs were stably transduced with an inducible suicide gene. Expanded γδ-T cells showed high expression of activation and memory markers without signs of exhaustion, maintained polyclonality and potent anti-tumour activity both in vitro (with immortalized and primary blasts) and in vivo studies without allo-reactivity events. The molecular characterization (phophoproteomic and gene-expression) of these cell products underlines their unique properties. These cells can further be armed with chimeric antigen receptors (CAR) to improve anti-tumour capacity and persistence.
We demonstrate the feasibility of establishing an allogeneic third-party, off-the-shelf and ready-to-use, γδ-T-cell bank. They represent an attractive therapeutic option endowed with broad clinical applications, including treatment of viral infections in highly immunocompromised patients by the presence of the memory Vδ1-subset, treatment of aggressive malignancies refractory to conventional approaches, bridging therapy to more targeted immunotherapeutic approaches and, ultimately, an innovative platform for the development of off-the-shelf CAR-T-cell products.

Keywords: γδ T-cells, Immunotherapy, Adoptive T-cell transfer, Anti-tumour effect, Universal product, ready-to-use product, anti-cytomegalovirus efficacy, engineered T- cells

Received: 12 Aug 2019; Accepted: 05 Nov 2019.

Copyright: © 2019 Polito, Cristantielli, Weber, Del Bufalo, Belardinilli, Arnone, Petretto, Antonucci, Giorda, Tumino, Pitisci, DE ANGELIS, Quintarelli, Locatelli and Caruana. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Ignazio Caruana, Department of Onco - Cellular and Genetic Hematology and Therapy, Bambino Gesù Children Hospital (IRCCS), Rome, Italy, ignazio.caruana@opbg.net