T Cell Antitumor Efficacy by Enhancing Immune/Tumor Cells Cluster

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T Cell Antitumor Efficacy by Enhancing Immune/Tumor Cells Cluster Open access Original research J Immunother Cancer: first published as 10.1136/jitc-2021-002866 on 25 August 2021. Downloaded from NK cells enhance CAR-T cell antitumor efficacy by enhancing immune/tumor cells cluster formation and improving CAR- T cell fitness 1 1 1 Mireia Bachiller, Lorena Perez- Amill, Anthony Matthew Battram , 1 2 3,4 5,6 Sebastian Ciro Carné, Amer Najjar, Els Verhoeyen, Manel Juan , 7,8 9 Alvaro Urbano- Ispizua, Beatriz Martin- Antonio To cite: Bachiller M, Perez- ABSTRACT INTRODUCTION Amill L, Battram AM, et al. Background Chimeric antigen receptor (CAR)- T cell In recent years, adoptive cell immunotherapy NK cells enhance CAR- T cell immunotherapy has modified the concept of treatment in antitumor efficacy by enhancing approaches, particularly administering hematological malignancies. In comparison with pediatric immune/tumor cells cluster chimeric antigen receptor (CAR)-modified T patients, where responses are maintained over many formation and improving cells, have been established as new methods years, older patients, such as those with non- Hodgkin’s CAR- T cell fitness. Journal for of treatment for patients with hematolog- lymphoma (NHL) and multiple myeloma (MM), present ImmunoTherapy of Cancer ical malignancies.1 To date, most clinical 2021;9:e002866. doi:10.1136/ lower persistence of CAR- T cells that might be due to jitc-2021-002866 decreased fitness of T cells acquired with aging. Moreover, studies in patients with B cell malignancies cord blood derived- NK cells (CB- NKs) and CAR- NK cells administer CAR-T cells in an autologous 2 3 ► Additional supplemental derived from CB- NK can be used ‘off- the- shelf’ as immune setting. However, there is a proportion of material is published online only. cells with antitumor properties for the treatment of cancer patients where the production of CAR-T cells To view, please visit the journal patients. However, to date, clinical studies have only results in an insufficient amount required for online (http:// dx. doi. org/ 10. demonstrated the safety of these therapies but not optimal the treatment, and unfortunately, patients 1136/ jitc- 2021- 002866). efficacy. To confront the shortcomings of each therapy, do not receive the therapy. For this type of MB and LP- A contributed we devised a novel approach consisting of simultaneous patient, a universal source of immune cells, equally. (CAR- )NK cell and CAR- T cell administration. In this setting, such as CAR-modified natural killer (NK) NK cells demonstrate an important immunoregulation of Accepted 28 July 2021 cells, are becoming an attractive option. T cells that could be exploited to enhance the efficacy of However, whereas CAR- NK cells have demon- CAR- T cells. http://jitc.bmj.com/ strated superiority over unmodified NK cells Methods A combinatorial treatment based on either 4 5 CAR- T and CAR- NK cells or CB- NK and CAR- T cells in two in preclinical studies and safety in clinical 6 models of NHL and MM was performed. Antitumor efficacy studies, their efficacy is still lower than that 1 7 was analyzed in vitro and in vivo, and parameters related of CAR-T cells. to early activation, exhaustion and senescence of T cells Specifically, CAR- T cells directed to CD19 were analyzed. (CART-19) have achieved outstanding on October 1, 2021 by guest. Protected copyright. Results We show that CAR- NK cells derived from CB- NK responses in acute lymphoblastic leukemia are only effective at high doses (high E:T ratio) and that (ALL) and non- Hodgkin’s lymphoma (NHL) their activity rapidly decreases over time in comparison patients,3 8–10 and B- cell maturation antigen with CAR- T cells. In comparison and to exploit the potential (BCMA) has emerged as the most promising of ‘off- the- shelf’ CB- NK, we demonstrate that a low target for CAR- T cells used to treat multiple number of CB- NK in the CAR- T cell product promotes an 11–16 early activation of CAR- T cells and their migration to MM myeloma (MM) patients. However, cells leading to enhanced anti- MM efficacy. Moreover, whereas pediatric ALL patients treated with © Author(s) (or their cytokines related to CRS development were not increased, CART-19 cells maintain durable responses 3 employer(s)) 2021. Re- use and importantly, CB-NK enhanced the fitness of both that correlate with CAR-T cell persistence, permitted under CC BY-NC. No pos neg 10 commercial re- use. See rights CAR and CAR T cells, promoting lower levels of NHL patients present poorer responses. and permissions. Published by exhaustion and senescence. Moreover, in MM patients, CART-BCMA BMJ. Conclusion This study demonstrates a relevant cells do not persist long, and patients end up For numbered affiliations see immunoregulatory role of CB- NK collaborating with relapsing despite achieving initial complete end of article. CAR- T cells to enhance their antitumor activity. A responses.15 16 These findings indicate the novel and different approach to consider in CAR-T cell need to improve CAR- T cell persistence and Correspondence to immunotherapy studies is presented here with the goal to efficacy in NHL and MM patients to avoid Dr Beatriz Martin- Antonio; enhance the efficacy of the treatment. beatriz. antonio@ quironsalud. es relapses. Bachiller M, et al. J Immunother Cancer 2021;9:e002866. doi:10.1136/jitc-2021-002866 1 Open access J Immunother Cancer: first published as 10.1136/jitc-2021-002866 on 25 August 2021. Downloaded from Cord blood- derived NK cells (CB-NKs) have been estab- with 10% FBS and 1% Pen/Strep. Tumor MM cell lines lished as a source to obtain ‘off-the- shelf’ NK cells for the were modified to express GFP-FireFlyLuciferase (GFP- treatment of cancer patients.17 18 CAR- NK cells obtained FFLuc) using the plasmids pLV-MSCV_Luc- T2A- GFP from CB- NK have demonstrated improved antitumor (kindly provided by Amer Najjar) coding for GFP-FFLuc, activity compared with unmodified CB- NK5 and have also and pMD2.G and psPAX2 coding for VSV-G and gag/ demonstrated safety in patients.6 19 We previously observed pol, respectively. Mycoplasma testing in cell lines was that when CB- NK come into contact with MM tumor cells, performed every 2 months. they secrete a variety of proinflammatory molecules that enhance the formation of tumor/immune cell clusters, Lentivirus production for CAR-T and CAR-NK cells bringing T lymphocytes and other immune cells into For CAR- T cells, either pCCL- EF1a- CAR19 or pCCL- close contact and enhancing the antitumor activity of T EF1a- CARBCMA with packaging plasmids pMDLg- pRRE, 20 lymphocytes. Therefore, we hypothesized that NK cells, pRSV- Rev and envelope plasmid VSV were used. For either CB- NK or CAR-NK cells, would enhance the effi- CAR- NK cells, pCCL- MSCV- CAR19 with pMDLg- pRRE, cacy of CAR- T cells leading to more durable responses. pRSV- Rev and envelope plasmid BaEV-TR (provided Here, we first confirmed that at low immune cell by Dr Els Verhoeyen) were used for production of virus numbers, CAR- T cells are superior to CAR-NK cells. Then, particles. Production of virus particles to transduce T cells to enhance the efficacy of CAR-T cells, we designed a was done in HEK293T cells using the same protocol previ- combinatorial treatment based on CAR-T cells with either ously described by us.14 Production of virus for CAR- NK CAR- NK cells or CB-NK. Two CARs directed against CD19 2 14 cells was done in HEK293T cells that were transfected with (ARI-0001) and BCMA (ARI2h), which were previously transfer vector pCCL-MCSV - CAR19 with pMDLg-pRRE, developed by us and which have been administered to pRSV- Rev and BaEV- TR plasmid. JetPEI (PolyPlus Trans- patients, were employed. We demonstrate that a combi- fection) was used as a transfection reagent. Transfection natorial treatment for NHL with CART-19 and CARNK-19 was performed using NaCl and JetPei following the manu- cells does not improve the efficacy compared with the facturer’s protocol. Viral supernatants were collected at same total number of CART-19 cells alone, suggesting 48 hours and concentrated with Lenti-X Concentrator that there is a minimum number of CAR-T cells that is (ClonTech) following the supplier’s protocol and stored critical for the antitumor efficacy. However, a combinato- at −80°C until use. rial treatment based on CAR- T cells with the addition of half the dose of CB-NK enhances the antitumor efficacy CB-NK expansion in a model of MM and ARI2h cells. This beneficial impact of CB- NK over ARI2h cells is initiated at incredibly early K562- mb21- 41BBL feeder cells were used to expand time points of tumor/immune cell contact where CB-NK untransduced NK cells. They were irradiated at 100 Gy facilitate earlier activation and enhanced migration of and added at a feeder cell:CB-NK ratio of 2:1. CB- NK were ARI2h cells to tumor cells. These events impact on the left to expand for 14 days, with new feeder cells added on day 7. fitness of ARI2h cells in the long term by ameliorating http://jitc.bmj.com/ exhaustion levels and the emergence of markers related to immunosenescence in ARI2h cells. T cells and CB-NK transduction T cells were obtained from buffy coats by Ficoll and magnetic T cell depletion (Miltenyi Biotec). T cells were METHODS expanded in Click’s media (50% RPMI, 50% Click’s (Irvine Scientific), 5% human serum, 1% Pen/Strep), Donors of immune cells on October 1, 2021 by guest. Protected copyright. CB- NK and peripheral blood T cells were obtained from activated with Dynabeads Human T-Activator CD3/CD28 the Banc de Sang i Teixits de Barcelona (BST) from (Thermo Fisher Scientific) and IL-2 (100 IU/mL) every either cord blood (CB) or peripheral blood from healthy other day.
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